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Chapter 28 Electronic Data Submissions for the Environmental Protection Agency and Pest Management Regulatory Agency: Zoxamide Fungicide 1

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Janet Ollinger , Paul H. Reibach , and Scott Swidersky 1

Rohm and Haas Company, 100 Independence Mall West, Philadelphia, PA 19106 Quality Associates Inc., Suite 102, 9017 Red Branch Road, Columbia,MD21045

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When a manufacturer petitions a regulatory agency to register a new pesticide, multiple copies of over 100 individual studies are submitted to support the petition. Historically, paper copies have been submitted and required. Submission and review of electronic copies is still a very new and evolving procedure. For registration of a new fungicide, called zoxamide, electronic copies of a text and tables of residue studies were submitted to EPA as part of a pilot program in addition to the paper copies. Additionally, full copies of zoxamide environmental fate studies were submitted electronically to PMRA.

Registration of Zoxamide Fungicide The Rohm and Haas Company provided electronic data submissions to both the United States Environmental Protection Agency (EPA), to Canada's Pest Management Regulatory Agency (PMRA), and to Mexico's CICOPLAFEST to support the registration of a new fungicide, called zoxamide. Rohm and Haas applied for the registration of zoxamide in December 1998 for control of late blight on potatoes and downy mildew on grapes. Zoxamide is an important productfroma regulatory viewpoint because the submission had two regulatory "firsts": 220

© 2002 American Chemical Society

Garner et al.; Capturing and Reporting Electronic Data ACS Symposium Series; American Chemical Society: Washington, DC, 2002.

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This will be the first joint tri-lateral NAFTA review and registration decision of a pesticide by EPA, Canada, and Mexico. Previous joint reviews of pesticides were between EPA and Canada; The submission included an international Organization for Economic Cooperation and Development (OECD) summary dossier, the first OECD dossier provided to EPA, Canada, and Mexico.

Zoxamide will also be an important product for the growers, especially the potato growers who need as many products as possible to control late blight, a devastating disease. Zoxamide has a very favorable toxicology and environmental fate profile. It is not acutely toxic, not genotoxic in mammalian systems, not neurotoxic, not oncogenic, and not developmentally or reproductively toxic. It degrades rapidly in soil and water, is not mobile in soil, and will not contaminate groundwater. Furthermore, it does not have adverse risks to birds, earthworms, bees, or other beneficial organisms. The initial submission of all studies to support the zoxamide registration with EPA/PMRA/CICOPLAFEST was a paper copy because Rohm and Haas had not planned to make an electronic submission. Thus, the dossier needed to be retrofitted for the electronic copies. Rohm and Haas appreciates the guidance given by both PMRA and EPA in providing the electronic submissions. Rohm and Haas provided two separate and distinct forms of electronic submissions to support Zoxamide's registration: 1. EPA pilot program: electronic copies of the text and tablesfromresidue studies were provided; 2. Canadian program: entire reports of environmental fate studies including text, tables, graphs, etc., were submitted electronically following the Canadian draft guidance for electronic submissions.

Components of a Pesticide Registration Submission The objective of the electronic submissions was to facilitate the regulatory review and to increase review efficiency. The registration is still pending, so an assessment of this objective is not yet possible. Types of Studies Included With a Registration Before discussing the electronic submissions, it is worthwhile to review the types of studies that are included in the dossier. These include physicochemical properties (hydrolysis, water solubility, octanol/water partition coefficient, etc.),



222 metabolism (soil, plant, animal), environmental fete (adsorption/desorption, leaching, water sediment, field dissipation, etc.), residue studies (field trials, methods, residue analysis, processing, etc.), ecotoxicology (birds, fish, algae, etc.), toxicology (acute, chronic, oncogenicity, genotoxicity, developmental toxicity, etc.), and risk assessments. Each study fulfills a particular requirement. The requirements are called a guideline number at EPA, a data code or DACO number in Canada, or an Annex Point Number under the European Union (EU) and the OECD system. For example, the hydrolysis study is OECD Annex Point Number IIA 2.9.1 in the OECD format and 2.9.1 in the EU, or 835.2120 in EPA's OPPTS system and 161-1 in EPA's OPP system, and 8.2.3.2 in Canada's DACO system (Table I).

Table I. Sample Guideline Numbers Guideline

OECD EU Annex IIA EPA OPPTS EPA OPP Canada DACO

Hydrolysis

Aged Column Leach

IIA 2.9.1 2.9.1 835.2120 161-1 8.2.3.2

IIA 7.4.5 7.1.3.2 835.1240 163-1 8.2.4.3

Different Forms of Information in a Report A report typically has information in many different forms, including: • •

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Text - Typically MS Word Document Tables - Excel Spreadsheets - Crop residue data tables in Word Chromatographic Data - HPLC and GC chromatograms - LC and GC mass spectra - Run Sheets - Data Reprocessing Other Information - Photographs - TLC images - Contract lab reports


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Zoxamide Electronic Submissions to EPA and PMRA


For the Zoxamide registration, EPA and PMRA divided the study reviews. EPA reviewed residue and processing studies, among others, and PMRA reviewed the environmental fete studies, among others. Because the reviews were shared between the two regulatory agencies, two separate and distinct electronic submissions were prepared: 1) A submission of electronic text and tablesfromZoxamide residue reports to EPA; 2) A submission of the complete and M l environmental fete studies to PMRA.

EPA Electronic Submission-Pilot Program

A residue submission was made to EPA as part of their electronic pilot program. It was possible to provide electronic copies of the residue report text and tables because the reports were originally prepared with text in Microsoft Word® and data tables in Word® or Excel® formats. These parts of the report would aid the reviewer because data tables could be incorporated into the review and would not need to be re-typed. However, it was not possible to provide the entire report because the chromatograms and other raw data were not available electronically. Thus, the electronic portions available, including text and tables, were converted to PDF format using the ADOBE Acrobat® software, and then sent to EPA. This was a very easy operation to carry out.

PMRA Electronic Submission

The zoxamide environmental fate studies were submitted electronically for the PMRA submission because PMRA was reviewing this portion of the submission. The studies were formatted using PMRA's Electronic Dossier Delivery and Evaluation (EDDE) pilot guidelines, which are available at PMRA's web site on the World Wide Web at http://www.hc-sc.gc.ca/pmra.arla. As noted previously, the original zoxamide submission was a paper copy. For the environmental fate studies, the report and data tables were in Word and Excel formats; however, the majority of the report was comprised of chromatograms and other data that were not available electronically. We decided that it would be easiest to startfromthe paper copy of the entire report. Thus, the entire reports, including text, tables, chromatograms, and other pertinent raw data, were scanned and prepared in electronic format.



224 The submission was prepared in a portable document format (.pdf) {image + hidden text, to be exact}. The reasons for supporting this format were to maintain the original document as a graphic file, while providing reviewers with full text search capabilities, and to provide the regulatory agencies with a non-platform specific format. Also, with the .pdf format, tables and text can be copied directly from an image file to another source document, without requiring data-entry. In order to track each of the reports electronically, an index describing the profiles of each of the studies using MS Access Database was created. This MS Access Database (Figure 1) had elements required by PMRA's EDDE, such as the File Name and Key Words, and other information that was not required by PMRA. For example, a line for the EPA Master Record Identification Number (MRID), was included because both the original paper submission and the electronic submissions were sent to EPA, PMRA, and to Mexico. For that reason, the EPA Guideline Number was also included in addition to PMRA's DACO number. Additional information was also populated in the .pdf (document information fields) to provide "catalog search" functionality for searching through multiple documents. As shown in Figure 1, the information in this database included: • • • • • •

Title Author Chemical DACO Number Letter of Designation Study Type

Animal Species US Guideline Study Number MRID File Name Key Words

After entry into the MS Access database, the reports were scanned as .TIFF images. The concatenation processfromthe MS Access database to produce the file name was used as the index for each of the documents. Once each of the documents was scanned and assigned its appropriate file name, it was convertedfroma .TIFFfileto pdf (image + hidden text). Utilizing the data produced in the MS Accessfile,a relation was created by file name and the remainder of the data to populate the assigned document information fields. Bookmarks and Hyperlinks were then created manually, because it was not possible to do this electronically, although several keystroke methods ensured that the process was efficient. The original Table of Contents for the reports was used to determine the significance of the Bookmarks. A Visual Basic Program was developed to create the directory structure and naming convention to facilitate the location of the data files. The program was designed to create organized DACO categories, whereby the report that



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Figure L File Directory Structure.



226 corresponded to a specific DACO requirement was entered into a folder with the specific DACO number. The directory structure is shown in Figure 2. With this format, a reviewer can simply locate the appropriate DACO folder, click on the folder, and find the report. Bookmarks and Hyperlinks help the reviewer find specific information. Another item that was created for the zoxamide PMRA electronic submission was the "Main Page". This page is not required by the EDDE Guidelines, but its creation greatly facilitates the use of the database. An example of the Main Page is shown in Table II. With all of these features, it is easy to find and search specific documents for the information desired. With the use of the Main Page, clicking on die DACO number or MRID number easily accesses the reports. Because the submission was a multi-agency submission, the "Main Page" enabled the different agencies to relate to the appropriate attributes.

Benefits of a PDF Submission The benefits to the reviewer are that: 1) The reviewer can find and retrieve reports efficiently with hyperlinks and bookmarks, 2) The reviewer can navigate for keywords and phrases, 3) The reviewer can incorporate electronic data/tables without recreating them, and 4) The electronic submission can potentially reduce document storage space. Benefits to the registrant are: 1) The registrant can more easily share electronic documents with multiple countries, 2) There are efficiency gains because fewer copies are required, and 3) Potentially shorter registration times due to increased efficiency with reviews.



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Figure 2. Database Example.


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Table II. Main Page Summary Chemical RH7281 Zoxium 80W "Clicking on the blue description for each report allows access to the clocuments" DACO NUMBER

STUDY TITLE

STUDY TYPE

14C-RH-117281: aerobic Degradation and aquatic 8.2.3.5.2 Metabolism in Aquatic metabolism Systems RH-117281 Fungicide: Section J, Summary of summary 8.1 Environmental Fate Studies RH-117281 Fungicide: Section J, Summary of summary 8.2.1 Environmental Fate Studies RH-117281 Fungicide: Section J, Summary of 8.3.1 summary Environmental Fate Studies RH-117281 Fungicide: 8.2.4.1 Section J, Summary of summary Environmental Fate Studies RH-117281 Fungicide: 8.2.3.1 Section J, Summary of summary Environmental Fate Studies

US STUDY MRID GUIDELINE NO.

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