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OPERATING POLICIES FOR IDENTIFICATION, ACQUISITION, AND ORGANIZATION OF DATA The available information on each of the 100 substances in the subsample was collected and organized to facilitate assessment of the quality and quantity of the toxicity data base. The algorithm for the identification, acquisition, and organization of the data is summarized schematically in Figure 2. This algorithm is the result of evolution and refinement through a series of procedures, whose rationale and results are described in Appendix M. The search pattern included several computerized data bases and the resources of the NRC Toxicology Information Center. Information was also sought from government and industry files. During this search, the NRC personnel in charge of the initial screening of data consistently tended to retain more information than committee members eventually found to be relevant. me Committee on Toxicity Data Elements formulated ground rules to: · Ensure that documents selected were pertinent to the relevant data base. · Circumscribe precisely the limits of the data base to be used (e.g., what was and what was not to be included). · Encourage early resolution of difficult problems encountered by the committee (e.g., the use of articles in foreign languages). · Avoid unnecessary repetition of steps in data identification, acquisition, and evaluation. Operating policies were established regarding the use of restricted-access or confidential information; toxicity information on humans; data on physical and chemical characteristics, manufacturing processes, production volumes, intended uses, and human exposures; chemical review articles; articles in foreign languages; and information on compounds structurally similar to those in the subsample. These policies are discussed below. RESTRICTED-ACCESS OR CONFIDENTIAL INFO~TION Restricted-access or confidential information, which includes proprietary or confidential business information supplied in the process of chemical registration, is contained in the files of the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA). Because the committees wanted the search for information to be as complete 51
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as possible, they requested from these agencies the maximal permissible access to restricted information related to the chemical and physical characteristics, manufacturing processes, production volumes, intended uses, environmental fate, human-exposure potentials, and animal and human toxicity of substances in the subsample. Confidential or restricted-access data were made available to the committees under two conditions, and two operating policies were adopted to suit these circumstances: · Some confidential or restricted-access information was made accessible only to specific committee members or staff of NRC. In such cases, the information was evaluated by those persons according to the prescribed procedure for all data evaluation but only the results of the evaluation were presented to and -~ _ =~ used by the Committee on Toxicity Data Elements and its panels. The evaluated documents remained confidential and unseen by other members of the committee. m us, some confidential or restricted-access information was incorporated into the evaluation process. · The committee was aware that confidential or restricted-access information was held in files that were not available for use in this study. ~ ~ ~ the evaluation of a substance's data base. The committee's policy on this matter reflected its general view that data not available for its confidential review were presumably not available for legitimate review by other interested parties; hence, in an operational sense, such data no longer exist, although staff members of the government agencies holding such information might have been able to use the data for statutory purposes. Under these circumstances, the data COULD not De considered In INFORMATION ON TOXICITY IN HUMANS To maintain consistency, all 100 substances in the subsample were evaluated on the basis of animal toxicity data and human sensitization and skin-penetration studies, when available. Other toxicity studies in humans were not judged for the adequacy of their testing protocols, because reference protocol guidelines do not exist for them. Information contained in reports of these studies was, however, considered in the final appraisal of a substance's toxicity-testing needs. The side effects of drugs in humans were determined from standard source books (see Appendix M); this procedure may have excluded some preclinical and clinical data contained in inaccessible FDA files. CHEMI CAL AND PHYSI CAL CEIARACTERI ST ICS, bLANUFACTURI NG PROCESSES, PRODUCTION VOLUMES, INTENDED USES, AND EXPOSURE OF HUMANS Information on these subjects included all the data elements listed in the "Physicochemical, Use, and Exposure Information" section 53 l
of Appendix L. Some elements were regarded by the committee as more likely to exist or be readily obtainable than others and were consequently pursued more aggressively. These were chemical identification (structure, nomenclature, and defined purity), intended use, production volume, chemical and physical data (e.g., state, density, vapor pressure, water and organic solubilities, octanol:water coefficient, and pH), and exposure potential in the various intended-use, environmental, and occupational settings. This last item included the probable routes of exposure and the manufacturing system used (open or closed and with or without an exhaust control mechanism and/or local ventilation). The various sources and procedures used to obtain this information are described in Appendix M. CHEMICAL REVIEW ARTICLES In every instance, the Committee on Toxicity Data Elements used primary-source literature in its evaluations. For substances with large data bases (more than 250 computer citations), comprehensive review articles were used as an aid to finding the primary-source literature. Primary-source references cited in the reviews were obtained; once those on the required test types (described later) for a given substance had been identified, the data search was continued only for the required test types that were still missing. The committee recognizes that unrequited test types may not have been found for substances with large data bases, but any such omissions would not affect the committee's assessment of toxicity-testing needs. ARTICLES IN FOREIGN LANGUAGES English summaries or translated abstracts of articles in foreign languages were examined to estimate their usefulness for the committee's task. When it was appropriate, complete articles were translated. Reasons for judgments concerning each abstract's usefulness (or lack of it) were documented. SUBSTANCES STRUCTURALLY SIMILAR TO THOSE IN THE SAMPLE The use of surrogate chemicals (those with similar chemical structures) was considered case by case. - ~ ~ ~ · . · . . . . ~ The policy established by the committee required that surrogate information not be used until all data on the substance in question had been completely evaluated. At that point, specific information on surrogates could be used to fill clearly defined voids where the data base was considered not to be adequate for conducting a health-hazard assessment. Information on surrogate substances was used on only two occasions. 54