Development of Chemical Categories in the HPV Challenge Program

I.   Introduction

Under EPA’s High Production Volume (HPV) Challenge Program the chemical industry is being challenged to voluntarily compile a Screening Information Data Set (SIDS) on all chemicals on the US HPV list. The SIDS, which has been internationally agreed to by member countries of the Organization for Economic Cooperation and Development (OECD), provides basic screening data needed for an initial assessment of the physicochemical properties, environmental fate, and human and environmental effects of chemicals. The information used to complete the SIDS can come from either existing data (including published or unpublished data on the same or analogous substances or from new tests conducted as part of the HPV Challenge Program.

The Challenge Program is designed to develop screening-level hazard information on about 2,800 HPV chemicals which were reported for the Toxic Substances Control Act’s 1990 Inventory Update Rule (IUR). More information on this list can be obtained at http://www.epa.gov/oppt/chemrtk/pubs/update/hpvchmlt.htm. The large number of chemicals to be tested makes it important to reduce the number of tests to be conducted, where this is scientifically justifiable. One approach is to consider closely related chemicals as a group, or category, rather than test them as individual chemicals. In the category approach, not every chemical needs to be tested for every SIDS endpoint. However, the test data finally compiled for the category must prove adequate to support a screening-level hazard assessment of the category and its members. That is, the final data set must allow one to assess the untested endpoints, ideally by interpolation between and among the category members. In certain cases, such as where toxicity does not change among tested category members, extrapolation to the higher category members may be acceptable.

The use of categories is encouraged in the Challenge Program and will have a number of benefits. First, the public will be informed earlier about any hazards of HPV chemicals when category testing can be completed sooner than individual tests for each chemical given that the CMA Framework (http://www.cmahq.com) recommends that categories be handled in the first two test years of the Challenge Program. Second, there is an economic savings since less testing may be needed for chemicals considered as a category. Third, a reduction in testing will result in fewer animals used to test a category of chemicals as opposed to doing each test on each individual chemical. Finally, category proposals may be expanded via the inclusion of: (1) HPV chemicals on the 1994 IUR (see http://www.epa.gov/oppt/chemrtk/index.htm.); (2) appropriate non-HPV chemicals that may have relevant data; and (3) chemicals in the OECD SIDS program, thereby gaining future efficiencies.

EPA has developed this guidance document to assist industry participants and others in constructing and supporting categories for the Challenge Program. Because this is a complex area, category proposals may need to be reconsidered as data become available in the Challenge Program; where needed, such an iterative process will help to ensure scientifically acceptable results consistent with the original premise for the category. This document will be updated as new experiences are gained through the Challenge Program.

II.  DEFINITIONS

A chemical category, for the purposes of the Challenge Program, is a group of chemicals whose physicochemical and toxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. These structural similarities may create a predictable pattern in any or all of the following parameters: physicochemical properties, environmental fate and environmental effects, and/or human health effects. The similarities should be based on the following:

•a common functional group (e.g., aldehyde, epoxide, ester, etc.); or

•the likelihood of common precursors and/or breakdown products, via physical or biological processes, which result in structurally similar chemicals (e.g., the "family approach" of examining related chemicals such as acid/ester/salt); and

•an incremental and constant change across the category (e.g., the dimethylene group difference between adjacent members of the alpha-olefins - see Appendix). Within a category different members can be selected for the endpoint desired - i.e., those selected for a category approach for environmental effects endpoints may not be suitable for assessing human health effect endpoints.

Categories can sometimes apply to series of chemical reaction products or chemical mixtures that are, again, related in some regular fashion. Analogous to the basic “discrete chemical” category model, in a mixture category some, but not all, of the individual mixtures may undergo testing. The Appendix presents an OECD SIDS category made up of linear alkylbenzene mixtures. This is a relatively simple example of the type of approach that can work in the Challenge Program. As experience is gained in dealing with more complex mixtures, additional EPA guidance for mixture categories will be forthcoming.

Categories accomplish the goal of the Challenge Program - to obtain screening level hazard information - through the strategic application of testing across the category. If these test results show that the chemicals in the category behave in a similar or predictable manner, then interpolation and/or extrapolation can be used to assess the chemicals in lieu of conducting additional screening-level testing.

III.  GENERAL APPROACH FOR DEVELOPING CATEGORIES FOR THE HPV CHALLENGE PROGRAM

Developing HPV Challenge categories can be considered a stepwise process (see Figure 1 for a schematic of the process and the Appendix for an example).

  Step 1: Develop a potential category by grouping a series of like chemicals. A category definition should describe the molecular structure a chemical must have to be included in the category including criteria such as carbon chain length, functionality, chemical or metabolic equivalence considerations, etc., and must list the specific substances covered. Consideration and rationale should be given for using a structure-activity relationship (SAR) approach to identify related members in the category (e.g., a series of acids and their corresponding salts, a list of alkenes or petroleum streams). Some category members need not be HPV chemicals, however, their presence and associated data might help describe the category for that endpoint.

  Step 2: Gather published and unpublished literature on physicochemical properties, environmental fate and effects, and health effects for each member of the category. This should include all existing relevant data and not be limited to the SIDS endpoints (e.g., metabolism and cancer studies are relevant but not part of SIDS). Literature searches may include unpublished data from non-U.S. producers and importers.

  Step 3: Evaluate available data for adequacy. Please see EPA guidance document on Data Adequacy (http://www.epa.gov/oppt/chemrtk/pubs/general/guidocs.htm).

  Step 4: Construct a matrix of SIDS endpoints vs. category members arranged in molecular weight order (or some other fashion indicating the structural progression of the category). Indicate in the cells of the matrix whether data are available or unavailable. An example of a completed matrix appears in the alpha-olefins example in the Appendix.

  Step 5: Evaluate the data to determine whether there is a correlation among category members and each SIDS endpoint. The same category members do not have to be used for each evaluation , i.e., the members selected for environmental fate may be different from those used to evaluate toxicology effects.

A. If there are substantial data, i.e., adequate data for a given SIDS endpoint, but no apparent pattern, the proposed category may not be appropriate and so testing may be required for all remaining category members for that SIDS endpoint. However, an alternative category proposal may be developed (go back to Step 1).

B. If there are substantial and adequate data that correlate well with structure, the category may be appropriate and the sponsor prepares a category proposal (Step 6).

C. If substantial and adequate data do not exist, but the sponsor believes the structure-based category is valid for one or more SIDS endpoints, then a category approach may still be proposed (go to Step 6).

  Step 6: Category rationale and testing scheme will be made available for review using the test plan formats such as those that are available in the U.S. Tracking System (http://www.hpvchallenge.com), or in the ICCA (International Council of Chemical Associations) Tracking System (http://www.icca-chem.org)(see Appendix for examples of category test plans). While sponsors are ultimately responsible for the success of their category proposals, EPA's position on individual proposals will reflect its need to anticipate the acceptability of the results in EPA's own chemical assessment programs and in OECD SIDS as appropriate.

   Step 7: Conduct the necessary testing.

  Step 8: Add the new data to the matrix and evaluate whether the existing data and the new data support the proposed category.

A. If the results support the category, the testing phase is complete. Sponsors then update/add the appropriate robust summaries and prepare a category analysis document. The category analysis document would include a summary of the one or more SIDS endpoints in which the category "holds", including the interpolation/extrapolation of test results to the remaining, untested matrix cells.

B. Otherwise, the sponsor must consider whether to revise the category (return to Step 5). Such a revision could include further testing and/or changing or dropping members of the category, dividing the category as appropriate, or dropping the category approach altogether. The latter implies that testing will then be done to fill all appropriate SIDS endpoints for each category member.

IV.  CONTENT OF CATEGORY TEST PLANS

Category test plans should include a category definition, rationale, and testing scheme (see example category test plans in the Appendix and at the following websites: http://www.hpvchallenge.com and http://www.icca-chem.org). The rationale supporting a category definition should be as simple and transparent as possible, and should explain why the existing data and proposed testing data in the matrix would allow interpolation or extrapolation to other cells in the matrix that have no data or proposed testing. The testing scheme considers the adequacy of the existing data, and how the proposed testing will adequately characterize the category.

Thus, an acceptable category test plan will consist of a matrix of category members and SIDS endpoints and some cells in this matrix must be filled with sufficient data. Assuming the SIDS endpoints are rows in the matrix, each row must have data in at least one cell. Assuming the columns are the category members, one or more columns may have all empty cells.

V.  EVALUATION AND CLOSURE OF CATEGORY APPROACH: THE CATEGORY ANALYSIS

Once the testing proposed for the category is completed, an evaluation is done to determine whether the new data support the proposed category. This evaluation will be in a category analysis document. This document will serve as a summary of the new and existing robust summary data, coupled with any interpolation/extrapolation used for one or more of the SIDS endpoints, that support or refute the proposed category.

VI.EPA’S EXPERIENCE IN DEVELOPING CATEGORIES FOR TESTING PURPOSES

OECD experience provides a framework for handling categories under the Challenge Program. That experience is limited, however, and the Challenge Program will take up numerous issues that will expand that experience. Within the OECD's Working Party on Existing Chemicals, the US has agreed to take lead responsibility for developing the category concept. Thus, lessons learned in the US and contributed to the OECD will provide a measure of feedback and review.

The largest categories in the OECD SIDS program to date contain eight to ten chemicals. This is not a formal maximum, but acceptable categories will tend to be self-limiting because structural variation cannot be pursued indefinitely without disturbing endpoint trends and because large categories will tend to be unwieldy in general. In this regard, approaches could consider groups of related individual categories as contributing elements in the design and implementation of an overall strategy. However, a more populous category may be justifiable in certain cases, such as when toxicity of the category is generally low.

The Appendix contains a number of examples of how a category approach has been taken for the purpose of collecting, reporting, and assessing hazard information in the OECD SIDS program.

Other examples of categorizing chemicals for hazard assessment purposes include the CONCAWE (the European oil company organization for environment, health and safety) approach of categorizing chemicals in petroleum streams (CONCAWE, 1998), and approaches to assess the ecotoxicity (Bowmer et al., 1998) and health effects (Clary, et al., 1998) of lactate esters.

VII REFERENCES

Bowmer, CT, RN Hooftman, AO Hanstveit, PWM Venderbosch and N van der Hoeven. 1998. The ecotoxicity and the biodegradability of lactic acid, alkyl lactate esters and lactate salts. Chemosphere (37)(7):1317-1333.

Clary, JJ, VJ Feron and JA van Velthuijsen. 1998. Safety assessment of lactate esters. Regul. Tox. and Pharm. (27):88-97.

CONCAWE. 1998. Heavy Fuel Oils Product Dossier, No. 98/109. CONCAWE, Brussels, May, 1998. (NOTE: Heavy Fuel Oils is one of the 11 product groups identified by CONCAWE. Their address is CONCAWE, Madouplein 1, 1210 Brussel, Belgium. Their website is http://www.concawe.be).

APPENDIX

Examples presented in this Appendix are drawn from the OECD SIDS program. They are modified to meet the purposes of presenting an example for the US HPV Challenge Program. The examples follow the steps for identification and development of categories noted in the main text of this guidance (see Figure 1 in main text). The examples are:

  A. Alpha-olefins - discrete chemicals with an incremental and constant change across the category;

  B. Linear alkyl benzenes - family of mixtures; and

  C. Brominated diphenyl ethers - family of congeners.

Step 1: Identification of structure-based category. The category was defined as olefins bearing a single medium-length, even-numbered, unbranched aliphatic chain with no other functional groups (“•-Olefins”). This category consists of discrete chemicals with an incremental and constant change across its members (dimethylene group). Because the double bond is terminal, possible metabolic reactions such as oxidation at the double bond or allyl position should not be unduly affected by the chain lengthening. The lower (C₆) and upper (C₁₄) boundaries were based on the available product lines of the sponsors involved in the OECD effort.

The chemical structure of the category is:

Step 2: Gather published and unpublished literature for each member of the category. A literature search resulted in identifying a significant amount of available data for most category members in most of the major SIDS endpoints.

Step 3: Evaluate available data for adequacy. The sponsor evaluated available data, at the individual study level, collected for each member of the category. Available data were compiled and included all SIDS endpoints and other relevant information; non-SIDS data were found and used in the hazard profile (e.g., aspiration hazard potential to humans).

Refer to the EPA guidance on Data Adequacy (http://www.epa.gov/oppt/chemrtk/pubs/general/guidocs.htm) for more information on this issue.

Step 4: Construct a matrix of SIDS endpoints indicating available/adequate data. Table A-1 is a matrix of SIDS endpoints and available/adequate data for each member of the alpha-olefin category. For simplicity, not all relevant data are presented.

Step 5: Evaluate matrix data patterns. The information in Table A-1 identifies where data gaps (noted as “-“ in the table) exist. Note that adequate data (noted as “” in the table) are available for most endpoints. Endpoint data were evaluated to determine whether they correlate with chemical structure to judge the acceptability of the category. Although not shown in Table A-1, the data suggested that water solubility decreased with increasing chain length and aquatic toxicity appeared to decrease with increasing chain length.