In an effort to identify chemicals to which children would have the highest likelihood of exposure, EPA selected chemicals which were found by biomonitoring data to be present in the human body (adipose tissue/ blood/breast milk/breath) and found by environmental data to be present in a person's environment (in food, drinking water, breast milk, air). If a chemical were listed in at least one biomonitoring database and at least one environmental database, it was identified as a candidate for the VCCEP.

The biomonitoring databases EPA used in chemical identification are:

The environmental databases EPA used in chemical identification are the following:

EPA used additional criteria to remove chemicals as candidates for the VCCEP. Among these criteria were:

A list of the over 150 chemicals found in the biomonitoring databases as well as a working list of candidate chemicals for VCCEP can be found in Methodology for Selecting Chemicals for the Voluntary Children's Chemical Evaluation Program (VCCEP) Pilot (Ref. 38). Descriptions of the databases used for chemical selection and additional details regarding the selection process are also included in this reference.

There was an exception to the identification process which was raised and discussed during the last stakeholder meeting. This exception relates to the identification of three polybrominated diphenyl ethers for the VCCEP without relying on the use of the databases. Polybrominated diphenyl ethers, as a class of chemicals, were found to be increasing in concentration in human breast milk in a recent Swedish study (Ref. 30). EPA used this
[[Page 81702]]
study and TSCA IUR reporting, which indicates that chemicals are manufactured in the United States, to identify specific chemicals in this chemical class to include in this program (Ref. 50). Although EPA did not rely on the databases for the identification of these chemicals, it believes that the study provides biomonitoring evidence of exposure of the mother and also environmental evidence of the potential exposure via a food source of the child.

The VCCEP candidate chemicals identified and screened by the criteria described in this Unit II.D. were further evaluated to select chemicals for the pilot as described in Unit III.A.
E. What is the Significance of a Chemical's Being Identified for the VCCEP?

The identification of chemicals for the VCCEP was one of the more challenging aspects of the program's development. Both EPA and some stakeholders agreed that available data sources provided limited insight on children's exposure to chemicals. Consequently, to identify chemicals for the VCCEP, EPA used existing data sources believed to be especially relevant to children's chemical exposures, such as presence of the chemical in human tissues/blood, in food and water children eat and drink and in air children breathe. EPA acknowledges that the chemical identification process does not take into account the unique aspects of children's potential for exposure, based on their behaviors and activities. For this reason, EPA wishes to make clear what the list of chemicals selected for the VCCEP represents and what it does not represent.

Identification for the VCCEP does not mean that the existing hazard and exposure data have been or will be determined to be inadequate. EPA has not made judgements regarding the adequacy or significance of existing hazard or exposure data for any of the chemicals selected for the pilot. While EPA recognizes that many of these chemicals are known to be relatively ``data rich,'' assessment of the adequacy and significance of hazard and exposure information will be a task of the sponsors participating in the voluntary program.

Identification for the VCCEP also does not mean that EPA has made or will make a determination that any uses of the chemical pose significant risks to children's health. The level of potential risk to children will be determined as part of the VCCEP. The chemical identification process for the VCCEP did not make this determination. It is also important to note that for any given chemical in the VCCEP, EPA may ultimately determine that reasonably anticipated exposures and risks from expected uses do not pose any unique or other concerns for children's health and safety.
F. How did EPA Decide Which Tests are Necessary to Evaluate a Chemical's Risk to Children?

EPA has undertaken significant technical efforts to define an appropriate test battery for the VCCEP over the last 2 years. The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel and invited members of the EPA Science Advisory Board (SAB) convened in late May 1999 to review the recommendations of the Toxicology Working Group of the 10X Task Force. The Toxicology Working Group had developed recommendations for a core data set necessary to assess the potential hazards to children following exposure to conventional food use pesticides (Ref. 32). These recommendations were prepared for consideration in developing the implementation policy for the Food Quality Protection Act's (FQPA) 10fold Safety Factor. EPA's OPPT sought input and advice from this EPA advisory group about the appropriateness of using a selected subset of the 10X battery to address industrial chemicals to which children were likely to be exposed. The subset of tests which EPA proposed included the following types of studies:

The SAP's comments were supportive with respect to the subset of tests which EPA proposed as the test battery for the VCCEP:

The Panel could not conclusively determine whether the proposed Children's Health Testing Program (now the VCCEP) battery was appropriate to evaluate the potential hazards of industrial/ commercial chemicals to which children may have high potential exposure. In any event, the Panel concluded that the Agency should retain the standard toxicology protocols and add the more specific developmental neurotoxicity, immunotoxicity, and neurotoxicity tests now proposed for pesticides . . . and that it was appropriate for the proposed battery of tests to be viewed as a single tier of studies. In addition, the Panel believes that non pesticide (industrial/commercial) chemicals be considered in the same manner as pesticides with regard to their potential to impact the health of children . . . and that being the case, it would be prudent for the Agency to require the same or similar types of toxicity data on chemicals of industrial/commercial use as pesticides. (Ref. 33)

These tests and the appropriate guidelines for conducting these tests in the VCCEP are discussed in Unit III.D.

G. Why does the VCCEP Need Exposure Assessments?

Although the biomonitoring data used in chemical selection (discussed in Unit II.D. and III.B.) provide strong qualitative evidence that human exposure to the VCCEP chemicals has occurred, not all of the data were obtained recently and there are questions regarding the quality of some of the data, causing some to question their relevance. Although EPA believes the biomonitoring data are still relevant, more information would be valuable to assure a full understanding of current exposure patterns and levels, especially as they relate to children. The VCCEP will provide sponsors the opportunity to submit exposure data that reflect current exposures. Submission of exposure information to EPA is included as a component in Tier 1, Tier 2, and Tier 3 of the VCCEP, as described in Unit III.H., III.J., III.K., and III.L.

An equally important reason for collecting exposure data in the VCCEP is its need in risk assessment. To assess risk, exposure data are needed as much as hazard data. Hazard data may indicate a chemical's potential to cause adverse health effects, but exposure data are needed to put those data in context. A chemical may test as potentially hazardous, but if there is no or very low exposure to the chemical, there may be a low risk of the chemical causing adverse health effects. Likewise, exposure data which indicate low or no exposure can support an argument that additional hazard data may not be necessary, thus avoiding unnecessary expenditures of testing resources. The VCCEP includes this principle in its design by requiring the consideration of exposure, hazard, and risk data before deciding whether data from the next tier of information are needed.
[[Page 81703]]
III. The VCCEP
A. How Were VCCEP Candidate Chemicals Further Culled to Identify Chemicals for the VCCEP Pilot?

The names of the 23 chemicals identified for the VCCEP pilot program are listed in Table 1 of this unit in CAS No. order. These chemicals were identified using the criteria discussed in Unit II.D. Table 1 of this unit indicates the specific databases which were the source of the biomonitoring data and the environmental monitoring data which together supported the selection of a chemical.
An additional factor which influenced which candidate chemicals were selected for the pilot program was the availability of hazard data. For reasons discussed in Unit III.C., EPA wanted to select chemicals for the pilot which have available Tier 1 hazard data. To identify such chemicals, EPA used two primary indications of data availability:

1. Data were available from the Organization for Economic Cooperation and Development (OECD) Screening Information Data Set (SIDS) Program, and

2. Chemicals with commitments in the High Production Volume (HPV) Challenge Program that had early start years, i.e., 2000 or 2001.

Table 1 of this unit indicates which chemicals have early start years in the HPV Challenge Program and which chemicals have available or soon to be available SIDS data.

In the final selection for the VCCEP pilot, several chemicals otherwise meeting the hazard data availability selection criterion were not included in the pilot.

1. The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) which is preparing detailed assessments of the scientific evidence for whether a given exposure or exposure circumstance may pose a hazard to reproduction and the health and welfare of children for seven phthalatesdibutyl phthalate (DBP), butylbenzyl phthalate (BBP), dinhexyl phthalate (DnHP), dinoctyl phthalate (DnOP), di(2.ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), and diisodecyl phthalate (DIDP). A separate assessment is being prepared for each phthalate by an expert panel chosen specifically for the phthalates. Each assessment will be an evaluation of the scientific evidence for whether adverse reproductive/ developmental health effects are associated with exposures to the phthalate and will include the expert panel's conclusions about knowledge gaps for the phthalate. (Ref. 53). Additional information is available on web site http://ntpserver.niehs.nih.gov/htdocs/liason/ CERHRPhthalatesAnnct.html.

2. The Consumer Product Safety Commission (CPSC) has convened a Chronic Hazard Advisory Panel (CHAP) to evaluate the existing information regarding whether chronic hazards (cancer, birth defects, and gene mutations) may be posed by DINP and the implications of these hazards on risks to children. The CHAP expert panel will evaluate available hazard and exposure information, including data generated by the CPSC in its testing laboratory on the amount of DINP that is likely to come out of a toy when chewed or mouthed by a young child. (Ref. 54).

3. The FDA is preparing a risk assessment of DEHP in medical devices, including medical devices that result in exposure to infants and newborn babies. (Ref. 55).

Additional information is available on web site http://www.fda.gov/ cdrh/present/DEHP_GHTF.pdf.

In addition, risk assessments of DBP, BBP, DEHP, DINP, and DIDP are being conducted by scientists in the European Union (EU).

Most of these assessments are close to being complete. It would be neither practical nor efficient to attempt to repeat all of the work of these other assessments under the VCCEP program, but EPA believes the outcome of these assessments will provide helpful information for deciding whether the risks of phthalates to children have been adequately characterized, and which, if any, of the phthalates are appropriate for inclusion in the VCCEP. In some cases, the work of these other bodies may facilitate review of phthalates under the VCCEP. In other cases, EPA may determine that in light of these hazard and risk assessments, further review under the VCCEP is either unnecessary or a low priority. Accordingly, EPA is not deciding whether to include phthalates in the VCCEP Pilot at this time. Instead, EPA will reevaluate the phthalates in approximately 69 months, after many of the assessments have been completed. The producers of phthalates have agreed to provide the assessments to EPA once they are completed, and to include in that submission their assessment of the extent to which further evaluation under the VCCEP is or is not necessary. EPA will review these materials when they are received to determine which phthalates, if any, the Agency believes are appropriate for further evaluation under the VCCEP at that time. The materials submitted by the producers will be made publicly available and EPA will invite input from other stakeholders before making its decisions.

1. The Styrene Information and Research Center (SIRC), which is composed of styrene manufacturers and users, has sponsored toxicological research covering nearly all the health endpoints to be addressed by the VCCEP and has funded additional 2generation reproduction and developmental neurotoxicity testing (Ref. 23).

2. The Center for Risk Analysis at the Harvard School of Public Health has created a risk assessment panel on styrene. The panel is undertaking an exposure assessment and an independent hazard analysis of styrene and is expected to include an evaluation of risks to children's health in its review (Ref. 23). The SIRC was asked to submit exposure data to support the assessment being conducted at Harvard (Ref. 23) which is expected to be available to EPA by July 2001.

3. EPA's Integrated Risk Information System (IRIS) program is currently conducting an assessment of available hazard data on styrene which will address all of the health endpoints included in the VCCEP. The IRIS assessment will address children as a
[[Page 81704]]
subpopulation in its review and may include both shortterm and long term health values for children in the IRIS summary document which EPA will issue for styrene (Ref. 23).

EPA believes these assessments will provide helpful information for whether the risks of styrene to children have been adequately characterized. EPA may determine after receipt of these hazard, exposure, and risk assessments, that further review under the VCCEP is either unnecessary or a low priority. As with the case with phthalates, materials submitted by the producers will be made publicly available and EPA will invite input from other stakeholders before making its decision.
Additional details on how chemicals were selected for the pilot are provided in the document Methodology for Selecting Chemicals for the Voluntary Children's Chemical Evaluation Program (VCCEP) Pilot (Ref. 38).
Table 1.Chemicals Identified for the VCCEP Pilot Chemicals found in human biological samples Chemicals found in human HPV Chall. environment CAS No. Chemical name Commit. \1\ SIDS\2\ NHANES NHEXAS TEAMS Human milk \3\ NCOD Indoor air 67641....................... Acetone......... .............. Y............... Y............... .............. .............. .............. .............. Y 71432....................... Benzene......... .............. Y............... Y............... Y............... Y............... .............. Y............... Y 75354....................... Vinylidenechlori Y............... .............. .............. .............. Y............... .............. Y............... Y de.
78933....................... Methyl ethyl .............. Y............... Y............... .............. .............. .............. .............. Y ketone.
79016....................... Trichloroethylen .............. Y............... Y............... .............. Y............... .............. Y............... Y e.
80568....................... Pinene Y............... .............. .............. .............. Y............... .............. .............. Y 95475....................... oXylene........ Y............... .............. Y............... .............. Y............... .............. Y............... Y 100414...................... Ethylbenzene.... .............. Y............... Y............... .............. Y............... .............. Y............... Y 106467...................... pDichloroben .............. Y............... Y............... .............. Y............... .............. Y............... Y zene.
106934...................... Ethylene Y............... .............. .............. .............. Y............... .............. Y............... Y dibromide.
107062...................... Ethylene Y............... .............. .............. .............. Y............... .............. Y............... Y dichloride.
108385...................... mXylene........ Y............... .............. .............. .............. Y............... .............. Y............... Y 108883...................... Toluene......... .............. Y............... Y............... .............. Y............... .............. Y............... Y 108907...................... Chlorobenzene... Y............... .............. Y............... .............. Y............... .............. Y............... Y 112403...................... nDodecane...... Y............... .............. .............. .............. Y............... .............. .............. Y 123911...................... pDioxane....... .............. Y............... .............. .............. Y............... .............. .............. Y 124185...................... Decane.......... .............. Y............... .............. .............. Y............... .............. .............. Y 127184...................... Tetrachloroethyl .............. Y............... Y............... Y............... Y............... .............. Y............... Y ene.
541731...................... m Y............... .............. .............. .............. Y............... .............. Y............... Y Dichlorobenzene.
1120214..................... Undecane........ .............. Y............... .............. .............. Y............... .............. .............. Y 1163195..................... Decabromodipheny .............. Y............... .............. .............. .............. Y............... .............. lether.
32534819.................... Pentabromodiphen .............. Y............... .............. .............. .............. Y............... .............. yl ether.
32536520.................... Octabromodipheny .............. Y............... .............. .............. .............. Y............... .............. l ether.
\1\ HPV Challenge commitment with early start year (2000 or 2001). \2\ SIDS Screening Information Assessment Report is available. \3\ The chemicals in this column were chemicals identified in Ref. 30 that were also reported to the TSCA IUR

EPA is aware of recent ongoing discussions between the Agency for Toxic Substances and Disease Registry (ATSDR) and the Halogenated Solvents Industries Association (HSIA) regarding the voluntary testing of two chemicals relevant to the VCCEP pilot, i.e., trichloroethylene (CAS No. 79016) and tetrachloroethylene (CAS No. 127184). These chemicals have been the subject of discussions relating to priority data needs identified by ATSDR as part of a proceeding under the Emergency Planning and Community RighttoKnow Act (EPCRA) section 110 and are also likely to be included in a test rule proposal being developed under TSCA section 4 at ATSDR's request. EPA understands that ATSDR and HSIA may soon come to agreement on arrangements to meet some of ATSDR's priority hazard data needs for these two pilot chemicals. While the testing being discussed would meet some of the hazard data needs of the VCCEP, it would not address exposure information needs and there appear to be several important deficiencies with regards to higher tier toxicity end points. In the event that ATSDR and HSIA can conclude their voluntary testing arrangement in the near future, EPA believes that a workable course of action in this case may be to use the ATSDRHSIA work as input to Tier 1 hazard information. If this occurs, the delivery date for Tier 1 information and assessments prepared by VCCEP pilot sponsors could be adjusted to take account of the timing elements in the ATSDRHSIA agreement. In the event that ATSDR and HSIA are unable to conclude a voluntary testing arrangement in the near future, EPA will consider the chemicals open for sponsorship under the Pilot as described in this notice.

Although only oxylene and mxylene are listed in Table 1 of this unit as pilot chemicals, the sponsors of these chemicals may want to consider addressing pxylene (CAS No. 106423) and mixed xylenes (CAS No. 1330207) as they proceed in the VCCEP pilot. These two xylenes were deferred from the pilot because they are not been sponsored in the HPV Challenge Program and there is no Tier 1 data available from the OECD SIDS program. EPA believes these 4 chemicals may present the potential for a group approach.
B. Has EPA Completed Any Evaluations that Demonstrate the Relevance of the Biomonitoring Data Sets?

EPA considers the biomonitoring data as strong evidence of exposure and as providing a strong rationale for identifying a chemical for this program. EPA has evaluated the biomonitoring data not only for the detection of a chemical by the monitoring program, but also the detection frequency and concentration of the chemical in the tested biological medium. Examples of these data for the VCCEP pilot chemicals are presented in Table 2 of
[[Page 81705]]
this unit. The information in Table 2 is intended to be illustrative rather than complete. Many of the listed chemicals were also found in other human monitoring studies, some of which report the frequency of occurrence and some of which do not. The blood levels shown in Table 2 are from NHANES III; the breath data are from TEAM studies; and the breast milk data are from a recent Swedish study (Ref. 30). A number of the candidate chemicals were also studied in NHEXAS, but these data are not included in Table 2 because all of the chemicals found in NHEXAS were also reported in NHANES III.

With the possible exception of the Swedish breast milk study, all of the monitoring programs from which these data were drawn were relatively large, broadscale studies. The blood data were derived from a subset of the national scale NHANES III population and were used to establish reference ranges for the chemicals studied. NHEXAS involved surveys in EPA Region 5 (Illinois, Indiana, Michigan, Minnesota, Ohio, and Wisconsin), in the State of Arizona, and in the Baltimore Metropolitan Area. TEAM studies were done in communities in California, New Jersey, North Carolina, and North Dakota. Because of the size and scope of these programs, the detection of a chemical at even a relatively low frequency may indicate exposure to a large population. The significance of the reported concentrations is difficult to interpret without information about the exposure events that led to a chemical's occurrence in that tissue and a detailed knowledge of that chemical's metabolic fate. At present, the reported data are best used simply as a qualitative indicator that exposure has occurred. The first substance in Table 2 of this unit does not exactly match the corresponding entries on the pilot chemical list. However, EPA believes that the TEAM data on the mixture of meta and para isomers of dichlorobenzene are relevant to the listing of mdichlorobenzene and p dichlorobenzene as individual isomers. Likewise, the NHANES III data on mixed meta and para isomers of xylene are relevant to the listing of m xylene in the pilot chemical list. Also, the listing of polybrominated diphenyl ethers in Table 2 of this unit and the data from the Swedish study (Ref. 30) is relevant to three entries on the pilot chemical list (decabromodiphenyl ether, pentabromodiphenyl ether, and
octabromodiphenyl ether).
Table 2.Frequency of Detection and Concentration of Select VCCEP Pilot Chemicals in Certain Human Biomonitoring Studies Detection CAS No. Chemical name Medium frequency Concentration m,p breath............ 91% of 49......... GM\1\= 1.81 g/m\3\ m,pXylene........ blood............. 75% of med\2\= 0.19 ppb 649. Polybrominated milk.............. ................ mean = 4 ng/g diphenylethers.
67641......................... Acetone........... blood............. 75% of med = 1,800 ppb 1062. 71432......................... Benzene........... blood............. 75% of med = 0.06 ppb 883. 75354......................... Vinylidene breath............ 95% of 49......... WAGM\3\ = 6.6 chloride. g/m\3\ 78933......................... Methyl ethyl blood............. 75% of med = 5.4 ppb ketone. 1101. 79016......................... Trichloroethylene. blood............. 13% of 677........ 80568......................... Pinene.. breath............ 92% of 110........ GM = 0.94 g/m\3\ 95476......................... oXylene.......... blood............. 75% of med = 0.11 ppb 711. 100414........................ Ethylbenzene...... blood............. 75% of med = 0.06 ppb 631. 106467........................ pDichlorobenzene. blood............. 75% of med = 0.33 ppb 1037. 106934........................ Ethylene dibromide breath............ 3% of 300......... GM = 0.4 g/m\3\ 107062........................ Ethylene breath............ (frequency data WAGM = 0.19 g/m\3\ 108883........................ Toluene........... blood............. 75% of med = 0.28 ppb 804. 108907........................ Chlorobenzene..... blood............. 21% of 1024....... 112403........................ nDodecane........ breath............ 30% of 110........ GM = 0.19 g/m\3\ 123911........................ pDioxane......... breath............ 8% of 110......... GM = 0.05 g/m\3\ 124185........................ Decane............ breath............ 53% of 110........ GM = 0.27 g/m\3\ 127184........................ Tetrachloroethylen blood............. 75% of med = 0.06 ppb e. 590. 1120214....................... Undecane.......... breath............ 56% of 110........ GM = 0.28 g/m\3\ \1\ GM = geometric mean.
\2\ Med = median.
\3\ WAGM = weighted average geometric mean.

C. Why Have a Pilot of the VCCEP?

EPA is running a pilot of the VCCEP so it can gain insight into how best to design and implement the VCCEP in order to effectively provide the Agency and the public with the means to understand the potential health risks to children associated with exposure to these and ultimately other chemicals to which children may be exposed. EPA intends the pilot to be the means of identifying efficiencies which can be applied to the subsequent implementation of the VCCEP.

Another purpose for running the pilot is the opportunity it will offer to test the performance of the Peer Consultation Process. Peer Consultation as it will apply to the VCCEP pilot is described in Unit III.P. through III.U. A number of stakeholders expressed concern that Peer Consultation may be a lengthy process and require a high commitment of time from those asked to participate. To expedite experience in determining how well the planned Peer Consultation Process works and what efficiencies might be introduced to expedite its work, EPA believes that chemicals which will present Tier 2 and Tier 3 assessment issues at an early point in time would be the most appropriate chemicals to include in the pilot. In selecting the chemicals for the pilot, EPA considered several indications of data availability to identify chemicals which already have extensive available hazard data (or nearly complete hazard data) . Screening level hazard data were considered available if Screening Information Data Set (SIDS) SIDS Initial Assessment Report (SIAR) had been prepared, or if the chemical is in the evaluation phase. Chemicals in the HPV Challenge Program with testing which is to begin in the years 2000 or 2001 were also included in the VCCEP pilot.

The pilot program will be evaluated at its completion as discussed in Unit III.W. The evaluation will consider what
[[Page 81706]]
modifications might be made which would make the VCCEP run more efficiently and the recommendations coming out of the pilot program evaluation will be used to improve the subsequent implementation of the VCCEP.
D. What Toxicity Studies Will Be Collected by the VCCEP and Will the Studies Be Divided into Tiers?

The toxicity studies EPA would collect for the VCCEP are the studies listed in Unit II.F. These are the studies EPA believes are appropriate to be included in a core toxicology data set to evaluate the toxicity of chemicals to which children have a significant potential for exposure. These are also the studies the SAP agreed with EPA regarding their inclusion in such a program. The SAP supported the application of this battery of tests as a single tier (Ref. 33). However, during stakeholder discussions, EPA frequently heard comments from various individuals that several of the studies in the test battery should be initiated only after lower level (e.g., HPV Challenge Program) tests and exposure information indicate additional cause for concern. In order to meet the needs of as many of the stakeholders as possible and to ensure the participation of industry sponsors in a voluntary program, testing tiers have been incorporated in the VCCEP. Also, many of the chemicals selected for this voluntary program are sponsored in the HPV Challenge Program and the health effects studies conducted in that Program will satisfy the Tier 1 test requirements of the VCCEP, thereby allowing a resourcesaving integration of the VCCEP and the HPV Challenge Program. Table 3 of this unit indicates how the test battery will be divided among three tiers and lists the appropriate guideline for conducting each test.
Table 3.Three Tiers of VCCEP Tests
Tier Test Test Guideline 1\1\ Acute oral toxicity OECD 425 or ASTM (up/down) OR E116398 Acute inhalation OECD 403 or 40 CFR toxicity 799.9130
In vitro gene OECD 471, mutation: 870.5100, or 40 Bacterial reverse CFR 799.9510 mutation assay

Combined repeated OECD 422 dose toxicity with
reproductive and
developmental
toxicity screens
OR
Repeated dose oral OECD 407 toxicity AND
Reproductive OECD 415/421 toxicity (1
generation)

In vitro OECD 473, chromosomal 870.5375, or 40 aberrations OR CFR 799.9537 In vivo chromosomal OECD 475, aberrations OR 870.5385, or 40 CFR 799.9538 In vivo mammalian OECD 474, erythrocyte 870.5395, or 40 micronucleus CFR 799.9539 2 90Day subchronic 870.3100 (oral), toxicity in 870.3250 rodents (dermal), 870.3465 (inhalation), or 40 CFR 799.9346 (inhalation)
Reproduction and 870.3800 or 40 CFR fertility effects 799.9380
Prenatal 870.3700 or 40 CFR developmental 799.9370 toxicity (two
species)

In vivo mammalian OECD 475, bone marrow 870.5385, or 40 chromosomal CFR 799.9538 aberrations, OR
In vivo mammalian OECD 474, erythrocyte 870.5395, or 40 micronucleus CFR 799.9539 (triggered off
results from in
vitro mammalian
chromosomal
aberration test if
conducted in Tier
1)

Immunotoxicity 870.7800 or 40 CFR 799.9780
Metabolism and 870.7485 or 40 CFR pharmacokinetics 799.9748 3 Carcinogenicity OR 870.4200 or 40 CFR 799.9420 chronic toxicity/ 870.4300 carcinogenicity

Neurotoxicity 870.6200 or 40 CFR screening battery 799.9620
Developmental 870.6300 or 40 CFR neurotoxicity 799.9630 \1\ The tests and test guidelines in Tier 1 are the same as those in the HPV Challenge Program. For example, under the HPV Challenge Program, EPA encourages persons required to conduct testing for chromosomal damage to use the in vitro Mammalian Chromosome Aberration Test to generate the needed data unless known chemical properties (e.g., physical/chemical properties, chemical class characteristics) preclude its use. As another example, if not superseded by a higher tier study, EPA recommends the use of the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. See HPV Challenge Program web site at http://www.epa.gov/chemrtk/.

For chemicals which are in both the HPV Challenge Program and the VCCEP, sponsors should consider conducting appropriate upper tier VCCEP test(s) instead of the screening studies (such as OECD 422 or OECD 407 and 415/421 studies) included in the HPV Challenge Program to avoid conducting the lower tier studies unnecessarily. For example, if a chemical which was included in the HPV Challenge Program as well as the VCCEP lacked repeated dose testing data, it would be prudent for the sponsor to conduct a 90day subchronic study to meet the needs of the VCCEP versus the recommended studies under the HPV Challenge program (OECD 422 or 407). Similarly, although the OECD 422 and 415/421 evaluate certain developmental and reproductive endpoints, they do not provide as full
[[Page 81707]]
an evaluation of those endpoints as would the Tier 2 VCCEP tests, i.e., the prenatal developmental toxicity test and the 2generation reproduction and fertility effects test, respectively.

For most tests listed in Table 3, the sponsor may choose among several alternative guidelines developed for different programs including the OECD, OPPTS, TSCA, and the American Society for Testing and Materials (ASTM). All but four of the TSCA test guidelines were published in the July 1, 1999, edition of the Code of Federal Regulations (CFR) at 40 CFR part 799 (Ref. 46). Revisions of the other four TSCA guidelines (40 CFR 799.9130, 799.9537, 799.9630, and 799.9748) will be published shortly in the Federal Register and should appear in the July 1, 2001 edition of the CFR. The published TSCA guidelines (Ref. 46) as well as the OECD, OPPTS, and ASTM guidelines (Refs. 4749) are available for review in the public docket for this notice, OPPTS00274D. Copies of the guidelines can also be obtained from other sources. OECD test guidelines are available on the Internet at http://www.oecd.org/ehs/guide/index.htm followed by the selection of a specific guideline number. The OPPTS test guidelines in the 870 series are available in hard copy from the Government Printing Office at telephone number (202) 5120132 and on the Internet in PDF format at http://www.epa.gov/opptsfrs/home/guidelin.htm/. followed by selections for ``870Health Effects Test Guidelines'' and ``Final Guidelines.'' The TSCA test guidelines are available on the Internet at http:// www.epa.gov/docs/epacfr40/chaptI.info/subchR/ followed by selections ``Part 799'' and ``Subpart H.'' The ASTM guideline E116398 can be purchased online at address http://www.ASTM.org followed by selections ``ASTM Store'' and ``Search for individual standards,'' and entering and selecting ``E116398.'' The ASTM test guideline E116398 can also be ordered from ASTM, 100 Barr Harbor Dr., West Conshohocken, PA 19428.

During the course of the VCCEP pilot, some of the guidelines listed in Table 3 may be revised by the entity which developed them, i.e., OECD, ASTM, or EPA. If revisions are made, the sponsor may conduct testing according to the guideline in effect on the date the sponsor made a commitment to provide that information or when the relevant test is initiated. Whenever practical, EPA encourages sponsors to use the most up to date guideline.

EPA believes that many of the chemicals selected for the VCCEP and its pilot may have been relatively well tested and therefore a significant amount of both lower and upper tier test data may already exist. Existing upper tier test data will be integrated into the program by having them submitted with Tier 1 information; this is consistent with the approach in the HPV Challenge Program. A possible outcome may be that the existing data may be sufficient such that no further hazard data development is needed at this time.

There may be instances when children have relevant exposures to VCCEP chemicals by multiple routes. EPA believes that needed information should be available on all relevant routes of exposure. In some instances, however, physiologically based pharmacokinetics (PBPK) testing and modeling may enable routetoroute extrapolation and be a possible alternative to multiple route testing. Ultimately, EPA plans to rely heavily on the reports of the third party contractor as described in Units III.P. through III.U. for compiling all scientific issues related to multiple route testing.
E. What Animal Welfare Considerations Have Been Made in the VCCEP?

In designing the VCCEP, EPA has taken several steps to reduce animal testing without unduly compromising the goal of protecting children from chemical hazards. EPA is committed to avoiding duplicative testing, and to reducing, refining, and replacing animal testing when valid alternatives exist. In the United States, EPA works within the framework of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM), and, internationally, with OECD to ensure the scientific acceptability of alternative test methods. All test methods must be scientifically validated to demonstrate their accuracy before they can be accepted for regulatory and international data sharing purposes. Without such safeguards, tests may need to be repeated, resulting in the use of additional animals. If relevant alternative test methods become validated during the implementation of the VCCEP or its pilot, EPA will consider their immediate implementation in the program. In an effort to avoid duplication of similar tests, Tier 1 of the VCCEP includes testing endpoints which will be satisfied by tests already designated in the HPV Challenge Program.

A key step in reducing the number of animals used for testing is to ensure maximum use of existing data and to combine tests where feasible. To ensure the maximum use of existing data, industry and others are encouraged to search for existing relevant and adequate data and to share sources of such information. Sponsors will, as part of this program, commit to identifying and assessing the adequacy of existing data. To facilitate this effort, EPA has developed guidance under the HPV Challenge Program and will develop additional guidance for this effort as needed. EPA encourages chemical sponsors to combine tests where possible to conserve resources and reduce the number of animals required for testing. An example of two tests which can be combined are the tests for subchronic toxicity and immunotoxicity. Sponsors are also encouraged to consider development of PBPK approaches to evaluate routetoroute extrapolation of test data which also may reduce the need for certain testing.

An important step EPA has taken to address animal welfare concerns was to use chemical selection criteria for the VCCEP pilot which clearly demonstrate that actual exposures to humans are likely to be occurring and for which there is a compelling need for children's health effects data, exposure data, and risk information to be made publicly available. The resulting list of chemicals selected for this pilot program and listed in Table 1 are known to be relatively well characterized. As such, EPA was in a position to focus less on test data development and structure the pilot VCCEP around data evaluation and emphasize the importance of gathering exposure data to support an assessment of the risks of chemicals to children.

The tiered testing design of the pilot program is another feature of the program that is responsive to animal welfare concerns. In the VCCEP pilot, the Tier 2 and Tier 3 testing will be limited to chemicals for which there is a clear need; i.e., Tier 2 and Tier 3 tests will not automatically be required. The need for testing will be considered as part of an overall assessment directed to judging whether the potential hazards, exposures and risks to children have been adequately evaluated. This will be done by EPA in this program and the Agency will be assisted by a deliberative, sciencebased Peer Consultation process that is intended to ensure that the hazard and exposure information developed via this program will inform the public on a chemical's potential health effects, exposure and risks to children. The Peer Consultation process will also serve as a forum for all stakeholders to provide input on the available hazard and exposure information for each chemical and the need for any additional information.
[[Page 81708]]
F. What is the Sequence of Events that Comprise the VCCEP Pilot?

A flow chart (Figure 1) depicts the sequence of events that comprise the VCCEP pilot. Each event is briefly described in Unit III.F.1. through III.F.15. and more fully described in the subsequent sections of Unit III.

1. Chemical selection. After receiving feedback on the Framework Document (Ref. 31) from various individuals at the April 2627, 2000, Stakeholder meeting and considering the written comments submitted to the docket and other communications, EPA identified candidate chemicals for the VCCEP and the pilot program. These chemicals are those judged by EPA to present, given the data at hand, the relatively greatest potential for exposures that may impact children. This notice initiates the voluntary program by identifying the test battery, outlining the program, and soliciting Tier 1 sponsorship of the pilot chemicals by their manufacturers and importers.

2. Tier 1 commitment. To sponsor a chemical at Tier 1, a company (or consortium) would send a letter to EPA indicating their commitment to handling a chemical under the VCCEP pilot as described in Unit I.C. and D. and Unit IV.B. Tier 1 commitments are requested between January 25, 2001 and June 25, 2001.

3. Submission of Tier 1 data. Sponsors (or consortium) would subsequently submit to EPA a Tier 1 Hazard Assessment described in Units III.H. and III.I., a Tier I Exposure Assessment as described in Units III.H., III.J., and III.K., and a Tier 1 Risk Assessment as described in Units III.H. and III.M. A Data Needs Assessment which would describe additional hazard testing and/or exposure data needed to fully evaluate the risks of a chemical to children and, where relevant, prospective parents would also be submitted to EPA as described in Units III.H., III.N., and III.O.

4. Peer Consultation regarding Tier 2 data needs. At EPA's request, the third party contractor would periodically convene a Peer Consultation to evaluate the Tier 1 information with emphasis on the Data Needs Assessment. The Peer Consultation would evaluate whether Tier 1 data needs were met by the sponsor's submission and whether the Tier 1 submission fully characterized the chemical's potential risk to children and whether there are remaining Tier 2 data needs. A possible conclusion of the Peer Consultation is that no more work is needed. Results and comments from the Peer Consultation Process will be compiled by the third party contractor and submitted to EPA.

5. EPA review of Peer Consultation results. EPA would review the sponsor's submission and the third party contractor report and announce the Tier 2 Data Needs Decision. The sponsor will be informed by mail and the public by the VCCEP web site. If EPA's approach differs substantially from that indicated by the third party report, sponsors and other stakeholders will have 60 days to comment on EPA's determination regarding Tier 2 data needs. EPA, following consideration of comments, will mail its final decision on Tier 2 data needs to the sponsor and announce it on the VCCEP web site.

6. Tier 2 commitment. The sponsor would have a period of 4 months after the issuance of EPA's final Tier 2 Data Needs Decision to commit to Tier 2 of the pilot program. This commitment would be made by letter to the Agency as described in Units I.C., I.D., and IV.C.

7. Development and submission of Tier 2 data. The sponsor will develop and submit to EPA Tier 2 hazard and exposure data in the form of a revised Hazard Assessment, revised Exposure Assessment, and revised Risk Assessment. The sponsor will also submit a Data Needs Assessment which addresses the need for Tier 3 information. The time allowed for this effort would be based on the time needed to conduct specific tests or exposure studies for each chemical using the guidance provi

FOR FURTHER INFORMATION CONTACT

For general information contact: Barbara Cunningham, Acting Director, Environmental Assistance Division (7408), Office of Pollution Prevention and Toxics, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (202) 5541404; email address: TSCAHotline@epa.gov.

For technical information contact: Ward Penberthy, Chemical Control Division (7405), Office of Pollution Prevention and Toxics, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (202) 2601730; email address: penberthy.ward@epa.gov.