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OAR Box 1846 

Prepped by Ollie Stewart 

Document Number: 

51) ll-F-5 

Docket Number: 

A-90-07 

Printed 11/18/2008 7:30:16 AM Sheet 51 of 93 
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ft -°lb-Ol 

MAR 2 3 1992 

NOTE 

FROM: 

TO: 

RE: 

Judy Gray 

Troy Hill 

• -J^Tn 

Transmittal of Additional NPRM Changes for the 

Fuels/Additives Program 

Pages of the NPRM containing the additional changes we 

discussed over the phone this morning are attached. To facilitate 

your review, the changed material is indicated by arrows in the 

left margin, and the page numbers in relation to previous drafts 

are shown in brackets in the lower right corner of the new page. 

Please give me a call (374-8231) as soon as you complete your 

review. 

Thank you. 
P.3 

exposures to emissions of the base fuel alone. EPA asks for 

comment on the mixing rules that should be adopted and on the 

validity of doping the base fuel with the fuel additive or 

—> active ingredient. Comment is also requested on appropriate 

—> additive concentration levels, if a doping procedure were to 

—» be adopted for the Final Rule. 

VI. Evaluation of Health and Welfare Effects 

The scope and general structure of proposed provisions 

for evaluating the potential health and welfare effects of 

fuels and fuel additives were discussed above in Sections 

11 I.E and F. The program focuses on the contribution of fuels 

and additives to harmful air pollution, and includes 

requirements to determine the composition and potential 

effects of fuel/additive emissions generated by both 

combustion and evaporative processes. Health effects testing 

provisions are specifically focused on the effects of 

inhalation exposure to fuel/additive emissions in regard to 

the following selected endpoints: carcinogenicity, 

mutagenicity, developmental effects, reproductive effects, 

pulmonary toxicity, and neurotoxicity. The impacts of fuel 

and additive emissions on the public welfare and the 

environment are addressed by data research methodologies. 

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i<rc>- V " 
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fuel families (e.g., methane or propane) should be exempted 

from particular Tier 2 testing requirements. 

The proposed health effects testing guidelines are 

included in the regulatory text for this proposal, available 

in the public docket or by request to EPA (see the section of 

this Notice entitled, "For Further Information"). Most of 

these testing guidelines are modified versions of guidelines 

previously published under TSCA (40 CFR Part 798). Methods 

for performing animal inhalation exposures to fuel/additive 

emissions are also included in the proposed regulatory text. 

—> Comments and suggestions are solicited on the adequacy of 

-» these proposed guidelines and methodologies for promoting 

—i* valid study design and adequate technical performance. EPA 

—> believes that these guidelines (perhaps amended for the Final 

—> Rule as a result of submitted commentary), together with 

—» published laboratory practice standards (referenced below), 

—> are sufficient to ensure that Tier 2 testing done in 

—> conformance with these guidelines will be acceptable upon 

—> subsequent evaluation by EPA. However, comments are requested 

-» on whether a review mechanism should nevertheless be 

—» established, enabling manufacturers to submit detailed 

—> protocols to EPA for approval prior to beginning the Tier 2 

—> testing. Such a mechanism would provide additional 

—» reassurance to manufacturers, but in view of the large number 

-» of individual protocols which would probably be submitted for 

—> review, would inevitably result in significant testing delays. 

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-> Thus, respondents who believe that a review mechanism is 

—» necessary are also asked for suggestions on how to make the 

—» process feasible, given the statutory time constraints for 

-» program compliance. 

Similar requirements among the various test guidelines in 

regard to animal subjects, exposure scenarios, and general 

technical principles provide opportunities for concurrent test 

performance at considerable cost savings. These shared study 

parameters include the following: 

Laboratory practices. To ensure the quality and 

integrity of test results, the performance of all studies will 

be required to conform with the Good Laboratory Practice 

Standards (GLPS) published in 40 CFR Part 792, or with 

comparable standards which may be developed specifically for 

this program. These GLPS include facility, equipment, 

organization, quality assurance, and personnel requirements, 

as well as specifications for proper care of laboratory 

animals, handling of reagents and test substances, and conduct 

of studies. In addition, the provisions of Subpart J of Part 

792 are to be followed for record keeping and reporting of 

results. 

Animal models. With the exception of the Ames Salmonella 

assay, the proposed test requirements entail the exposure of 

live laboratory animals to fuel/additive emissions. Mammalian 

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required to further explicate the results of the screening 

batteries performed under Tier 2, but might also address other 

areas of concern highlighted by the Tier 1 literature search 

or emission characterization procedures. The need for Tier 3 

testing would depend on whether sufficient toxicity and 

exposure information were available to determine whether use 

of a fuel or fuel additive presents an unacceptable health 

risk. The criteria for this determination are discussed 

below. 

When a determination has been made that Tier 3 testing 

will be required, EPA will inform the responsible producer(s) 

by certified mail of the purpose and nature of the testing to 

be performed. Subsequently, relevant study guidelines and a 

timetable for completion of all requirements will be 

specified. The producer(s) will be expected to submit 

detailed protocols for review and approval by EPA prior to 

—» beginning the tests. Tier 3 testing performed in full 

—» conformity with a protocol pre-approved by EPA for the given 

—> product(s) and test objective will be deemed satisfactory 

-» compliance with the Tier 3 testing requirement. 

1. Need for Discretionary Tier 3 Determinations 

Given the variety of evaluation methodologies and 

subjects included in Tiers 1 and 2 and the wide range of 

possible interrelated outcomes which could be obtained, EPA 

believes that it is neither practical nor necessarily 

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enable manufacturers to predict and plan for their maximum 

registration responsibilities and would simplify EPA's data 

evaluation tasks. EPA requests comment on the relative merits 

of the discretionary vs. automatic approaches for determining 

Tier 3 applicability. Respondents who prefer the automatic 

approach are also asked for suggestions as to the specific 

"triggers" and follow-up tests which should be established. 

—> While EPA proposes to retain discretion in the decision 

—» to require Tier 3 testing, it is possible to predict some sets 

—> of circumstances which would indicate that Tier 3 will not be 

—» required. These factors are discussed in the sections which 

—> follow. EPA requests comments on these circumstances, and 

—» asks for suggestions on other combinations of criteria which 

—» should be established for determining when a fuel or additive 

—» should not be considered for possible elevation to Tier 3. 

2. Criteria for Escalation to Tier 3 

This section presents some of the guidelines and 

considerations which EPA would use in determining the 

necessity for additional testing under a discretionary Tier 3 

testing approach. Consistent with the proposed discretionary 

decision-making process for Tier 3, this discussion is not 

intended to provide an exhaustive or definitive listing of 

relevant criteria. Rather, the major purpose of this 

discussion is to help furnish a basis for meaningful public 

comments and suggestions on the proposed Tier 3 provisions. 

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of the observed effects (e.g., whether the effects would be 

likely to lead to incapacitating or irreversible conditions), 

5) the number of species involved in the reported tests, and 

6) the consistency and clarity of apparent mechanisms, target 

organs, and outcomes. Additional parameters which would 

influence the decision on whether to require Tier 3 would 

include 1) findings of environmental persistence of the 

emissions and/or the ability of the emissions to accumulate in 

living organisms, 2) the nature and amount of known toxic 

agents in the emissions stream, and 3) the observation of 

lesions which specifically implicate inhalation as an 

important exposure route for inducing adverse health effects. 

These criteria would be evaluated in conjunction with the 

results of the exposure assessment to determine whether or not 

higher level testing was needed. In this decision, both the 

biological and statistical significance of the results of 

Tiers 1 and 2 would be taken into account. Generally, 

escalation to Tier 3 would be considered when remaining 

uncertainties about the significance of observed outcomes 

and/or exposures interfered with EPA's ability to make 

reasonable estimates of the attendant public health risks. On 

the other hand, if no statistically significant effects were 

obtained at any exposure level in a scientifically sound Tier 

—> 2 study (or existing test submitted in lieu of Tier 2 testing 

—» and not contradicted by other published reports) , and if other 

—» ma jor sources of concern did not arise (e.g., toxic effects of 

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—> structurally related compounds) , then Tier 3 testing would not 

—> be required for the endpoint in question. This assumes that 

relevant, high-quality statistical analysis had been done to 

permit the negative test results to be properly evaluated and 

interpreted. The statistical analyses recommended for Tier 2 

in an earlier discussion, including determination of Type I 

and II error, should enable reasonable conclusions to be drawn 

as to the significance of negative findings. Factors to be 

taken into account include the toxicological nature of the 

findings and the exposure levels used in the test. For 

example, if the statistical analyses were applied to a 

"severe" endpoint (e.g., major fetal abnormalities, major lung 

pathology, etc.) and the exposure in question was moderate, 

then 0.1 would be an appropriate Type II error level. In 

contrast, if a high concentration limit test caused a 

relatively minor effect (e.g., a small change in lung lavage 

protein), a higher Type II error would be allowed (e.g., 0.2), 

effectively increasing the chance of false negative 

conclusions. 

Evaluation of Tier 2 Results. The specific outcomes 

which would be considered positive and negative results for 

each proposed Tier 2 test are mentioned briefly in the 

previous descriptions of Tier 2 requirements and are defined 

and interpreted more precisely in the proposed regulatory 

text. For example, three primary studies are included in Tier 

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2 which relate to carcinogenicity and mutagenicity: the Ames, 

SCE, and micronucleus assays. As compared with appropriate 

controls, a statistically significant dose-related positive 

response in any one of these assays could be cause for 

concern, as would positive outcomes for at least one 

concentration in two or more of these tests. Such outcomes 

would be indicative of mutagenic risk; however, depending on 

the internal and historical consistency of these results and 

their relationship to projected exposures, further testing 

might be required to determine the significance of this 

mutagenic activity in human populations exposed by inhalation. 

These outcomes would also indicate that the emissions could 

initiate some of the mechanisms involved in carcinogenesis. 

However, the production of malignancy is a multi-step process, 

and these results would generally not in themselves be 

sufficient to determine whether the emissions were in fact 

carcinogenic. Thus, additional testing might be required 

under Tier 3 to better evaluate the associated cancer risks. 

In contrast, if no statistically significant results were 

obtained in the three assays and no conflicting results found 

-* in the literature or in other Tier 2 tests, then Tier 3 

-» follow-up for carcinogenicity/mutagenicity would not be 

-> required. 

To take another example, determination of the need to 

further investigate teratogenic risks would take into account 

the results of both the inhalation developmental toxicity 

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study and the reproduction and fertility assessment of Tier 2. 

—> If negative results were obtained in both of these tests 

—> (according to statistically sound principles) , and if these 

—> results were not refuted by the existing literature, then 

—> additional testing would not be required at the Tier 3 level 

—» for developmental or reproductive effects. Positive results 

would include a decrease in neonatal viability relative to 

that in control studies, a significant change in the 

proportion of viable male vs. female fetuses or offspring, the 

presence of soft tissue or skeletal abnormalities, and an 

increased rate of embryonic or fetal resorption. Other 

positive outcomes of the reproduction and fertility 

assessment, such as abnormal changes in sperm structure or 

function, vaginal cytology, or reproductive organ 

histopathology, would be indicative of hazards to the adult 

reproductive systems. The need for additional evaluation 

under Tier 3 would depend on the number of species for which 

positive results were obtained, the specificity, severity, and 

consistency of results, the presence or absence of a 

concentration-effect relationship, and the significance of 

these outcomes in view of projected exposure scenarios. The 

greater the remaining uncertainty regarding the risk of 

teratogenic or reproductive effects after analysis of such 

factors, the higher would be the likelihood that Tier 3 would 

be required. 

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-> Similarly, consistent and statistically significant 

—» negative results obtained in other Tier 2 tests, in the 

—» absence of significant related concerns raised in the 

—» literature, would make Tier 3 unnecessary. On the other hand, 

if adverse effects are found at Tier 2 and/or reported in the 

literature, EPA would determine if Tier 3 follow-up is 

required by attempting to evaluate the nature, severity, and 

significance of the findings in light of the likely exposures. 

If EPA determines that Tier 3 testing is required to resolve 

the remaining uncertainties, the Tier 3 requirements would 

reflect both positive and negative results. For example, if 

the results of Tier 2 were positive for pulmonary effects but 

negative for neurotoxicity (according to criteria discussed 

earlier), and if these results were consistent with the 

literature, only pulmonary toxicity would be a likely 

candidate for Tier 3 follow-up testing. 

Acute Health Assessment. Under the assumption that 

emissions exposures will generally be low and thus more likely 

to cause longer-term effects, this proposed rulemaking does 

not focus on acute effects. However, the purpose of CAA 

section 211 is to protect the public health, whatever the 

exposure duration, and potential acute effects could also be 

a consideration in the Tier 3 decision. 

EPA is currently developing a standardized method of 

assessing acute noncancer health effects, and this method 

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individual manufacturers, a hypothetical example may help to 

clarify the proposed scope, time frame, and costs of the 

program. Based on the analysis provided in the regulatory 

support document, a possible testing scenario and the 

associated compliance costs for a hypothetical group of 

products is discussed below and summarized in Figure 6. These 

costs would pertain to the evaluation and testing of a fuel 

selected to represent the hypothetical group. The total costs 

would subsequently be shared by all of the manufacturers with 

products enrolled in the group. The requirements and costs 

assume that the group consists of 40 fuels and additives which 

contain no "atypical" elements, that the group does not 

qualify for exemption from evaporative emission testing, and 

that adequate existing studies are not available to fulfill 

any of the speciation or biological test requirements. 

Therefore, under this hypothetical situation, all of the 

potential requirements of Tiers 1 and 2 must be conducted. 

Combustion emission generation procedures are assumed to be 

performed using one light-duty vehicle, for both emission 

characterization and biological testing purposes. 

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The approach which EPA plans to use in determining the 

potential need for greater precision and accuracy in the 

exposure information is to consider the slope of the toxic 

response. If the slope is steep within the range of potential 

human exposures, then a small change in exposure is likely to 

have a major impact on the eventual risk assessment. Greater 

precision would thus be required in the exposure calculation. 

If adverse health effects appear likely within the projected 

range of exposures, improved estimates might also be needed to 

determine the conditions and locations under which these 

exposures might occur as well as the size of the potentially 

affected populations. On the other hand, if only minor health 

effects occur at levels well above ambient concentrations and 

only a relatively small number of people are likely to be 

exposed, then additional refinements of the exposure 

calculations would not be warranted. 

-> Tier 3 exposure assessment could include physical 

—» monitoring studies or the application of more sophisticated 

—> modeling techniques, some of which are described in Section 

—> VI.B.2. However, the precise nature of these studies would be 

—»strongly influenced by interim advances that are expected in 

—»the growing science of exposure assessment. The general topic 

—» of gasoline exposure is receiving increased attention by the 

scientific community as a topic for research, in recognition 

of the limited knowledge base currently available for 

determining the risks from mobile source emissions and from 

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over the three-year compliance period, the Tier 3 testing cost 

per product in this group would be in the range of $17-21,000 

annually for three years. 

In sum, EPA estimates that the total costs to this 

hypothetical group would range from approximately 3 to 3.5 

million dollars, incurred over a seven or eight year time 

period. The total cost for each product would range from 

about $75,000 to $87,500, averaging about $10-12,000 per year. 

—> EPA seeks comments on these estimates, given such a scenario. 

—> The above discussion illustrates the compliance costs 

—> which the proposed program might entail for a group of 

—» fuel/additive producers. However, the proposed program could 

—> have some indirect cost implications, as well. For example, 

—> if the costs of compliance represented a significant entry 

—» barrier into the fuel/additive marketplace, an economic cost 

—> could be incurred as a result of delayed or deterred 

—»innovation. These potential economic costs have not as yet 

—»been quantified, and EPA requests comment, along with 

—»supporting data, on how to evaluate and quantify the possible 

—> indirect economic impacts of the program. 

& 2/7 (ufa) 

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