EPA-600/1-77-005
January 1977
FUELS AND FUEL ADDITIVES FOR HIGHWAY VEHICLES AND THEIR COMBUSTION PRODUCTS
A Guide to Evaluation of Their Potential Effects on Health
By
Committee on Toxicology
Assembly of Life Sciences
National Research Council
National Academy of Sciences
Washington, D.C.
Contract No. 68-01-0432
Project Officer
Thomas W. Lamb
Criteria and Special Studies Office
Health Effects Research Laboratory
Research Triangle Park, N.C. 27711
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
HEALTH EFFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK, N.C. 27711
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DISCLAIMER
This report has been reviewed by the Health Effects Research Laboratory,
U.S. Environmental Protection Agency, and approved for publication. Approval
does not signify that the contents necessarily reflect the views and policies
of the U.S. Environmental Protection Agency, nor does mention of trade names
or commercial products constitute endorsement or recommendation for use.
NOTICE
The project that is the subject of this report was approved by the
Governing Board of the National Research Council, whose members are drawn
from the Councils of the National Academy of Sciences, the National Academy
of Engineering, and the Institute of Medicine. The members of the Committee
responsible for the report were chosen for their special competences and
with regard for appropriate balance.
This report has been reviewed by a group other than the authors
according to procedures approved by a Report Review Committee consisting of
members of the National Academy of Sciences, the National Academy of Engineering,
and the Institute of Medicine.
ACKNOWLEDGMENTS
This report was prepared under contract number 68-01-0432 between the
Environmental Protection Agency and the National Academy of Sciences.
Responsibility for the report was assigned to the Committee on Toxicology
which was assisted by a Subcommittee.
The Subcommittee wishes to acknowledge with thanks the assistance of
David W. Fassett, M.D., who served as consultant in the preparation of this
report, and A.J. Pallotta, Ph.D. who served as editor.
ii
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FOREWORD
The many benefits of our modern, developing, industrial society are
accompanied by certain hazards. Careful assessment of the relative risk
of existing and new man-made environmental hazards is necessary for the
establishment of sound regulatory policy. These regulations serve to
enhance the quality of our environment in order to promote the public
health and welfare and the productive capacity of our Nation's population.
The Health Effects Research Laboratory, Research Triangle Park
conducts a coordinated environmental health research program in toxicology,
epidemiology, and clinical studies using human volunteer subjects. These
studies address problems in air pollution, non-ionizing radiation,
environmental carcinogenesis and the toxicology of pesticides as well as
other chemical pollutants. The Laboratory develops and revises air quality
criteria documents on pollutants for which national ambient air quality
standards exist or are proposed, provides the data for registration of new
pesticides or proposed suspension of those already in use, conducts research
on hazardous and toxic materials, and is preparing the health basis for
non-ionizing radiation standards. Direct support to the regulatory function
of the Agency is provided in the form of expert testimony and preparation of
affidavits as well as expert advice to the Administrator to assure the
adequacy of health care and surveillance of persons having suffered imminent
and substantial endangerment of their health.
To aid the Health Effects Research Laboratory in fulfilling the
functions listed above, the National Research Council prepares reports
under various contracts. This report was prepared by the Committee on
Toxicology, Under EPA Contract No. 68-01-0432 and will be utilized in the
development of test procedures for fuels, fuel additives, and their combustion
products.
JoW~H.
Knelson, M.D.
Director
Health Effects Research Laboratory
iii
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Committee on Fuels, Fuel Additives, and Their Combustion Products
Arthur B. DuBois, Yale University, Chairman
Yves Alarie, University of Pittsburgh
Mary 0. Amdur, Harvard University
Moreno L. Keplinger, Industrial
Biotest Laboratories
Donald J. Patterson, University of Michigan
Robert A. Scala, Exxon Research and
Engineering Company
Frank G. Standaert, Georgetown University
James G. Wilson, University of Cincinnati
Consultant: David W. Fassett
Staff Officer: Ralph C. Wands
EPA Liaison Representatives
Kenneth Bridbord Robert McGaughy
David L. Coffin John B. Moran
John Finklea Jerry F. Stara
F. Gordon Hueter J. Wesley Clayton
Committee on Toxicology
Bertram D. Dinman, Aluminum Company of America, Chairman
Yves Alarie, University of Pittsburgh
Arthur B. DuBois, John B. Pierce Foundation Laboratory,
and Yale University
Seymour L. Friess, Naval Medical Research Institute
Harold M. Peck, Merck Institute for Therapeutic Research
Charles F. Reinhardt, E. I. duPont de Nemours and Company
C. Boyd Shaffer, American Cyanamid Company
Frank G. Standaert, Georgetown University School of Medicine
Richard D. Stewart, Medical College of Wisconsin
Herbert E. Stokinger, National Institute for Occupational
Safety and Health
iv
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CONTENTS
Page
I. Introduction 1
II. Summary and Conclusions 3
III. Considerations in Developing Protocols 5
a. Composition of fuel additives and fuels 5
b. Sources of exposure to fuels, fuel additives 5
and their combustion products
c. Known and suspected health effects from com- 6
bustion products
d. Selection of practical approaches 6
e. The value of various methods for assessing 7
biologic effects of fuels, fuel additives
and their combustion products
f. Recommendations and comments 8
IV. Analytic Chemistry and Generation of Exhaust Emissions 10
a. Generation and irradiation of exhaust 10
b. Purpose of analytic studies 10
c. Analytic procedures 10
d. Some relations between analytic data and 11
biologic effects
V. Recommended Approaches for Evaluating Fuels and Fuel 12
Additives
VI. Outline of Proposed Animal Procedures for Evaluating 14
the Safety of Fuels and Fuel Additives Used in Inter-
nal Combustion Engines
a. Methods for evaluating the toxicity of fuels 14
and fuel additives before combustion
b. Methods for evaluating the safety of combustion 15
products of fuels and fuel additives
c. Evaluating hazards of metal-containing additives 18
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Page
d. Carcinogenesis, mutagenesis and teratogenesis 19
e. Behavior studies 20
f. Summary comment 20
VII. Criteria for Evaluating Health Hazards 21
a. Analytic data 21
b. Toxicologic data 22
VIII. Data Collection, Storage and Retrieval Systems 24
IX. Recommendations for Research 25
a. Analytic methods 25
b. Miniaturization of the combustion process 25
c. Eye irritation 26
d. Use of condensates and filtrates 26
e. Interactions of irradiated exhaust effluent com- 26
pounds with sulfur dioxide or other materials
f. Epidemiology 26
g. Validation 27
h. Occupational exposures 27
REFERENCES 28
APPENDICES
I. POINTS OF POTENTIAL SOURCES OF POLLUTION FOR 34
ENVIRONMENTAL HAZARDS
II. PROTOCOL FOR EYE IRRITATION TEST (VAPOR) IN 35
ALBINO RABBITS
III. COMPOSITION OF FUEL ADDITIVES 36
IV. COMPOSITION OF FUELS 38
V. EXAMPLES OF THE CLASSIFICATION SCHEME AND RATINGS 40
VI. COMMENTS ON GENERATION OF EXHAUST EMISSIONS 41
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I. INTRODUCTION
The Clean Air Act of 1970 increased the authority of the Environ-
mental Protection Agency (EPA) to regulate fuels and fuel additives.
Section 211 of the Act (PL-91-604) states that the Administrator
"may require the manufacturer to conduct tests to
determine potential public health effects of fuel
or additives (including but not limited to carcinogenic,
teratogenic or mutagenic effects)," and that "tests
shall be conducted in conformity with the test procedures
and protocols established by the Administrator."
Therefore, the need exists for selecting useful test procedures and
protocols for predicting potential public health effects of fuels and
fuel additives. These needs are further specified as "Proposed Rules"
of the EPA. 19
At the request of the EPA, the Committee on Toxicology of the
National Research Council, assisted by the Advisory Center on Toxicology,
proposed to evaluate the usefulness of existing protocols for predicting
public health hazards that might be caused by environmental pollution
from fuels, fuel additives and their combustion products arising from
highway vehicles. The study was to be concerned with three principal
areas:
1. the evaluation and recommendation of test protocols for
necessary toxicologic investigations; 2. the collection of
information on the composition of fuels, fuel additives and
their combustion products; and 3. the development of a
classification scheme for the substances involved, based on
their known toxicity and potential as a public health hazard.
The present problem of setting emission standards for known toxic com-
ponents, such as nitric oxide and nitrogen dioxide, sulfur dioxide,
carbon monoxide and polycyclic aromatics, was not to be considered.
However, evaluating changes caused by additives in the profile of com-
bustion products was to be investigated. Suggestions were requested
about mechanisms for systematically collecting and retrieving toxicologic
data.
The Committee on Toxicology advised that a separate committee be
formed to study the problem. The vice-chairman of the Committee on
Toxicology served as chairman and one of its former members was appointed
as a consultant. The new committee was named the Committee on Fuels, Fuel
Additives and their Combustion Products. Liaison with EPA was provided
by persons from the National Environmental Research Centers in Research
Triangle Park, North Carolina and Cincinnati, Ohio, as well as head-
quarters staff.
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Although the term "public health effects" could be interpreted to
include many biologic effects, the Committee was asked to limit its
consideration to protocols that might be useful in predicting effects
on humans, and particularly to the evaluation of methods suitable for
examining toxic effects of combustion products. However, it was recog-
nized that toxicologic investigations of fuel additives per :s_e would
be essential nonetheless, because of the likelihood of direct contact
with the fuel or its evaporative products. Protocols were desired for
evaluating vehicular fuels, including all additives for fuel and lubri-
cants, motor vehicle gasoline, and motor vehicle diesel fuel.
In February 1973, a working conference sponsored by the National
Academy of Sciences at the request of EPA was held on Principles for
Evaluating Chemicals in the Environment. 50 Several committee members,
the consultant, and staff participated. Many concepts developed there
directly relate to the current problem of designing effective protocols
for evaluating the safety of fuels and fuel additives. Because the
report has already been published, much of the material that evolved
from the conference is not discussed in detail here. It is recommended
that the reader consult that document. Wherever possible, the thinking
developed in the conference report has been reflected in the conclusions
of the committee.
Several documents were particularly valuable to the Committee in
its search for information on the nature of fuels, fuel additives, and
their combustion products; current views of the health effects of auto-
motive air pollutants from fuels and fuel additives; and current sugges-
tions for protocols for evaluation of materials in the environment. ^»
21,42,50,51
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II. SUMMARY AND CONCLUSIONS
The Committee's principal concern was to evaluate protocols for
experimental prediction of the hazards of automotive fuels, fuel additives,
and their combustion products. The problem is so complex that it is
questionable whether fixed protocols should be adopted now. Although
techniques for inhalation toxicology are advancing rapidly, toxicologists
have had little experience with automotive combustion products. Nor is
there much information which would help to assess the predictive value of
some methods now being developed.
The most clearly established human health responses from air
pollutants are relatively simple and immediate, such as eye or possibly
respiratory irritation and odors. Considerable evidence exists and these
responses can be predicted by appropriate animal and human volunteer studies,
Present data are too insufficient to establish whether fuel additives or
their combustion products are carcinogens, teratogens or mutagens, and
obviously data should be obtained. At present, procedures to evaluate
such data are still in early stages and need much research. The inter-
pretation of chronic toxicity data (including carcinogenesis) from animal
inhalation, is not well standardized; it likewise needs evaluation,
especially in regard to the significance of the studies to man.
Most fuel additives are organic, used in very low concentrations,
and thought to be largely combustible. Exceptions include organometallics,
organohalides, and sulfur compounds, which are partly combustible.
Finally, analytic methods for automotive combustion products have
progressed to where their routine application in cases of changing fuels
or fuel additives can provide a basis for tentatively predicting potential
changes in hazards and for guiding the type of biologic research needed.
The Committee reached the following conclusions:
1. The initial evaluation of the safety of a new fuel-additive
combination should include a comparison between a standard fuel and the
new combination that considers the analytic profile of the combustion
products and certain biologic effects,,
2. The biologic methods suggested for the initial evaluation should
be sensitive to the possibility that known health effects on humans from
such sources may increase or diminish. They also should be able to detect
unexpected toxic effects of fuels and fuel additives.
3. Separate considerations and more extensive research on most
metal-containing additives should be required because of their persistence
in the environment after combustion and their tendency to accumulate in
the body.
4. All recommended methods will need careful validation and inter-
laboratory studies to determine their practicality and repeatability.
They should be regarded as tentative and administrative flexibility will
be needed if adopted for regulatory use.
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5. Interpreting results of studies on combustion products is diffi-
cult at best, and decisions should be made by informed scientists who have
considered all relevant information.
6. Appropriate epidemiologic and analytic studies should be conducted
whenever new fuel-additive combinations are put into use, so that predic-
tions made from experimental work may be confirmed or corrected.
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III. CONSIDERATIONS IN DEVELOPING PROTOCOLS
As with other environmental problems, information on the chemical
nature of the compounds to which people are exposed, routes of exposure,
health of persons exposed, known or suspected effects of the compounds on
human health, and evidence that experimental studies can predict such
effects,50 is necessary to develop protocols, such information is
summarized below.
a. Composition of fuel additives and fuels
About 325 fuel additives were registered as early as 1972. They
are usually added to the fuel in very small amounts (a few ppm to a few
hundred ppm). They can be classified into about 15 chemical types (see
Appendix III and reference 20). Fuels vary in their composition and
physical properties, depending on use, seasonal and geographic factors,
and origin (see Appendix IV and references 20, 21, 12, and 52a).
b. Sources of exposure to fuels, fuel additives, and their
combustion products
As indicated in the diagram of Appendix I, the public is exposed
to these materials in several ways. It shows four principal sources of
exposure that may be hazardous to health: the risk of occupational hazards
during the manufacture, blending and distribution of fuel additives;
evaporative losses; the possibility that lubricants and additives contami-
nated by combustion products from piston blow-by may enter the environment
as waste lubricants; and what the committee regards as most importantf
the inevitable human exposure to exhaust products before or after solar
radiation.
Although fuel additives are largely nonvolatile, they are of course
aerosolized during the mixing of the air and gasoline before combustion,
and it is conceivable that traces might be carried out in uncombusted
form, probably in the particulate fraction. The Committee is not primarily
concerned with the effects of catalysts on automotive engine performance,
but it does recognize that the catalyst or emission control systems may
significantly alter the chemical nature of compounds found in the exhaust.
It also recognizes that materials from the catalyst itself may escape into
the exhaust stream. Some volatile components of fuel may be lost and they,
along with some combustion products (NOX, aldehydes) undergo photochemical
reactions thought to account for some of the irritating properties in
atmospheres which contain them. The organic portion of organometallic
compounds is largely combusted and the metal is released in inorganic
form.^
The many major classes of engines (gasoline, diesel, rotary, turbine,
jet) use a large number of fuel additives and are operated in different
modes. Each system produces different exhaust compositions and thus
presents potentially different health and environmental hazards. Such
diversity creates a problem in selecting and limiting the standard fuels,
lubricants, and conditions of operations, for study in the type of engine
for which new materials are being proposed. All these technical factors
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are crucial to the proper design of analytic and toxicological studies
and will be discussed later.
c. Known and suspected health effects from combustion products
One of the most important principles in selecting protocols for
the study of combustion products is to choose those that would predict
most closely the best known acute or chronic human health effects. It is
clear from both past and recent1^2 reviews, that two acute effects of auto-
motive air pollution are well established: the transient and reversible
eye irritation observed with high levels of oxidants and odors from some
types of exhaust. These effects probably arise from the fuel and its
combustion products rather than from the small amounts of additive present.
The Committee suspects that other acute effects associated with
automotive exhaust may include increased asthmatic attacks and deteriorating
condition of people with pre-existing chronic bronchitis or heart disease.
The anginal syndrome in persons with coronary disease may be aggravated
by carbon monoxide exposure.6* 7, 8 xhe exact cause of these suspected
acute effects, or even their occurrence, is far from certain because of
the difficulties of observation and the absence of reliable experimental
animal models.
The most likely chronic effects of pollution by combustion products
would be an increase in the amount or severity of chronic bronchitis and
emphysema cases. Studies of increased respiratory disease in children
and adults in areas with higher nitrogen oxide levels are poorly documented,
and the need for more reliable epidemiologic studies is apparent.4-2
Polycyclic aromatic hydrocarbons isolated from auto exhaust have
been found to be active in mouse skin carcinogenesis studies.33,34,47,58,65
Lung cancer has increased more in cities than in rural areas, an elevation
not entirely accounted for by smoking. However, definitive evidence that
it is caused by auto exhaust is not available.^2
Mutagenic compounds, including such materials as epoxides, have also
been said to be part of air pollutants. However, no specific evidence
relates chemical air pollution to human genetic mutation or teratogenesis.
Although teratogenic effects are known to result from drugs, pesticides,
hormones and viruses, they have generally occurred at relatively high
dosage levels at critical stages or organogenesis. Thus, hazards to the
fetus would arise primarily from exposure to high concentrations of
pollutants during those critical stages.
d. Selection of practical approaches
Obviously the task of describing protocols which can evaluate
public health effects from fuels and fuel additives and their combustion
products is complex. These environmental contaminants comprise hundreds
of different compounds, including virtually all physical and chemical
forms of material (vapors, gases, aerosols, metals, and nonmetals).
Moreover, the composition of the contaminants as breathed by humans will
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vary according to atmospheric conditions, photochemical reactions, engine
characteristics, mode of engine operation and performance, effects of
emission control devices, and interactions between these factors. Not
only are original compositions variable, but it is increasingly clear that
synergistic effects or altered responses from mixtures of various components
may occur.^
Only a few environmental toxicologists have had experience in. evalu-
ating these compounds. The extensive records developed over the past 50
years on individual industrial chemicals, commercial products, and
Pharmaceuticals is lacking for environmental pollutants. Since the dosage
levels from combustion products in the air is very much lower than those
encountered with industrial chemicals, some consumer item and medications,
it is inherently more difficult to detect and study the specific biologic
consequences of fuel contaminants.
Although the Clear Air Act requires the Administrator to specify
protocols and test methods, protocols based on our limited knowledge
should be regarded as tentative. Their usefulness and practicality in
predicting the safety of the combustion products of fuels and fuel addi-
tives should be continuously reviewed. The need for scientific judgement
in the prescription of protocols also must be recognized, especially
because of the uncertain validity of animal studies for predicting human
health hazards from combustion products. Various types of exploratory
research should be carried out and the most promising should be selected
for continuation. The Committee reviewed the more important studies
being carried out, and has recommended research priorities. They are set
forth below.
e. The value of various methods for assessing biologic effects of
fuels, fuel additives and their combustion products
Those procedures that are amenable to standard bioassay and
statistical evaluation techniques that have long been used in other fields
will have the greatest chance of success and therefore are assigned a
high priority. Toxicologists have found that the simpler type of responses
-- such as relative irritant potency, general toxicity potency, or
reproducible physiologic or biochemical effects — are most likely to
elicit a successful dose-response curve which often can be clearly related
to health effects known in humans. The best known and the first observed
human responses (especially to air pollutants from automotive exhaust)
are odor, eye irritation, and sometimes irritant effects on the upper and
lower respiratory tract. These should constitute the first line of
screening.
Although many studies have been carried out on air pollutants, few
have been concerned with the sort of bioassay techniques of interest now.
The most extensive series of long-term studies with whole exhausts is
still underway.38 Sponsored by EPA, it uses relatively sophisticated
analytic methods and advanced techniques to generate atmospheres. This
study would not be suitable for an initial evaluation, but it does provide
valuable information from which better predictive tests may be eventually
developed.
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The role of in vitro test in routine screening such as those
suggested in the Durham Conference was considered by the Committee,, These
tests make use of condensates or particulate fractions from auto exhaust
to which cells in tissue culture are exposed, or of isolated alveolar
macrophages, etc. A variety of submammalian tests for mutagenesis, are
also made. These tests may be very useful; however, they do need a
thorough validation by direct comparison wherever possible with tests on
intact animalso
It was suggested at the Durham Conference on Health Intelligence
for Fuels and Fuel Additives ^ that if such _in vitro tests were negative,
the materials might be registered without further study; if they were
positive, then it would be necessary to try various forms of in vivo
study in animals and other experimental or epidemiologic studies. Because
of the experimental nature and uncertainty of interpretation of such
in vitro studies, the Committee felt it would be unwise to adopt this
approach since if in vitro tests were negative, there would have to be
some independent in vivo confirmation. If in vitro tests were positive,
it would still be necessary to proceed with in vivo tests„
The Committee concluded that it would be better to use whole animal
experiments and human volunteers (as recommended later in this report)
wherever possible as the primary approach, and to plan for an orderly
parallel evaluation of the various in vitro or other tests as a longer
range program to develop quicker and less expensive screening tests.
Careful analytic study of condensates or fractions obtained by
filtration is necessary to determine their constancy under standard
conditions. Charleson reports that mass spectrometry has identified some
200 compounds from such sources.^ It is also difficult to know whether
information obtained by using condensates in experimental animals is
comparable with that obtained with the same animals exposed normally to
the generated atmospheres. Nevertheless, a thorough, systematic evalua-
tion of the toxic properties of condensates might be valuable, at least
in comparative'studies between standard and new fuels. Evidently little
work has been done on ordinary toxicology of condensates, that is, the
determination of the 1,050 (median lethal dose), evaluation of skin and
eye irritancy, skin sensitization or other similar tests.
The Committee repeats its finding that the problem of evaluating
the safety of fuels and their additives encompasses many difficult
problems, and therefore the design of research programs should be
extremely flexible.
f. Recommendations and comments
1. It is recommended that a standard test engine, as small as
available, be selected. It should be operated in a minimum number of
modes selected from the EPA standard engine cycling.
2. It is recommended that a comparison between a standard
fuel-lubricant system with previously used additives and the same standard
system using the proposed new additives be emphasized. The prime
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objective of the initial evaluation should therefore be to develop
reliable, appropriate comparative bioassays between standard and new fuel-
lubricant systems.
3. It is recommended that protocols be chosen that might be
expected to predict those human health effects that are most clearly
known or suspected. For automotive air pollution, the most certainly
established effects are eye irritation, odor, and respiratory irritation.
Protocols for them are recommended below.
Other possible effects that are less clearly established --
chronic respiratory effects, carcinogenesis, teratogenesis and mutagenesis
-- may need investigation. Research on protocols for predicting these
effects is also discussed below.
4. It is recommended that analytic measurements of the exhaust
profile constitute a major part of the investigation. The extent of such
studies needs to be determined by experience. In some cases, these data
might be crucial to judgements on safety and health. (But considerable
advances in analytic techniques will be needed for maximal utility.)
5. It is recommended that the additive should be subjected to
standard toxicological screening procedures described later even though
primary concern is for the combustion products. This is because it is
probable there will be direct contact with the product and it is conceivable
that some amount of additive might escape combustion.
6. It is essential to know effects of a new fuel or fuel addi-
tive on the level of well known pollutants (carbon monoxide, nitrogen
oxides, ozone, hydrocarbons) which are generated by irradiated or non-
irradiated auto exhaust. The Committee did recommend the study of the
biologic effects of such substances, since they already are the subject
of past and present toxicologic and medical investigations.
7. It was recognized that novel problems and novel fuels
(e.g., hydrogen, methane, methanol, etcc) might arise which would have
to be considered eventually but have not been included in this report.
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IV. ANALYTIC CHEMISTRY AND GENERATION OF EXHAUST EMISSIONS
Hundreds of compounds are present in the emission of fuel combustion,
and it is practically impossible to detect and measure each one for the pur-
poses of toxicologic experiments. However, by comparing the general pro-
files of exhaust components and specific classes of compounds from ex-
perimental fuels with those from standard fuels, it should be possible to
make sound decisions on the likelihood of changes in health effects as
well as the extent and type of toxicologic research needed.
a. Generation and irradiation of exhaust
The design of systems used for generating and controlling auto
exhaust for toxicologic studies have been described by Hinners e_t al. »
21,30 Since the raw exhaust is hot and contains lethal amounts of car-
bon monoxide, cooling and dilution are necessary before animals can be
exposed. Procedures for exhaust irradiation are necessary and have been
frequently described >21»5j because major increases in irritant effects
have been noted after irradiation of exhaust. Although experimental
atmospheres are reproducible some losses of particulates and condensation
occur so that it is difficult to duplicate the conditions as they occur
in outdoor atmospheres.
b. Purpose of analytic studies
Analytic studies are necessary for three purposes to: provide the
necessary profile of exhaust products so new and standard fuels and fuel
additives can be compared; monitor animal exposure, and help detect
possible changes in biologic effects and the need for other toxicologic
tests.
c. Analytic procedures
These procedures should include at least the analysis of carbon
monoxide, total hydrocarbons, oxidants, nitrogen, oxides. It also would
be valuable to have information on the nature of exhaust hydrocarbons,
olefins, and oxygenated compounds, polynuclear aromatics (PNA) content,
particulates and metals. The analytic procedures used in EPA animal
studies for characterization of exhaust systems have been described. '
Necessary equipment includes carbon monoxide recorders, gas chroma-
tographs, flame ionization spectroscopes, infrared and ultraviolet spec-
troscopes, filters and sizing equipment for particulates plus that re-
quired for various wet chemical methods.
Particle collection and analysis from auto exhaust is complicated--
particles tend to be wet and sticky, making it difficult to determine
their size and composition. >
Many analytic procedures that have already been worked out by
industry and EPA to study exhaust composition as effected by changes in
fuel and catalyst systems can be used in toxicologic procedures. For
example, the standard federal test procedures include methods for record-
10
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ing carbon monoxide, exhaust manifold pressure, carbon dioxide, nitrogen
oxide, oxygen, and total hydrocarbons. EPA regulations dealing with
methods and other matters were published under Title 40 in the
25 November 1971 Federal Register. Revisions appeared in Federal
Register for 28 June 1973 *' and 31 October 1973.18 However, because
human health effects as eye irritation may be related to the nature of
hydrocarbons and oxygenated compounds, it may be necessary to use
additional methods for studying these compounds such as those given by
Wigg ej^ a_l, Gross, and Heuss and Glasson. 27,29,62,63
The fate of the fuel additive in the combustion process should be
determined. To date, little work has been done on following radioactive
labeled components of fuels and fuel additives to their fate in exhaust,
probably because miniaturized systems for generating exhaust products
necessary for practical use of radioactive tracers are unavailable. If
such system were available the extent of combustion and the nature of
products generated from additives in fuel-lubricant system would be more
rapidly ascertainable.
The recent development of fuel injection systems may be an alterna-
tive to miniaturization. A fuel injection engine could be fitted with
two switchable injectors. One could provide standard fuel, the other
a fuel being tested. The resulting exhaust streams similarly could be
switched between collection bags, analytic systems, or exposure chambers.
The effect of the mode of engine operation on the exhaust would remain
constant.
d. Some relations between analytic data and biologic effects
One of the major uses of analytic data will be to point to
possible biologic effects that may need further study. At present, eye
irritation is not thought to result from ozone per se, but to oxygenated
compounds, or possibly nitro-olefins. Heuss and Glasson 29 studied the
relation between hydrocarbon structures formed by exhaust irradiation
and resulting human eye irritation. The benzylic hydrocarbons and
aromatic olefins were felt to be potent precursors of eye irritation.
Yeung and Phillips 66 aiso suggested that hydrocarbon structure and
reactivity might be predictive. Alarie !>2»3 has pointed out that
lachrymators and similar compounds are often in a category of strong
dienophiles. Perhaps the exhausts from fuels and fuel additives being
tested should be examined for the occurrence and any major changes in
such components. Polynuclear aromatics (polycyclic hydrocarbons) have
been isolated from exhaust and skin painting on mice has shown them to be
carcinogenic. Therefore, special attention should be paid to these
fractions.
There has been increasing recognition of the importance of the inter-
action of air pollutants either in the atmosphere or even possibly with-
in the lung itself. This phenomenon was discussed in a recent NAS con-
ference, 42 where evidence was reported showing that the combination of
ozone and sulfur dioxide would significantly increase the acute pulmonary
irritant effects in humans. The possibility of any increased formation of
sulfur compounds to acid sulfates in fuel and fuel additives should be in-
vestigated.
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V. RECOMMENDED APPROACHES FOR EVALUATING FUELS AND FUEL ADDITIVES
Based on previous discussions and the assumption that organic com-
ponents will be largely combusted, it is recommended that all new fuels
and fuel additives be evaluated initially in comparison with the standard
as follows:
1. Obtain acute toxicity data on the oral LDcQ, skin and eye irrita-
tion, skin sensitization, and an inhalation LC , (median lethal concentra-
tion) on the compounds before combustion and compare them with standard
materials.
2. Determine the acute and short-term LC,-g or LTrg (median lethal
time) by inhalation of the diluted exhaust, both before and after irradia-
tion and compare them with exhaust from standard fuel and clean air as a
control.
3. Determine eye irritation of exhaust before and after irradiation
and compare with standard fuel and with clean air as a control.
4. Evaluate the acute irritant effects of exhaust on the respiratory
system before and after irradiation and compare with standard fuel and with
clean air as a control.
5. Evaluate the odor potency and olfactory characteristics of exhaust
and compare with standard fuel exhaust.
6. Evaluate the exhaust analytic profile before and after irradiation
and compare with exhaust profiles of standard fuel.
The above methods should provide an initial evaluation of effects
on the eyes and respiratory tract as well as on the target organs most
clearly involved in the known human health effects of pollutants from
automotive exhaust.
Few problems should be encountered in developing acute toxicity infor-
mation such as the oral LD^g and skin and eye irritation with fuel additives
per se since standard methods should suffice. For acute inhalation of fuel
additives, some difficulties may be encountered if they are not volatile.
Aerosol techniques would be needed and it may be difficult to aerosolize
such materials.
Any proposed animal studies of eye irritation would require validation
with human experience. Not only has there been little correlation between
animal and human work, but the most pertinent information about eye irri-
tation caused by air pollution has come from human subjects. Hamming and
MacPhee evaluated the role of NOX in eye irritation. Panels of five
members were exposed through eye ports and a quantitative study was made
from the time of exposure to the first onset of irritation. The work of
Heuss and Glasson ^9 has been mentioned.
Using 16 chemicals and irradiated auto exhaust, Buchbert et al
evaluated the interaction of several atmospheric variables. Wilson and
Levy 64 were concerned with the role of sulfur dioxide in photochemical
aerosols in eye irritation from photochemical smog. Seven-member panels
were used and a determination made of the time of exposure to onset of
irritation. The above studies can be used as guides to the equipment and
procedures needed for development of a standard method for measuring human
eye irritation. Research is recommended for developing such methods and
correlating them with parallel animal studies. Determination of
12
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odor requires human subjects, and a considerable amount of basic informa-
tion is available on the measurement of odor potency. Leonardos et al
used an environment low in odor and evaporated measured liquid volumes of
pure chemical. Four experienced panel members were used for each test.
Only one test was performed per day on any subject. Such methods are
useful for determining the minimum identifiable odor under ideal circum-
stances. Rounds and Pearsall correlated diesel exhaust gas odor with
exhaust gas composition. 54 Fiala and Zerchmann 23 use(j a dilution
technique to determine the minimum identifiable odor. It seems feasible
to carry out odor studies in conjunction with eye irritation experiments
using the same generating equipment.
The Committee recognizes the difficulties in recommending the use
of human subjects for any type of toxicologic investigation. 14,49 HOW_
ever, little hazard is involved in this sort of study, because the ex-
posures are to relatively dilute materials for a few seconds or a few
minutes. Despite the innocuous nature of such studies, all customary
procedures and explanations to volunteers should be explained. These
studies should be under medical supervision and preceded by appropriate
animal experiments. It is possible that unusual irritant effects or
odors may be noted during the study of the effectiveness of new additives
or fuels. Any such events should be fully documented and noted. Attempts
should be made to document the presence or absence of adverse effects in
the synthesis, handling, or testing of any new fuels or additives.
Additional approaches needed for organometallics are discussed in
the following section.
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VI. AN OUTLINE OF PROPOSED EXPERIMENTAL ANIMAL PROCEDURES FOR
EVALUATING THE SAFETY OF FUELS AND FUEL ADDITIVES USED IN
INTERNAL COMBUSTION ENGINES.
The procedures are suggested for the initial evaluation of a new
fuel or a fuel additive. They are tentative and some have not previously
been applied for this purpose. The principal objectives are to detect
qualitative or quantitative differences between standard and new fuel-
additive systems before and after combustion and provide additional
assurance that unexpectedly toxic or irritating substances are not present
in effluents. Because of the tentative nature of the protocols, the
experimental design and selection of species should be extremely flexible.
Similarly, scientific judgment is needed to interpret the data. As ex-
perience is obtained, more precise methodology may be prescribed for
regulatory purposes. In the absence of such experience, the suggested
procedures are grouped according to their potential for quick inexpensive
reproducible results which can most reasonably be translated to man. From
these EPA should select those procedures for their applicability to the
nature of the product, volume of use, extent of distribution, and associ-
ated degree of public exposure. It should be noted that none of the
recommended procedures are without cost and for some the costs may be
significant. All data should be evaluated using appropriate statistical
methods.
a. Methods for evaluating the toxicity of fuels and fuel additives
before combustion
Group 1 - High Priority:
• Determine the oral LD5Q in 2 species preferably the rat and mouse
by following the procedures of the Federal Hazardous Substances Act and
NRG Publication 1138. 44
Problems may be encountered in finding suitable solvents or suspending
agents for such compounds and the toxicity of such solvents or vehicles
should be determined at the same time. Observe the animal for weight gain,
food intake, and signs of toxicity for 14 days after administering the
dose.
• Determine primary irritation and acute dermal toxicity with rabbit
skin in the manner described in the Federal Hazardous Substances Act. 44
For primary irritation and acute dermal toxicity, it would be useful
to have the additive dissolved in the same solvent used for its incorpora-
tion into fuel. Modifications in this technique will be needed if such
solvents cause too severe an irritation under an impervious cuff.
• Determine the eye irritation capacity in the rabbit eye using the
procedures in the Federal Hazardous Substances Act. 15,44
Although the validity of applying results from rabbit eye to predict
human eye irritation has been questioned, this method probably is useful
14
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for comparative purposes. It will be preferable if and when it is corre-
lated with human studies. Since the fuels and some fuel additives are
volatile compounds, it is desirable to have a suitable method for determin-
ing acute eye irritation from exposure to vapors. Perhaps a procedure
similar to Keplinger's ^2 couid be adopted for this purpose. Since the
procedure has not been published, it is presented in Appendix II. It will,
of course, need validation.
• Determine the acute inhalation toxicity in two species, preferably
and guinea pi]
Publication 1138.'
Group 2 - Intermediate Priority:
rat and guinea pig. by the inhalation procedures described in the NRG
• Determine skin sensitization using the guinea pig in a manner sim-
ilar to that described in NRG Publication 1138.44
Although strong skin sensitizers in the guinea pig are frequently
strong skin sensitizers in man, a negative result in the guinea pig does
not necessarily mean that the compound will be inactive in man. Human
patch tests are frequently used to confirm negative data in guinea pigs.
Based on the above animal data and any available information on
irritant or toxic effects in workers handling such compounds, fuels and
fuel additives could be classified as to skin or eye irritancy and
systemic toxicity by any route of administration, according to the scheme
used in NAS-NRC Publication 1465, January 1974 Revision.43 Some modifica-
tions may be needed to adapt the scheme to fuels and fuel additives. This
rating system is outlined in Appendix V. The rating system of Hodge and
Sterner 31 may also be useful.
b. Methods for evaluating the safety of combustion products of fuels
and fuel additives
The principal objective is to determine the qualitative or quantita-
tive differences between the standard fuel and new fuel or fuel additive.
Such studies are considerably more complex than those dealing with ad-
ditives per se, because of the elaborate equipment and controls needed for
generation and analysis of the combustion products. Interpretation of
results may not always be precise.
The test vehicle and chassis dynamometer should be operated according
to federal test procedures. Provision should be made for control air
purification and for cooling and dilution of the exhaust. Appropriate
size and type of exposure chambers will be needed. (See also Section IV).
Hinners et al. 12,21,30 have described methods used for producing and
irradiating automobile exhaust in connection with the EPA animal studies.
Group 1 - High Priority:
• Pulmonary irritation
15
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Evaluate the acute respiratory irritant effects in guinea pigs using
techniques of Murphy and Ulrich, ^ or Amdur and Mead,^ or in mice by the
method of Alarie. 1>2,3
The purpose of these studies is to determine the irritant effects on
either the upper or the lower respiratory tract by measuring respiratory
flow rates, respiratory frequency, tidal volume, and compliance. The
principles used are those developed by Amdur and Mead. -> Murphy and
Ulrich 41 modified their technique to permit the use of several animals
at a time although at the expense of losing the compliance data. They
also eliminated the need for inserting intrapleural catheters, and the
animals can be exposed repeatedly as well. Experience may show that
measurement of respiratory functions in other species will be equally
useful.
Exposures should be about 4-6 hours to at least three concentrations.
In general, irritants tending to affect the upper respiratory tract will
cause flow resistance to increase and frequency of respiration to decrease.
Irritants such as ozone and nitrogen dioxide which affect the lower res-
piratory tracts, may not affect flow resistance much, but they will cause
a delayed increase in frequency of respiration. Direct measurements show
compliance 5 decreases with irritants affecting the lower respiratory
tract. In the guinea pig exposure periods of at least an hour appear to
be needed to reach a plateau for upper respiratory irritants, and 3-4 hrs
for lower tract responses. The percent change in response from control
is plotted against concentration of oxidants, nitrogen dioxide, or total
aldehydes to determine the 50% change from control values.
123
Alarie ' » has described methods for evaluating sensory irritant
effects on the respiratory tract by measuring respiratory frequency in
mice exposed for 3 min. to relatively concentrated vapors of pure sub-
stances. His procedure has not been applied to whole automotive exhaust
products, but it may be a relatively simple method of detecting upper or
lower respiratory tract irritants in automotive exhaust. The short dura-
tion of exposure would allow relatively high concentrations of exhaust to
be used without encountering significant toxic effects from carbon monoxide.
Concentration is plotted against percent change in response relative to
control values. Both these methods should be validated by interlaboratory
studies using the most identical exposure conditions possible. The
following three other published procedures may be helpful in evaluating
acute pulmonary effects if results from previously described studies are
conflicting or doubtful. They provide different indicators of pulmonary
responses:
i. One of the characteristic effects of irritants affecting the
lower respiratory tract is protein leakage into the alveolar spaces. This
effect has been studied by measuring the wet weight of the lung, and by re-
covering iodinated albumen from the alveolar spaces 6 hr after its intra-
venous injection into exposed rats. Such techniques could be applied to
rats exposed to exhaust before and after irradiation. Alpert e_t al.^
applied this method to ozone. Six-hr exposures to ozone at levels as low
as 0.5 ppm showed significantly increased quantities of radioactivity in
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the lavage fluid. Lung wet weight measurements were somewhat less sensi-
tive, showing effects at 2.5 ppm ozone. Lung lavage and dis-gel electro-
phoresis have also been used to study effects of nitrogen dioxide. 59
ii. Lately, attention has been paid to the role of alveolar macro-
phages in removing particles and some infectious agents (such as bacteria)
from the respiratory tract. 9,10 Effects appear relatively rapidly and
are capable of some quantitation. Injections of the living bacterial
organisms such as staphylococcus aureus permit the functional activity
of macrophages to be evaluated; by sacrificing the animals after a short
time for phagocytosis of organisms, homogenization of the excised lung,
and counting the viable and nonviable organisms recovered from the homo-
genate. 26 Brain 9,10 has also given details of techniques for measuring
the number of alveolar macrophages and certain functional parameters after
intratracheal injection of particles.
iii. The technique of evaluating the clearance mechanisms of the
lungs by inhalation of inert particles such as titanium dioxide (Ti02)
after exposure to irritants has recently been explored in many laboratories.
In this type of experiment, rats are exposed to varying concentrations of
irritant gases for approximately 7 hr/day, 5 day/wk for about 70-170 hr.
At the end of that period, the animals are exposed for 7 hr to a respir-
able size titanium oxide aerosol at a concentration of ISjig/nP. Compar-
able doses of titanium oxide are given to controls and the total lung
content of retained titanium oxide in individual rats determined chemically.
One-hundred seventy hours exposure to sulfur dioxide at as low as 1 ppm
was concluded to have caused a depression of the rate of lung clearance of
titanium oxide.22
• Eye irritation
Keplinger's technique 32 as described in Appendix II uses a relative-
ly short exposure of 60 seconds. It is probable that a longer exposure
would be needed for diluted auto exhaust. Irradiated exhaust should be
the focus of research because human data indicate that it is the primary
source of human eye irritation. The effect of condensates from irradiated
auto exhaust applied directly to the rabbit eye and scored by the Draize
method 15 has not been studied much. Freeze-out or filtrate samples
applied to the rabbit eye at intervals after irradiation might provide an
index of irritancy.
28
Hamming and McPhee have provided basic information on sensory
effects of pollutants on the human eye. The exposures were extremely
short — less than 4 min--and the sensory irritant effect was rapidly re-
versible. Eye ports in the irradiation chambers were provided for panels
of five members and the time to onset of sensory irritation was noted.
The geometric mean of the number of seconds to initial detection of the
irritation was calculated for members of the panel. Animal studies need
to be correlated with human data to make future extrapolations and pre-
dictions more meaningful.
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• Odor determination
Brief exploratory experiments have been done to date, mostly with
diesel exhaust. The techniques for odor threshold determination of
chemicals used by Leonardos e_t aJL.^7 should be applicable to auto exhaust.
The exposure time for recognizing odor at varying concentrations of exhaust
would be very short. Sampling ports and air dilution facilities would be
needed. It is best to use trained subjects who have demonstrated an
ability to distinguish odors critically.
Group 2 - Intermediate Priority.
• Using irradiated and non-irradiated exhaust with at least 3
dilutions each, determine an approximate LC5Q for a 4-6 hr exposure with
groups of 10 male rats and 10 male guinea pigs for each exposure.
Determining an 1/159 may also be useful. 21
Observation should include analysis of blood carboxyhemoglobin at the
end of the exposure, observations of survivors for 14 days, and measure-
ment of weight loss or gain, behavior and food intake. The purposes of
the study would be to discover any acute toxic effects other than those
expected from carbon monoxide, to provide a background for other studies
on pulmonary effects, and determine needed dilution levels for such
experiments. For example, it is known that guinea pigs can tolerate
about 500 ppm carbon monoxide for 4 hr with little or no effect on their
respiratory function. ^° More inhalation bioassays are needed to determine
optimal conditions and species.
Perform repeated 4-6 hr studies with rats and guinea pigs at the
maximum tolerated concentration noted in single dose studies and at one-
fifth of the maximum tolerated concentration in exposures repeated daily,
5 day/wk for at least 2 wk. Autopsies should include measurement of blood
carboxyhemoglobin; weights of lung, liver, and kidneys histologic examina-
tion of selected tissues. Depending on the nature of the fuels or fuel
additives and of analytic data on exhaust products, longer and more complex
pathologic studies may be required of other organ systems (hematologic,
central nervous system, renal). Various biochemical indicators of response
and tissue analyses may prove useful.
c. Evaluating hazards of metal-containing additives
Group 3 - Low Priority:
No specific methods are suggested because extensive research and
long-term studies are necessary to evaluate hazards. Determining the
chemical form of the metal in the exhaust, and its particle size and
other characteristics will be important for predicting the hazard. Special
attention should be given to the presence of metal carbonyl compounds.
Recent NAS publications on lead ^5 and manganese ^ review pertinent
literature. Metals tend to persist in the environment after combustion
and may enter the food chain. 2^ They also may enter the body by inhala-
tion and some are skin sensitizers. Some may interact with essential
18
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trace metals. A number of metals also tend to persist in the body;
therefore, acquiring data on their absorption, excretion and biological
half-times is important.
The report of the task group on metal accumulation of the Permanent
Commission and International Association on Occupational Health -*2 pro-
vides a comprehensive discussion on evaluating this aspect of metal toxicity.
The 1972 annual report of EPA's Environmental Toxicology Research Laboratory
gives several examples of preliminary screening examinations for
evaluating metal toxicity.
Much information is already available on many metals that could be
used in preliminary evaluations. For some metals (such as lead), it is
possible to find the critical organ concentration, and make extrapolations
from it on the likelihood of health hazards from environmental contamina-
tion. 5^ Many metals can be neutron-activated to facilitate study of
their metabolic fate, but their use in combustion product toxicology will
be limited unless the combustion process can be greatly miniaturized.
However, modern analytic techniques can determine many metals with
sufficient precision and specificity without tagging.
d. Carcinogenesis, mutagenesis and teratogenesis
Group 3 - Low Priority:
As mentioned, evidence for the occurance of these effects in humans
in relation to air pollution is considerably more uncertain than those
related to primary irritation. Attempts to induce lung cancer in animals
by direct inhalation of air pollutants have generally been unsuccessful
and experimenters have resorted to direct implantation techniques or
intratracheal injections as well as the use of adjuvants such as iron
oxide or carbon particles. 55 Only a few chemical agents, e.g., bis-
chloromethyl ether and vinyl chloride, have shown pulmonary and systemic
carcinogenic effects when inhaled. 35,39,57,61 skin painting techniques
in mice using particulate fractions from auto or aircraft engine exhausts
have shown carcinogenic activity. 33,34,47,58,65 From the literature, it
is expected that skin painting with appropriate particulate fractions
would be the most probable choice for a useful comparative bioassay.
Intratracheal techniques may also prove useful, but measuring quantitative
or relative potency of carcinogens is much more difficult than that of
systemic toxicity or relative irritancy. It is unknown whether any
techniques lend themselves to a reliable extrapolation to human carcino-
genesis of combustion or exhaust products as naturally encountered. If
carcinogenicity tests are conducted the data should be considered as
research information rather than being used for regulatory purposes with-
out confirmation.
Useful guides have been written to the study of mutagenesis, terato-
genesis, and carcinogenesis. 13,50,60 Some variation of the dominant
lethal test exposing male rats or mice to inhalation at several dose
levels might offer promise of a useful bioassay, but considerable valida-
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tion would be necessary before specific recommendations could be made.
Pregnant rats have been exposed to varying doses by inhalation at appro-
priate times to elicit potential teratogenic effects, but no recommenda-
tions can be made on the usefulness of this approach for automotive exhaust,
High concentrations of certain solvents have been shown to have potential
toxic effects on both embryo and fetus.
e. Behavior studies
Group 3 - Low Priority:
No recommendations are made at this time because the usefulness of
such studies as comparative bioassays for auto exhaust has not been deter-
mined. However, EPA exploratory research 21,25 appears to indicate that
simple wheel running activity in rats is depressed considerably during
exposure to auto exhaust; it is apparently not caused by carbon monoxide
although other gaseous components or irritants may be involved. The
depression disappears upon cessation of exposure. Water licking of rats
was also depressed, but it was complicated by a simultaneous weight loss.
Studies of spontaneous motor activity might lead to development of a
comparative bioassay for acute effects, although the mechanism may be a
nonspecific, protective response to exposure to irritant gases or other
components. Again, complex animal behaviors need to be correlated to human
activities. It is suggested that EPA monitor the progress of this develop-
ing field for additional methods.
f. Summary comment
Tests suggested for use with the fuels, additives, or their combustion
products in the Group 1 High Priority category should be considered
minimum tests to be applied to all candidate materials. Those in the
Group 2 Intermediate category may provide data to supplement the findings
of Group 1 procedures.
Those tests in the Group 3 Low Priority category are generally
expensive--about $50,000 to $100,000--and their application to man is
controversial. In addition, the sensitivity and reproducibility of these
procedures is in question. In view of these factors and the low levels of
exposures of the public this group of procedures will probably be of use
only for materials in high volume use with wide distribution, resulting
in widespread exposures.
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VII. CRITERIA FOR EVALUATING HEALTH HAZARDS
The following recommendations for evaluating human health hazards
from the proposed analytic and toxicologic studies should be regarded as
tentative until sufficient experience is acquired in the use of new
procedures.
Before commencing any analytic or toxicologic studies, a thorough
search should be made of the published literature and available unpublished
reports. Some compounds may be rejected at once for toxicologic reasons,
e.g., highly toxic metals such as mercury, thallium, etc. A special
effort should be made to document any observations on occupational hazards
in the course of synthesis or handling of compounds. It is also assumed
that comparative data will be available on the extent of use, and that
methods for determining appropriate compounds will be available in the
gaseous and particulate phase of the qxhaust.
The proposed scheme for evaluating health hazards from the combustion
products of a new fuel-lubricant system consists of a combined, comparison
of the analytic and toxicologic profiles of an appropriate standard system
with those of a candidate new system. The simpler toxicologic studies can
proceed independently of the analytic determinations; however, an evalua-
tion of the nature and amount of some selected exhaust components will
usually precede the more complex toxicologic studies. Some analytic
methods will be required for monitoring exposures of animals. Important
considerations in evaluating health hazards follow.
a. Analytic data
1. The most important comparisons will be those of the type and amount
of selected components between standard and test materials and before and
after irradiation. It is possible for a given component to make up a
relatively larger proportion of the pre-irradiated exhaust and ultimately
to become lower in concentration, depending on precursors or rates of
reaction, for examples, a change in profile with a shift toward oxygenated
materials, aromatic olefins or benzylic hydrocarbons might indicate the
possibility of new types of primary irritants. Primary irritant responses
often have steep dose-response curves; therefore, precise determinations
of concentrations encountered by the exposed animals are important.
2. Changes in the typical temporal course of the appearance and
die-away curves of major oxidant components such as nitrogen dioxide and
ozone might reveal changes in probable biologic effects, which in turn
would suggest appropriate biologic studies.
3. Increases in total concentrations of nitrogen dioxide, oxidants,
nitro-olefins or nitrated peroxy compounds, dienophils or other structures
typical of lachrymators or pulmonary irritants are undesirable and would
require primary irritation studies.
4. Increases in polycyclic aromatic fractions or changes in their
type might lead to consideration of comparative carcinogenic tests such
as skin painting in mice.
21
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5. For stable organic additives or those having relatively imcomplete
combustion more thorough and long-term studies on the inhalation toxicology
of the additive per se, would be indicated. It is desirable to know the
chemical fate of an additive—whether it was present in the exhaust in
gaseous or vapor form, particulate phase, or ash. Knowing the size and
physicochemical behavior of particles would be helpful when considering
the probability of particles being retained in the lung. This knowledge
will help identify the toxicity test procedures and observations.
6. In the case of organometallic compounds, determinating the amounts
present in the exhaust and their persistence in the atmosphere are essen-
tial, as many organometallics have different toxicity than the metal or
its inorganic compounds. ^
7. Present knowledge is inadequate for evaluating the hazard of a
component in fuels, fuel additives, or their combustion products based
upon its class of organic compound. Toxicity varies widely within classes.
b. Toxicologic data
1. Data from studies of additives or novel fuels per se should allow
judgments as to the type and potency of acute toxic effects when compared
to standard materials. Judgments should not be difficult, because the
techniques used are well known and permit classification. More extensive
studies may be needed if no combustion occurs. Observation of new types
of toxic effects not seen with standard materials or the detection of
significantly delayed responses might also require additional work. The
data will be particularly useful for evaluating occupational hazards and
making some initial judgments of public hazards if the substance is
found unchanged in the exhaust. The estimation of hazard demands a
knowledge of exposure levels as well as the type of response and potency
of the compound.
2. Interpreting post-combustion toxicity data requires especially
careful comparison with data on standard systems and with analytic data.
If procedures must be chosen, post-irradiation data are probably more
significant, based on the literature. Certainly any definite increases
in eye irritation, especially if confirmed in humans, would be an adverse
finding. Such tests are conducted under exaggerated conditions, and
might, if other factors warranted, be repeated under less severe or more
normal circumstances. The same would apply to odor potency or unpleasantness.
Clearcut evidence of comparatively increased primary irritant effects
on the upper or lower respiratory tract in pulmonary ventilation studies
would imply that clearance studies and explorations of effects on
phagocytosis be undertaken.
Alveolar protein leakage could be evaluated if evidence were ob-
tained of lower respiratory irritation or increases in lung weight.
Consistent reporting of increased pulmonary tract irritation at lower
than standard concentrations would suggest an increased hazard.
22
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3. Metals present particularly difficult problems in interpretation.
The critical organ concentration concept provides a useful approach in
some cases, but it requires extensive and usually unavailable metabolic
and toxicologic data. Possible interference of metal contaminants with
essential trace metals should be considered, the environmental pathways
of metals, which may be sources of food and water for humans and animals,
must also be considered.
4. Interpreting carcinogenic studies is also difficult; more data
are needed to show that dose-response curves can be reliably repeated for
comparisons. Further experimental and epidemiologic research on carcino-
genesis and mutagenesis is needed. Analytic evidence of exhaust com-
ponents closely related chemically to known carcinogens would require
comprehensive toxicologic evaluation.
5. Classification of effects
Since the approach suggested is to compare new and standard conditions,
a simple classification of increase, decrease or no effect in analytic and
toxicologic parameters would be useful in an initial scrutiny of data. A
further grading of slight, moderate or marked increases or decreases could
be made if warranted by studies on the reliability and reproducibility of
data. For instance, an oversimplified evaluation is explained below.
Analytic Data Toxicity of Exhaust
CO Eye irritation )
HC Odor ) Indication of
NOX plus Pulmonary irritation ) equals Relative Hazard
03 Inhalation toxicity )
Oxidants
Polynuclear Aromatics
Aldehydes
Metals
Particulates
The test material would be rejected or studied further if either its
analytic or toxicity data showed significant increases beyond those of
the standard. If these data were the same or less than the standard the
material would be accepted.
As declared, it will be necessary to consider all available
information, as no routine hierarchy of test procedures is completely
reliable. There is no substitute for the informed judgment of scien-
tists at present.
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.VIIL DATA COLLECTION. STORAGE, AND RETRIEVAL SYSTEMS
It is important that EPA have an available system for collecting,
storing and retrieving data on the safety of fuels, fuel additives, and
their combustion products. The system need not be automated, because the
total number of materials involved is not large. Such a system should
be capable of rapid up-dating, easy expansion (preferably open-ended),
and should include multiple indexing and cross-indexing to permit several
entries. Besides the mechanics of automatic or manual data processing,
professional capability for organizing the data and performing preliminary
evaluations and interpretations is necessary.
The nucleus of this kind of system may exist in several places. A
comprehensive study has not been made, but among those known to the
Committee, the most promising organizations are:
Advisory Center on Toxicology
National Academy of Sciences
2101 Constitution Avenue
Washington, B.C. 20418
Air Pollution Technical Information
Center
Environmental Protection Agency
Research Triangle Park, N.C. 27711
BioSciences Information Services
2100 Arch Street
Philadelphia, Pa. 19103
Technical Information Services
Branch
National Institute of Occupational
Safety and Health
P. 0. Building
5th and Walnut
Cincinnati, Ohio 45202
Specialized Information Services
National Library of Medicine
8600 Rockville Pike
Bethesda, Md. 20014
Toxicology Information Response
Center
Oak Ridge National Laboratory
P. 0. Box Y
Oak Ridge, Tenn. 37830
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IX. RECOMMENDATIONS FOR RESEARCH
Throughout this report, the Committee has repeatedly pointed out the
need for further research, especially in the area of combustion product
toxicology. It should not be difficult to evaluate fuel additives or
new types of fuel per se^ before combustion, since traditional toxicologic
procedures can be adapted to these needs easily.
Present difficulties in the conduct of toxicologic studies on com-
bustion products lie not only in the massive outlays for equipment and
personnel needed to plan, analyze and control the facilities for proper
generation and irradiation of combusted products, but also in the lack
of clearcut knowledge about human responses to air pollutants in relation
to any specific categories of substances. Now it appears that.adverse
health effects may arise not only from single isolated pollutants, but
from mixtures and complex chemical reaction products and from physico-
chemical and biologic interactions among the pollutants. (See Appendix VI)
The greatest research needs are listed below.
a. Analytic methods
Despite extensive research and much available knowledge, we are
still not able to determine the material or class of materials res-
ponsible for eye irritation, one of the major symptoms related to
automotive exhaust. Research needs to be continued to detect and measure
materials in the class of known lachrymators and test them individually
to see whether they are actually responsible or if their effects are
additive. Little is known now about the fate of the organic fuel additive
molecules, although it is presumed that most are more or less completely
combusted. Research needs to be continued on the generation and fate of
complex reaction products, which should be studied not only in smog
chambers, but in actual atmospheric situations.
b. Miniaturization of the combustion process
The Committee believes that miniature engines or combustion processes
to facilitate toxicologic research should be developed. At present, the
massive equipment such as V8 automotive engines are satisfactory for
functional and technical studies. However, they are awkward and impracti-
cal for general toxicologic investigation of such materials as the toxi-
cology of 'combusted fuel additives, especially in the early phases of
screening new additives for potential toxicity, when ideally only rela-
tively small exposure chambers are used. It is possible that engines
burning fuel on a steady state rather than in a batch process could be
used, but such equipment would need to be tested thoroughly to determine
the analytic profile of the exhaust products.
Miniaturization would also make it possible to use radioactive
tracers or stable isotopes to study the fate of fuel additives, metals,
and components of new fuels. Irradiation of exhaust products would be
much simpler with smaller equipment. Perhaps the serious losses of
material that now occur when automotive engine exhaust is conducted
25
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through the irradiation chamber to the animal exposure chambers could be
minimized. It might be worthwhile to try a fuel injection engine modified
for switching from a standard to a test fuel and which could separate
exhausts.
c. Eye irritation
Useful experiments with eye irritation in animals exposed to whole
exhaust are limited, because most species simply close their eyes and
nictitating membranes to avoid contact with the suspected irritant.
Proposed techniques for studying fuels and fuel additives have not yet
been validated, and it seems unlikely that we will know whether such
techniques are useful for predicting human eye irritation unless human
volunteers are observed. Although there are problems in the use of
human volunteers, the hazard in this case is minimal because of the very
short exposure times needed and because past experience with human
volunteers has shown that very successful research can be carried out
with eye ports in standard smog chambers. Similar reasoning applies to
the determination of odor, which can only be measured with human subjects.^**
d. Use of condensates and filtrates
These substances are potentially useful because experimental conditions
can be very much simpler than those in which animals are exposed to full
exhaust. However, with the exception of painting mouse skin for carcino-
genesis studies, few measurements and bioassays of the irritant or other
toxic effects of condensates on the eye, the skin, and by intratracheal
injection have been reported. Little data appear to be available on the
toxicity of such condensates, and systematic exploration might be useful
for purposes of comparative bioassay although direct extrapolation to
human health might be difficult or impossible. Methods for collecting
condensates would have to be carefully studied and the difficulties in
reproducing condensates would have to be minimized by attention to proce-
dures and proper analytic studies, including interlaboratory collaborative
tests. The relation between data from condensates and data from actual
exposure to emissions would have to be established.
e. Interactions of irradiated exhaust effluent compounds with sulfur
dioxide or other materials
The interactions between ozone and sulfur dioxide may greatly increase
the toxic effect, probably because sulfuric acid and acid sulfate aerosols
are formed. After irradiation, it is conceivable that a fuel additive or
a new fuel might produce a different type of oxidant mix in the atmosphere.
Therefore, such interactions should be explored whenever major changes are
made in fuels or fuel additives. The existence of interactions could be
ascertained by analytic methods and pulmonary function tests.
f. Epidemiology
Epidemiology is not of particular interest to this report, but
epidemiologic studies should be continued and improved. ^2 Some suspected
adverse effects attributed to one or another of the chemical air pollutants
26
-------
may have been caused not only by primary pollutants themselves, but with
other as yet unknown and unidentified reaction products generated in the
atmosphere or within the lung itself. If major changes are made in fuel
additives or types of fuel, it would be desirable (although obviously
difficult) to prepare for epidemiologic studies carried out over long
periods of time and in diverse communities to determine whether trend
exists in the occurrence of disease that might be related to such sources.
g. Validation
Several suggested procedures have not been subjected to scientific
peer review. Others have not been replicated in other laboratories. It
is important that any procedure adopted for screening purposes or regula-
tory action should be thoroughly validated for its sensitivity, repro-
ducibility and, if possible, its correlation with human effects.
h. Occupational exposures
Manufactures of fuels, lubricants, and additives should be encouraged
to collect data on levels of occupational exposures to such products and
the associated effects (if any). Such data should be made available for
use in evaluating the environmental effects of a product. EPA should
explore ways of obtaining these pertinent occupational exposure data from
NIOSH and OSHA.
27
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26.. Green, G.M., and Kass, E.H. Mechanisms of resistance to bacterial
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auto exhaust to eye irritation - further results of chamber studies.
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29. Heuss, J.M., and Glasson, W.A. Hydrocarbon reactivity and eye
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30. Hinners, R.G. Engineering the chronic exposure of animals to
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31. Hodge, H.C., and Sterner, J. H. Tabulation of toxicity classes.
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32. Keplinger, M.L. Personal communication.
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34. Kotin, P., Falk, H.L., and Thomas, M. Aromatic hydrocarbons. III.
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35. Laskin, S., Kuschner, M., Drew, R.T., Cappiello, V.P., and Nelson, N.
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36. Lee, R.E., Jr., Patterson, R.K., Crider, W.L., and Wagman, J.
Concentration and particle size distribution of particulate
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38. Lewis, T.R., Moorman, W.J., Yang, Y.-Y., and Stara, J.F. Long term
exposure to auto exhaust and other pollutant mixtures: Effects
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29:102-106, 1974.
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39. Maltoni, C., and Lefemine, G. Carcinogenicity bioassays of vinyl
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Food Chemicals, Proceedings of a Conference. NAS Publ. No. 1491
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56. Schwetz, B.A., Leong, B.K.J., and Gehring, P.J. Embryo- and feto-toxi-
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57. Selikoff, I.J., and Hammond, E.G., eds. Toxicity of vinyl chloride-
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of guinea pigs exposed to 0.4 ppm nitrogen dioxide. Arch.Environ.
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32
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61. Viola, P.L., Bigotti, A., and Caputo, A. Oncogenic response of rat
skin, lungs, and bones to vinyl chloride. Cancer Res. 31:516-522,
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62. Wigg, E.E. Fuel exhaust compositional relationships in current and
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hydrocarbon composition on exhaust hydrocarbon and oxygenate
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64. Wilson, W.E., Jr., Levy, A., and McDonald, E.H. Role of SC>2 and
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Environ.Sci.Technol. 6:423-427, 1972.
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33
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APPENDIX I
POINTS OF POTENTIAL SOURCES OF POLLUTION
FOR ENVIRONMENTAL HAZARDS
Potential Hazards
for public
Evaporative Losses
Potential Hazards
for workers & public
AUTO GAS TANK
Carburetion
Aerosol and Vapor
*
ENGINE
COMBUSTION
Blow-by
LUBRICATION
Potential Hazard
for Environment
from waste
FUEL SUPPLY SYSTEM
Gasoline Refining
Additive Manufacture
Blending
Distribution (spills)
1
i
SOLAR
RADIATION
Primary
Public and
Environmental
Hazard
34
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APPENDIX II
PROTOCOL FOR EYE IRRITATION TEST (VAPOR) IN ALBINO RABBITS*
Six albino rabbits of the New Zealand strain are used to evaluate the
eye-irritating properties of the test material vapors. Air is allowed to
circulate through the test material at a rate of 3.0 1/min. The vapor
mixture is then allowed to pass over the right eye of each rabbit through
a small funnel for a period of 60 sec. The funnel channels the vapor
mixture over the eye and helps keep the eye open. The average nominal
concentration will be calculated by dividing the weight loss of the test
material by the total volume of air circulated during the period of ex-
posure. Such calculations should be checked by analytic measurements
if possible.
One, 2, 4, 24, and 72 hr, and 7 days following contact, the cornea,
iris and palpebral conjunctiva will be examined and graded for irritation
and injury according to a standard scoring system. l->
It is recommended that the foregoing procedure be validated by an
interlaboratory "round-robin" study.
*The Committee expresses its appreciation to Dr. Keplinger for
making this unpublished procedure available.
35
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APPENDIX III
COMPOSITION OF FUEL ADDITIVES
About 325 commercial fuel additives had been registered up to
31 December 1972. The additives fall into several functional classes,
such as anti-knock compounds, antioxidants, surfactants, and deposit
modifiers. Anti-knock compounds contain materials such as tetraethyl lead;
the antioxidants are made up of hindered phenols, phenylenediamines, and
metal deactivators; the surfactants contain various aliphatic amines,
carboxylates, amine carboxylates, and amine phosphates and the deposit
modifiers include shortchain halogenated hydrocarbons. Other functional
classes are also listed. 20 Anti-knock compounds and smoke suppressants
are discussed in recent NAS reports on lead and manganese. 45,4b ^hus the
relatively large number of commercial fuel additives fall into a relatively
small number of basic chemical types. Information provided by the EPA
indicates that fuel additives can be divided into about fifteen chemical
classes, set forth in the first table. This table also shows the relative
frequency of use of each chemical class. The second table lists the fuel
concentrations of antioxidants, surfactants, and deposit modifiers.
Chemical Classes and Relative Usage Indices
Number of Number of Additives
Compounds in Each Containing a Compound
Chemical Class Chemical Class From Each Chemical Class
Lead Compounds 6 95
Alkyl Halides 2 79
Azo Naphthols 22 67
Amines 20 42
Aromatics 5 33
Phenylenediamines 10 32
Alkyl Polyamines 10 30
Alcohols 4 29
Phenols 10 29
Aromatic Phosphates 7 26
Alkyl Phosphates 11 23
Anthroquinones 10 22
Azo Compounds 7 16
Naphthalenes 8 11
Trace Substances 7 10
36
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APPENDIX III (cont'd)
Fuel Additives - Composition, Concentration and Usage of Antioxidants,
Surfactants, and Deposit Modifiers
Antioxidants
Concentration in Fuel ppm
5-20
5-20
Type
Hindered phenols
*Phenylene diamines
Metal deactivators
Type
Amines
R-NH2
R-aliphatic
N-may be primary,
secondary or
tertiary
Carboxylates
RCOQ-
R"C16 - 18
Amine carboxylates
R-C16 - 18
RCOO NH3R'
Amine phosphates
Use
Prevent peroxides
Type
Alkyl halides
C1CH2-CH2 Cl
BrCH2-CH2 Br
Prevent peroxides
Prevent polymerization
Chelates copper
Surfactants
Use
Detergent
1-10
Concentration in Fuel ppm
40-300
Deicing -
Not necessary with
air preheaters
Anti-rust
Improve fuel distribution
Deposit Modifiers
Use
40-150
5-20
40-150
Concentration in Fuel ppm
1 atom Cl) afcom pb
^ atom Br)
* The antioxidants and surfactants are all relatively nonvolatile or-
ganic compounds thought to be largely combusted. The various aromatic and
aliphatic amines probably undergo more complete combustion than those con-
taining only hydrocarbons.
37
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APPENDIX IV
COMPOSITION OF FUELS
The following tables list the ranges of physical properties and com-
position for motor gasolines and diesel fuel. The data were acquired in
private communications from Bureau of Mines surveys and Exxon Research and
Engineering.
Motor Gasoline
A. Vapor Pressure Summer Winter
Aver, range Aver, range
1. Reid vapor pressure,
(psig @ 100°F) 9 (7-11) 12 (9-15)
2. Distillation curve, ASTM
50% 200-220°F 170-250
90% 310-350°F 310-374
Final boiling point <\, 400°F 395-437
B. Composition
1. Hydrocarbon class*, average % by volume (range)
Premium (100 RON) Regular (94 RON)
Summer Winter Summer Winter
Aromatics 29 (23-36) 34 (26-40) 25 (19-30) 31 (22-40)
Olefins 7 (3-10) 7 (1-14) 7 (2-14) 9 (3-20)
Saturates 64 (54-74) 59 (48-66) 68 (64-76) 60 (51-64)
2. Lead content 2.4-2.7 g Pb/gal
3. Carbon no. range = 4-11
4. Polynuclear aromatics, as benz(a)pyrene 2r 0.3 - 0.4 ppm
5. Sulfur is known to be present but quantitative data were not avail-
able to the Committee.
* Northeastern U. S. compositions
38
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APPENDIX IV (cont'd)
Diesel Fuel
Minimum
Maximum
144
-40
-20
Aver.
498°F
579°F
626°F
Range
456-533
536-628
582-698
194
15
24
A. Properties
1. Flash point, °F
2. Pour point, °F
3. Cloud point, °F
4. Distillation curve, ASTM
50%
90%
Final boiling point
B. Composition
1. Hydrocarbon class*, average % by volume
(alkylbenzenes, 2-3 ring aromatics)
(n-Paraffins cycloalkanes)
2. Carbon no. range =10-19
3. Polynuclear aromatics, as benz (a) pyrenej^ 0.03 ppm
4. Information on sulfur content was not available to the Committee.
* Northeastern U. S. compositions
Aromatics
Olefins
Saturates
35
1-2
64
39
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APPENDIX V
EXAMPLES OF THE CLASSIFICATION SCHEME AND RATINGS
The toxicity hazard rating system presented here is adapted from one
recommended by the Committee on Toxicology of the NRG to the U. S. Coast
Guard. It is based upon absolute determinations of acute toxicity rather
than upon a relative rating such as proposed in this report for auto ex-
hausts. This scheme may be useful for describing the toxicity hazards
associated with uncombusted fuels and fuel additives. Relatively brief,
isolated exposures are assumed.
Outline of Rating System
Grade
0
1
2
Vapor Irritants
No effect
Slight effect
Moderate irritation;
temporary effect
Irritating; cannot
be tolerated
Liquid or Solid
Irritants
No effect
Poisons
No effect
Causes skin smarting Slightly toxic
First-degree burns,
short exposure
Second-degree burns,
few minutes exposure
Severe effect; may do Second-degree and
permanent injury third-degree burns
Intermediate
toxicity
Moderately
toxic
Severely toxic
a. Vapor irritants
The hazard rated here is that presented by chemicals which are gases,
or which emit vapors or fogs irritating to the skin or the mucous membranes
of the eyes, nose, throat, and lungs. The grade assigned is based on the
likelihood of developing injury including a consideration of volatility and
injurious concentrations and the severity and permanence of that injury.
This hazard is based on the effect of exposure to vapors or fumes
evolved from the chemical, and not to splashes of the liquid itself. A
nonvolatile chemical with a low rating may still cause severe damage if
splashed into the eyes, and is rated accordingly as a liquid or solid
irritant. This rating does not include the potential hazard of suffocation
because of displaced air as might be encountered in a confined space.
Grade 0 Nonvolatile materials or vapors which are not irritating to
the eyes and throat.
Grade 1 Materials that cause a slight smarting of the eyes or res-
piratory system if present in high concentrations.
Grade 2 Materials with vapors that cause moderate irritation, such
that humans will find high concentrations unpleasant. The
effect is temporary.
40
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APPENDIX V (cont'd)
Grade 3 Moderately irritating volatile materials, such that humans
will not usually tolerate moderate or high vapor concentra-
tions.
Grade 4 Severe eye or throat irritants, vapors which are capable of
causing eye or lung injury, and which are Intolerable even
at low concentrations.
b. Liquid or solid irritants
Materials in this category are rated with regard to their tendency
to chemically burn or irritate human skin from contact in the liquid or
solid state. Substances that burn the skin are usually very severe in
their effect on the eyes. Hence materials given a high rating in this
column will usually be painful and injurious if splashed into the eyes.
In most cases, volatile materials that evaporate rapidly are less hazar-
dous than less volatile ones that remain in clothing or on the skin. Ratings
are to be increased one grade for materials known to cause an allergic
reaction.
Dermal effects from prolonged or repeated contact have not been con-
sidered.
Grade. 0 No appreciable hazard. These materials are practically
harmless to the skin. Included are certain very volatile
compounds that evaporate quickly from the skin.
Grade 1 Minimum hazard. Usually includes materials that will cause
smarting and reddening of the skin if spilled on clothing
and allowed to remain.
Grade 2 Materials that cause smarting of the skin and first-degree
burns on short exposure and may cause second-degree burns
on long exposure.
Grade 3 Fairly severe skin irritants, usually causing pain and
second-degree burns after a few minutes of contact.
Grade 4 Severe skin irritants, causing second- and third-degree
burns on short contact and very injurious to the eyes.
c. Chemical poisons
The systemic toxicity hazards from chemicals, that is, chemicals that
enter the body through inhalation, oral ingestion, or skin penetration and
cause bodily harm are classified here. Volatile chemicals producing toxic
effects by inhalation are of the most concern; chemicals toxic by skin
absorption are of less concern. Chemicals which are toxic only by oral
ingestion usually are not given a high hazard rating, except in a few cases
where severe injury may occur.
41
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APPENDIX V (cont'd)
Many parts of the body may be affected when exposed to chemicals, all
of which are considered here. Chemicals are rated as health hazards if
they are anesthetics, narcotics, or have a cumulative toxic effect, as well
as if they are acutely toxic. However, protecting the general public from
fuels and fuel additives per s_e is primarily a concern for acute, rather
than cumulative toxicity, and hence acute toxicity is given greater weight
in the ratings.
Grade 0 No likelihood of producing injury.
Grade 1 Minimum hazard; includes most chemicals having threshold
limit values above 500 ppm.
Grade 2 Some hazard, typically having threshold limits of 100 to
500 ppm.
Grade 3 Moderately hazardous chemicals.
Grade 4 Severely hazardous chemicals usually having threshold limits
below 10 ppm.
42
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APPENDIX VI
COMMENTS ON GENERATION OF EXHAUST EMISSIONS
Some special comments are needed on subject of generating emissions.
The toxicologist needs a procedure for generating emissions from engines
operating on a fuel to which additives have been introduced. The proce-
dure must also provide a representative distribution of potentially toxic
compounds so that incremental toxicity can be determined. Such procedures
should not be unduly complex.
It is recognized that different engine families exist and one or
more test procedures may be needed. The batch process type includes
gasoline, diesel and stratified charge. They may employ either recipro-
cating or rotary mechanisms. The continuous burner type includes turbine,
jet Stirling and steam. Various fuel additives are used or may be used in
each of these types.
The Committee recognizes the importance of different engine emission
control systems and exhaust treatment control systems to the amount and
distribution of emissions. Flexibility and judgment must be used in en-
gine fuel and cycle selection for testing. A typical engine emission con-
trol system should be employed for standard tests within each engine-emis-
sion control system. Where variations in exhaust treatment systems are
suspected to change significantly the distribution of emissions, additional
tests should be made with the alternate systems. The possible incremental
toxicity of principal additives for a given engine type should be evaluated,
with that type being used as the emission source.
Most fuel additives can be evaluated in a standard engine with a
standard fuel. Where the gaseous emissions are of principal concern
Cashless additives, for example) a medium load, steady state engine test
might be used. Since most future fuel additives are expected to be of
this type, a steady engine test might become the predominant one. Where
incremental toxicity from liquid aerosols or particulates is suspected,
transient operation is desirable. An example is the federal exhaust test
cycle, unless the additive being tested is used in an engine normally run
under steady conditions. When measuring particulates or aerosols, dilu-
tion is necessary to avoid condensation. The dilution must be controlled
when determing particulate or aerosol effects because the size distribution
is affected by dilution.
The Committee emphasizes the desirability of a simple emission
source such as a laboratory burner system. No laboratory system is known
which correlates with engine exhaust, and such a study seems a worthy
research effort. The use of a laboratory burner system may be more
realistic for the steady burner type engines.
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1 REPORT NO.
EPA-600/1-77-005
2.
3. RECIPIENT'S ACCESSION-NO.
4. TITLE AND S1. 3TITLE
FUELS AND FUEL ADDITIVES FOR HIGHWAY VEHICLES AND THEIF
COMBUSTION PRODUCTS. A Guide to Evaluation of Their
Potential Effects on Health
5. REPORT DATE
January 1977
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Committee on Toxicology
8. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Assembly of Life Sciences
National Research Council
National Academy of Sciences
Washington, D.C.
10. PROGRAM ELEMENT NO.
1AA601
11. CONTRACT/GRANT NO.
68-01-0432
12. SPONSORING AGENCY NAME AND ADDRESS
Health Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, N.C. 27711
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA-ORD
15. SUPPLEMENTARY NOTES
16. ABSTRACT
Except for those fuels and additives which contain metals, ha!ides and sulfur,
most such substances are organic compounds thought to be largely combusted.
The most frequent human responses to these substances are the detection of
odors, eye irritation and respiratory irritation. These effects can be predicted
from studies on animals. Chronic inhalation toxicology is not well standardized
and there are insufficient data to make conclusions about mutagenic, teratoqenic or
carcinogenic effects.
The prediction of health hazards from the use of fuel and fuel additives is so
complex that it is questionnable whether fixed protocols should be adopted at the
present time. The committe concluded: (1) that the initial evaluation of a new
fuel-additive combination should include a comparison with the chemical and biologic-
al properties of a standard fuel, (2) that certain tests to detect unexpected
(3) that metal-containing additives should require more
,_. -- - •- interpretations of studies should be made by informed
_lb; that all present methods should be considered tentative and that
jye flexibility in regulatory action should be provided, and (6) that
long-term epidemiological studies should accompany the introduction of new additive
combinations in nrdPr tn vprifv n- ™f,,+* *L ^timation: of :ara". 5dd1t1ve
extensive
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
Fuels
Fuel Additives
Toxicity
06 T
8. DISTRIBUTION STATEMEN1
RELEASE TO PUBLIC
19. SECURITY CLASS (ThisReport)
20. SECURITY CLASS (Thispage)
UNCLASSIFIED
21. NO. OF PAGES
-52-
22. PRICE
EPA Form 2220-1 (9-73)
44
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