United States
Environmental Protection
Offici
Toxic Substances
Washington, DC 20460
Second Report of the
TSCA Interagency Testing
Committee to the
Administrator,
Environmental Protection
Agency
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SECOND REPORT OF THE TSCA INTERAGENCY TESTING COMMITTEE
TO THE
ADMINISTRATOR, ENVIRONMENTAL PROTECTION AGENCY
APRIL 1978
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CONTENTS
PART A. SECOND REPORT OF THE TSCA INTERAGENCY
TESTING COMMITTEE TO THE ADMINISTRATOR,
ENVIRONMENTAL PROTECTION AGENCY, APRIL 1978
Committee Membership
Acknowledgments
SUMMARY
CHAPTER 1. INTRODUCTION 1
1.1 Committee Establishment and
Responsibilities 1
1.2 Initial Report 1
1.3 Committee Activities During This
Reporting Period 2
1.4 Future Activities of the Committee 3
CHAPTER 2. CONSIDERATION OF AVAILABILITY OF
TESTING FACILITIES AND PERSONNEL.... 4
CHAPTER 3. RECOMMENDATIONS OF THE COMMITTEE.... 6
3.1 Substances and Categories of Substances
Recommended for Testing 6
3.2 Reasons for Recommending Testing of
the Additional Substances and
Categories of Substances 6
3.2. A Acrylamide 9
3.2.B Aryl Phosphates 10
3 . 2 . C Chlorinated Naphthalenes 12
3 . 2 . D Dichloromethane 13
3.2.E Halogenated Alkyl Epoxides 14
3 . 2 . F Polychlorinated TerphenyIs 15
3 . 2 . G Pyridine 16
3.2.H 1,1,1-Trichloroethane 18
PART B. INFORMATION DOSSIERS ON SUBSTANCES
DESIGNATED BY THE TSCA INTERAGENCY
TESTING COMMITTEE Section
Foreword
Acrylamide I
Aryl Phosphates II
Chlorinated Naphthalenes Ill
Methane , Dichloro IV
Halogenated Alkyl Epoxides V
Polychlorinated Terphenyls VI
Pyridine VII
Ethane, 1,1,1-Trichloro- VIII
General References Appendix A
Key to Abbreviations Appendix B
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M . A . TOXIC SUBSTANCES CONTROL ACT
Member Agencies
E^ntaiouaiity INTERAGENCY TESTING COMMITTEE
Department of Commerce „„„ , ,
Environmental Protection Agency 722 Jackson Place' N'W-
National Cancer Institute Washington, D.C. 20006
National Institute of Environmental
Health Sciences
National Institute for Occupational
Safety and Health
National Science Foundation April 10, 1978
Occupational Safety and Health
Administration
Liaison Agencies
Consumer Product Safety Commission
Department of Defense
Department of the Interior
Food and Drug Administration
Honorable Douglas M. Costle
Admini strator
Environmental Protection Agency
Washington, D.C. 20460
Dear Mr. Costle:
In accordance with the requirements of the Toxic
Substances Control Act, the TSCA Interagency Testing
Committee is now recommending the addition of eight
designated entries to the Section 4(e) Priority List.
These revisions and the Committee's reasons for
recommending them are presented in the enclosed document
entitled, "Second Report of the TSCA Interagency Testing
Committee to the Administrator, Environmental Protection
Agency." The representatives of the statutory member
agencies are in consensus on these revisions.
Also, the report contains two special recommendations
which bear on the activities of the Environmental
Protection Agency. First, it is recommended that EPA
consider taking the initiative in the development of a
comprehensive survey of health and environmental effects
testing facilities in the United States. And second,
your agency is encouraged to join in the effort to provide
increased training support in the fields of mammalian
and environmental toxicology, pathology, occupational
health and epidemiology as these fields relate to the
need for greater numbers of qualified personnel to meet
the increasing demand for testing.
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- 2 -
The Committee has not yet completed its review of all
of those chemical substances and categories of substances
identified during our initial activities in 1977. This
review is to continue and will be a subject of future
Committee reports. In addition, candidate chemicals
recommended by the Committee members or public comment
will be reviewed by the Committee as such information
is made available.
We trust that this report will be of value to EPA as it
continues to carry out the Toxic Substances Control Act.
Sincerely,
<1 -^r^«--p"
Marvin E. Stephenson
Chairperson
TSCA Interagency Testing Committee
Enclosure
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SECOND REPORT
OF THE
TSCA INTERAGENCY TESTING COMMITTEE
TO THE
ADMINISTRATOR, ENVIRONMENTAL PROTECTION AGENCY
APRIL 1978
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TSCA INTERAGENCY TESTING COMMITTEE
Statutory Member Agencies
COUNCIL ON ENVIRONMENTAL QUALITY
Carroll Leslie Bastian
Nathan J. Karen, Alternate
DEPARTMENT OF COMMERCE
Orville E. Paynter
Bernard Greifer, Alternate
ENVIRONMENTAL PROTECTION AGENCY
Warren R. Muir
Joseph J. Merenda, Alternate
NATIONAL SCIENCE FOUNDATION
Marvin E. Stephenson, Chairperson
Carter Schuth, Alternate
NATIONAL INSTITUTE OF ENVIRONMENTAL
HEALTH SCIENCES
Hans L. Falk
Warren T. Piver, Alternate
NATIONAL INSTITUTE FOR OCCUPATIONAL
SAFETY AND HEALTH
Jean G. French, Vice Chairperson
Vera W. Hudson, Alternate
NATIONAL CANCER INSTITUTE
James M. Sontag
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OCCUPATIONAL SAFETY AND HEALTH
ADMINISTRATION
Joseph K. Wagoner
Fred W. Clayton, Alternate
Liaison Agencies
DEPARTMENT OF DEFENSE
Seymour L. Friess
FOOD AND DRUG ADMINISTRATION
Allen H. Helm
Winston deMonsabert
DEPARTMENT OF THE INTERIOR
Charles R. Walker
Raymond E. Corcoran
U.S. CONSUMER PRODUCT SAFETY
COMMISSION
Robert M. Hehir
Joseph McLaughlin
COMMITTEE STAFF
Executive Secretary: Carol A. Mapes
Secretary: Phyllis D. Tucker
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ACKNOWLEDGEMENTS
The Committee wishes to acknowledge the important contributions
of the many individuals and groups who have significantly
aided us in our work. These include:
the Federal agencies who have cooperated by providing
support through the liaison members;
Clement Associates, Inc., technical support contractor;
the National Science Foundation, for funding and
managing the technical support contract and the National
Institute of Environmental Health Sciences, for assisting
in that funding;
former Committee members:
Sidney R. Caller, Department of Commerce
William M. Upholt, Environmental Protection Agency
Norbert P. Page, National Institute for Occupational
Safety and Health
Grover C. Wrenn, Occupational Safety and Health
Administration
EPA staff members who assisted the Committee in a
variety of activities, and particularly:
Donald G. Barnes, Office of Toxic Substances
John W. Lyon, Office of General Counsel
Ralph C. Northrop, Jr., Office of Toxic Substances
the numerous experts who prepared presentations and
materials for the Committee; and
the many individuals and organizations who responded
to the Committee's Initial Report to the Administrator,
Environmental Protection Agency.
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SUMMARY
A central provision of the Toxic Substances Control Act
(TSCA, P.L. 94-469) concerns the testing of chemical sub-
stances and mixtures which are used in commerce or may
represent an unreasonable risk of injury to human health or
the environment. The Act provides for continuing advice
from certain Federal agencies having common interests in
identifying chemical substances or mixtures for testing.
Accordingly, the TSCA Interagency Testing Committee, which
is composed of representatives from those concerned Federal
agencies, regularly provides to the Administrator of the
Environmental Protection Agency (EPA) recommendations on
chemicals and mixtures to which the Administrator should
give priority consideration for the promulgation of testing
rules.
As a result of its deliberations during the past six months,
the Committee has elected to revise the TSCA Section 4(e)
Priority List by the addition of four individual substances
and four categories of substances. The Committee considers
these additions to be of the same priority as the previously
designated entries. The chemical substances or categories
being designated for addition to the Priority List and the
testing recommendations are presented alphabetically as
follows:
Substance or Category
Acrylamide
Aryl Phosphates
Chlorinated Naphthalenes
Dichloromethane
Testing Recommended
Carcinogenicity, mutagenicity,
teratogenicity, environmental
effects and epidemiological
study.
Carcinogenicity, mutagenicity,
teratogenicity, other chronic
effects, environmental effects
and epidemiological study
Carcinogenicity, mutagenicity,
teratogenicity, other chronic
effects, environmental effects
and epidemiological study
Carcinogenicity, mutagenicity,
teratogenicity, other chronic
effects, environmental effects,
and epidemiological study
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Carcinogenicity, mutagenicity,
teratogenicity, other chronic
effects, and epidemiological
study
Carcinogenicity, mutagenicity,
teratogenicity, other chronic
effects, and environmental
effects
Carcinogenicity, mutagenicity,
teratogenicity, other chronic
effects, environmental effects,
and epidemiological study
Carcinogenicity, mutagenicity,
teratogenicity, other chronic
effects, and epidemiological
study
A set of dossiers containing information on the additional
entries designated to the Priority List will be forwarded to
the EPA Administrator within a few weeks.
Halogenated Alkyl
Epoxides
Polychlorinated
Terphenyls
Pyridine
1,1,1-Trichloroethane
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SECOND REPORT
OF THE
TSCA INTERAGENCY TESTING COMMITTEE
TO THE
ADMINISTRATOR, ENVIRONMENTAL PROTECTION AGENCY
APRIL 1978
CHAPTER 1. INTRODUCTION
1.1 Committee Establishment and Responsibilities
The Toxic Substances Control Act (P.L. 94-469) establishes
the TSCA Interagency Testing Committee under Section 4(e).
The Committee has the continuing responsibility to identify
and recommend to the Administrator of the Environmental
Protection Agency (EPA) chemical substances or mixtures which
should be tested to determine their hazard to human health
or the environment. The statute requires that the Committee
consider revisions to its previous recommendations at least
every six months.
The Committee has eight statutory members appointed by the
Federal agencies identified for membership in Section 4(e)(2)(A)
of the Act, a number of alternate members as permitted by
Section 4(e)(2)(B)(i) , and liaison members from several Federal
agencies with programs related to the control of toxic sub-
stances. Current Committee members, alternates, and liaison
representatives are identified at the beginning of'this report.
1.2 Initial Report
In July 1977, the Committee published a Preliminary List of
330 chemical substances and categories of such substances
including background information describing the methods used
by the Committee in making those selections [Reference No. 1].
The Preliminary List contains substances and categories
selected primarily on the basis of their potential for human
exposure and environmental release. Subsequently, the chemicals
on the Preliminary List and chemicals added to the Preliminary
List on the basis of public comments and Committee recommenda-
tions were screened further by the Committee. The screening
process was based primarily on the chemicals' potential for
causing adverse human and/or environmental effects but also
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considered their exposure potential. Available data on these
chemicals were reviewed with regard to: potential for carci-
nogenic, mutagenic, teratogenic, and chronic toxic effects;
their ability to bioaccumulate or cause deleterious environ-
mental effects; and possible toxic impurities. A scoring
system was used in this process which took into account both
available information and the lack of it for these factors.
The Committee further narrowed the list of substances and
categories under consideration on the basis of its scientific
judgment and the scoring results, and requested its technical
contractor to prepare dossiers on these chemicals. The
Committee was able to review about one-half of these substances
and categories aided by information in the dossiers. Four
individual chemicals and six categories of chemical substances
were selected for inclusion in the Initial Report to the
Administrator, Environmental Protection Agency [Reference No. 2]
dated October 1, 1977.
In addition to the listing of the chemicals designated by
the Committee for consideration by EPA, the report contains
a detailed description of the methods used in developing
the Committee's initial recommendations including data
sources and methods used for production, release and exposure
scores, as well as biological and environmental scores.
Later, on February 7, 1978, a finalized set of supporting
dossiers on the designated entries on the Priority List was
officially transmitted to the Administrator.
1.3 Committee Activities During This Reporting Period
Since completion of its initial recommendations in
October 1977, the Committee has continued to consider indi-
vidual chemical substances and mixtures identified for
in-depth consideration by the screening process mentioned in
the preceding section.
This review has given specific consideration to the factors
described in TSCA Section 4(e)(1)(A) and other relevant
factors identified by the Committee. Readily available
information on these factors and the knowledge and profes-
sional judgment of the Committee members have been employed to
select additional entries to the TSCA Section 4(e) Priority
List. On the basis of the review of more, but not all, of
the previously requested dossiers, the Committee is now
recommending the addition of four chemical substances and
four categories of chemical substances to the 4(e) Priority
List.
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1.4 Future Activities of the Committee
In the course of developing its third report, the Committee
expects to continue reviewing those dossiers in hand and
consider new dossiers on additional chemicals and groups.
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CHAPTER 2. CONSIDERATION OF AVAILABILITY OF TESTING
FACILITIES AND PERSONNEL
Section 4(e)(1)(A) of TSCA requires that the Committee
consider, among other factors, the reasonably foreseeable
availability of facilities and personnel for carrying out
the testing on the substances or mixtures recommended to
the Administrator for priority consideration. The Committee
concludes that testing capabilities are presently adequate
to carry out the recommended health effects and environmental
tests on the chemicals listed in Table 1. However, the
concerns expressed by the Committee in its first report
[Reference No. 2, p.55048] regarding the limited national
capability for conducting long-term tests for environmental
effects are reiterated.
The expansion of testing facilities by industry, contracting
laboratories, and universities seems to be proceeding at a
satisfactory rate, especially in the area of health effects
testing. Estimates indicate a significant increase in
facilities over the next five years. While this is encourag-
ing, the Committee is aware that the increasing requirements
of various government agencies are creating competition for the
same testing facilities and personnel. Therefore, the projected
need and capacity for health and environmental effects testing
is somewhat uncertain and should be more accurately surveyed.
The Committee recommends that EPA assume the leadership in the
development of a comprehensive survey of availability of cur-
rent Federal and private health effects testing facilities in
the United States and the projected annual capacity of such
facilities during the next five years. In those cases where
testing is likely to involve animal bioassay, the survey
should include an evaluation of the capacity to provide
appropriate and sufficient populations of test species.
Of paramount concern to the Committee is the availability of
qualified personnel. All indices contained in the Report of
the Second Task Force for Research Planning in the Environmental
Health Sciences [Reference No. 3] indicate a current and future
shortage of research professionals in the fields of mammalian
and environmental toxicology, pathology, occupational health,
and epidemiology. There will be a dearth of professionals and
supporting technical personnel in these various skills for many
years unless increased training efforts occur at the national
level. The Committee notes that several Federal agencies are
involved in augmenting training support and recommends that EPA
join in these efforts in a significant way.
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There is also a need to maintain viable basic research pro-
grams in toxicology and other related health fields. This
basic need should not be neglected in order to assure short-
term gains in the practical application of the present state
of the art. Because of the interdisciplinary nature of
toxicology and environmental health research, the educational
training for some of the disciplines can be provided only by
facilities with personnel engaged in this type of research.
The Committee believes that the Civil Service Commission
could do much to stimulate interest in these professions by
creating professional series and registers for such scarce
categories as toxicologists, pathologists, epidemiologists
and other scientific fields in environmental protection.
Recognition of these environmental health professions by the
Commission could encourage students to investigate careers in
fields thus far hidden as Federal employment opportunities.
It is concluded that such an action by the Commission would
have the effect of increasing the available scientific man-
power in these speciality fields both in the Government and
in industry where the demand for such personnel exists.
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CHAPTER 3. RECOMMENDATIONS OF THE COMMITTEE
3.1 Substances and Categories of Substances Recommended
for Testing
On the basis of the review and evaluation of chemical sub-
stances which was carried out according to the methods and
procedures described in Sections 1.2 and 1.3, the Committee
is revising the TSCA Section 4(e) Priority List to add certain
substances and categories of substances for which specific
testing is recommended. The Priority List and the date each
item was placed on the List are given in Table 1. The testing
recommendations and reasons for such recommendations are
indicated in Section 3.2 for the new entries. Supporting
dossiers of information are being prepared in final form and
will be forwarded to the Administrator, EPA, at an early date.
All additions to the List are designated chemical substances
and categories of chemical substances which the Committee has
determined require the Administrator's action under TSCA
Section 4(a) within twelve months. The Committee considers
these additions to be of the same priority as the previously
designated entries. In recommending a category of chemical
substances for testing (e.g., the aryl phosphates), the
Committee recognizes that certain chemicals which are members
of the category may have been tested previously for an
effect of concern. For those chemicals no additional testing
may be warranted if the results of previously completed tests
are judged adequate for assessing the effect of concern. The
Committee also recognizes that the definition and inclusive
limits of a given listed category of substances may require
additional specification or change in specification as the
testing rule is developed. Unless stated otherwise, the
chemical substance recommended for testing should be the
product to which the population is exposed.
3.2 Reasons for Recommending Testing of the Additional
Substances and Categories of Substances
In accordance with the reporting requirements of the Act, the
Committee has listed in the following sections the test rec-
ommendations and reasons for recommending testing for those
entries being placed on the Priority List at this time.
Table 2 presents a summary of the testing recommendations
for each addition to the List.
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Table 1. THE TSCA SECTION 4 (e) PRIORITY LIST, BY
ALPHABETICAL ARRANGEMENT
Designated Entry
Date of Entry
Acrylamide
Alkyl Epoxides
Alkyl Phthalates
Aryl Phosphates
Chlorinated Benzenes, Mono- and Di-
Chlorinated Naphthalenes
Chlorinated Paraffins
Chloromethane
Cresols
Dichloromethane
Halogenated Alkyl Epoxides
Hexachloro-1,3-Butadiene
Nitrobenzene
Polychlorinated Terphenyls
Pyridine
Toluene
1,1,1-Trichloroethane
Xylenes
April 1978
October 1977
October 1977
April 1978
October 1977
April 1978
October 1977
October 1977
October 1977
April 1978
April 1978
October 1977
October 1977
April 1978
April 1978
October 1977
April 1978
October 1977
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Table 2. SUMMARY OF TESTING RECOMMENDATIONS BY THE TSCA INTERAGENCY TESTING COMMITTEE
CD
Substance Carcino-
or Category genicity
Acrylamide
Aryl Phosphates
Chlorinated
Naphthalenes
Dichlorome thane
Halogenated Alkyl
Epoxides
Polychlorinated
Terphenyls
Pyridine
X
X
X
X
X
X
X
Mutage-
nicity
X
X
X
X
X
X
X
Terato- Other Environ-
genicity Chronic mental
Effects Effects
X X
X XX
X XX
X. XX
X X
X XX
X XX
Epidemiology
Study
X
X
X
X
X
X
1,1,1-Trichloro-
ethane
X
X
X
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3.2.A ACRYLAMIDE
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Environmental Effects
Epidemiology
SUBSTANCE IDENTIFICATION: CAS NO. 79-06-1
REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure: The 1976 U.S. production
of acrylamide monomer is estimated at 64 million pounds, and
indications point to a high growth rate of around 12 percent
for the next decade. Eighty percent of the acrylamide
produced is used captively in polymer production for water
treatment, papermaking and wastewater clarification. About
5 percent is used in chemical grouts as the acrylamide
monomer, for soil stabilization and sewer rehabilitation.
The remainder is consumed in other chemical syntheses.
Other uses are in the paper and paperboard industry, coal
industry, mining and ore benefication industry, and secondary
oil recovery industry.
Acrylamide release to the environment (usually ending up in
surface and ground water) occurs at manufacturing sites, soil
grouting sites, polymer application sites and in handling.
General population, low-level exposure to acrylamide is likely
to occur wherever polyacrylamides are utilized. No data are
available on release rates into the environment or actual
concentration levels. NIOSH estimates that 20,000 workers
are potentially exposed in the workplace.
Carcinogenicity: Acrylamide has not been tested for Carcino-
genicity- Because of widespread low-level exposure to the
population, acrylamide should be tested for Carcinogenicity.
Mutagenicity: Although the results of two independently
reported Ames tests were negative, the Committee believes
that additional tests, employing other systems, are required
to evaluate the mutagenic potential of this chemical.
Teratogenicity; Transplacental transport of acrylamide was
demonstrated in rats; therefore, it should be tested con-
clusively for teratogenicity.
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Environmental Effects: In view of the high degree of neuro-
toxicity and neuropathy caused by cumulative exposure and the
extensive use of this material in waste water treatment and
soil grouting, studies should be initiated to determine the
degree of leaching of the monomer from the polymer with water
and various solvents. Further, the potential for environmental
exposures to the aquatic ecosystem, movement in soil solution
and leachate from soil waste must be determined for biological
effects on plant and animal life.
Epidemiology: No epidemiological reports on acrylamide have
been found in the literature. Studies are needed to provide
information on human exposure to acrylamide and to determine
the relationship between airborne concentrations and observed
effects on humans.
3.2.B ARYL PHOSPHATES
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
Epidemiology
CATEGORY IDENTIFICATION: This category consists of phosphate
esters of phenol or of alkyl-substituted phenols. Tri-aryl
and mixed alkyl and aryl esters are included, but tri-alkyl
esters are excluded.
REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure: As a category, the aryl
phosphates are produced in quantities exceeding 65 million
pounds/year. Several individual aryl phosphates, such as
tritolyl phosphate and triphenyl phosphate, have annual
production greater than 10 million pounds. Aryl phosphates
are widely used as plasticizers in polymers (principally in
polyvinyl chloride) and in hydraulic fluids and high pres-
sure lubricants. Such uses provide opportunity for exten-
sive occupational exposure to these compounds beyond that
encountered in their manufacture. NIOSH estimates that over
2 million workers are so exposed. Because of the nature of
their uses, most of the aryl phosphates manufactured will
ultimately be released into the environment, although those
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used as plasticizers may be released quite slowly. Persis-
tence of aryl phosphates in the environment for significant
periods (at least on the order of months) is indicated by
the available data.
Carcinogenicity: With the exception of several tests of
inadequate duration using triphenyl phosphate, the carcino-
genic potential of aryl phosphates has not been assessed.
Carcinogenicity testing should be performed on aryl phos-
phates having substantial human exposure and/or environmental
release.
Mutagenicity: No mutagenicity testing has been reported
for aryl phosphates. Such testing should be performed
because of the potential of these substances for widespread
environmental release and human exposure.
Teratogenicity: No teratogenicity testing has been reported
for aryl phosphates. Such testing should be conducted for
aryl phosphates having substantial human exposure and/or
environmental release.
Other Chronic Effects; The neurotoxicity of certain aryl
phosphates is well documented. The Committee recommends
that aryl phosphates be tested for chronic effects with
special emphasis on neurotoxic activity.
Environmental Effects; Available data, although limited,
indicate a potential for persistence of aryl phosphates in
the aquatic environment, as well as a potential for their
bioaccumulation in aquatic species. There is evidence of
chronic toxicity of aryl phosphate hydraulic fluids to fish.
Several aryl phosphates potentiate the toxic effects of
organophosphate pesticides on insects and one (tri-o-cresyl
phosphate) has been shown to potentiate such effects in non-
target organisms including mammals. In view of this, the
environmental fate and effects on aquatic and terrestrial
systems should be evaluated for aryl phosphates.
§>
Epidemiology; Because of the large-scale production and
potential for substantial occupational exposure of certain
aryl phosphates, the Committee recommends that epidemiological
studies be conducted.
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3.2.C CHLORINATED NAPHTHALENES
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
Epidemiology
CATEGORY IDENTIFICATION: This category consists of chlorinated
derivatives of naphthalene (empirical formula ciQHxC1y'
where x+y=8).
REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure: Available data indicate
a production volume on the order of millions of pounds
annually. These products have both moderately dispersive
uses (e.g., lubricating and cutting oil additives) and
enclosed uses (e.g., dielectric for automotive capacitors).
Although NIOSH has estimated that several thousand workers
are exposed to these compounds, little is known about the
ultimate release of these materials from the workplace,
during product use, or as a result of disposal.
Health Effects: Animal studies and analysis of human exposure
reveal that these compounds are biologically active, with
reports of dermatological (e.g., chloracne) and systemic
(liver) effects. To date, there are no reported data on the
carcinogenicity, mutagenicity, or teratogenicity of these
compounds. Thus, there is a need to conduct such studies, as
well as to investigate more thoroughly the chronic effects
of these materials. Epidemiological studies should be under-
taken where appropriate.
Environmental Effects: Little information on the ecological
effects of these materials is available, but the detection of
chlorinated naphthalenes in stream sediments, fish, and fish-
eating birds points to their dispersal, persistence, and bio-
accumulation in the food chain. Therefore, testing is needed
to obtain data for judging the environmental effects of these
chemicals.
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3.2.D DICHLOROMETHANE
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
Epidemiology
SUBSTANCE IDENTIFICATION: CAS NO. 75-09-2
REASONS FOR RECOMMENDATIONS:
Production, Release/ and Exposure: The 1976 U.S. production
of dichloromethane (also known as methylene chloride) exceeded
500 million pounds, a 12 percent increase over the 1972 level.
An average 9 percent annual growth rate is projected over the
next several years as this chemical enters markets dominated
by fluorochlorocarbons in the past. Approximately 3/4 of the
volume produced is thought to be released to the environment
through activities at industrial sites, in homes and elsewhere,
NIOSH estimated that 2.5 million workers are exposed to this
material at their place of work. Its use in an array of
aerosol spray products and other household products brings
a large fraction of the general population into contact with
this chemical.
Carcinogenicity; No carcinogenicity test data were found in
the searched literature. There is sufficient concern
for the Committee to recommend this chemical for such testing.
The Committee is aware of two studies currently under way,
however, whose results may be judged adequate to obviate the
need for additional testing.
Mutagenicity: No mutagenicity test data have been reported.
Such studies should be conducted in view of the widespread
exposure to this chemical and its demonstrated biological
activity.
Teratogenicity: One study has reported equivocal findings
of abnormalities in the offspring of pregnant rats and mice
exposed to this chemical. Additional testing is needed to
assess this potential hazard.
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Other Chronic Effects; Laboratory investigations and case
studies have reported that dichloromethane can affect various
organs (e.g., lungs and eye) and systems (blood), as well as
behavior. Given the widespread use of this chemical under
many different conditions, this information indicates a need
for further testing.
Environmental Effects: Dichloromethane is being released
in large quantities and in a broad dispersion pattern through-
out the environment. Low-level residues have been measured
in water. The exact nature of this exposure and its chronic
effects on the biota need to be determined.
Epidemiology: Epidemiological studies should be conducted
to assess human risk.
3.2.E HALOGENATED ALKYL EPOXIDES
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Epidemiology
CATEGORY IDENTIFICATION: This category consists of halogenated
noncyclic aliphatic hydrocarbons with one or more epoxy
functional groups.
REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure: The 1975 U.S. production
of epichlorohydrin (l-chloro-2,3-epoxypropane) exceeded
500 million pounds. NIOSH estimates that between 50,000 and
140,000 workers are exposed to epichlorohydrin annually.
While epichlorohydrin is currently the only widely used
halogenated alkyl epoxide, advertising and trends in the
chemical industry lead the Committee to the conclusion that
chemicals of this type may find wider use in the future.
Carcinogenicity; Halogenation of an alkyl epoxide enhances
its activity as an alkylating agent and hence its biological
activity. Halogenated alkyl epoxides also may inhibit
detoxifying enzymes in mammals. Equivocal results of recent
Carcinogenicity studies on epichlorohydrin further point out
the need for testing this chemical category for potential
Carcinogenicity.
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Mutagenicity; Epichlorohydrin has been shown to be mutagenic
to mice and bacteria. The potential human toxicity of this
and other halogenated alkyl epoxides should be evaluated.
Teratogenicity; No information could be found on the potential
for teratogenicity of the halogenated alkyl epoxides and they
should be studied for this effect.
Other Chronic Effects: Epichlorohydrin has been reported
to penetrate human skin and cause systemic effects. This
raises concern for other toxic effects and target organ
toxicity of all the halogenated alkyl epoxides. Appropri-
ate studies for these effects are recommended.
Epidemiology; No epidemiological studies of any of the
halogenated alkyl epoxides were found in the literature.
Studies are needed to provide information on the effects
of human exposure to these compounds.
3.2.F POLYCHLORINATED TERPHENYLS
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
CATEGORY IDENTIFICATION: This category consists of the
polychlorinated ortho-, meta- and para-terphenyls.
REASONS FOR RECOMMENDATIONS:
Production, Release and Exposure: Although the production
of polychlorinated terphenyls was discontinued in the United
States in 1972, there has been an increase in imports of
polychlorinated terphenyls from 160,000 pounds in 1973 to
400,000 pounds in 1975. Polychlorinated terphenyls are
presently used in waxes for investment casting and this use
leads to wide environmental dispersion. Residues of poly-
chlorinated terphenyls have been found in human fat and milk
and in samples of water and sludge. In a group of 27
individuals tested for blood levels of polychlorinated
terphenyls and polychlorinated biphenyls, the average
concentration of polychlorinated terphenyls in the blood
was greater than that of polychlorinated biphenyls, despite a
far greater industrial use of polychlorinated biphenyls in
the area of study.
15
-------
Carcinogenicity: No reports of long-term carcinogenicity
studies of polychlorinated terphenyls were found in the
searched literature. The Committee recommends that poly-
chlorinated terphenyls be tested for carcinogenicity.
Mutagenicity: No information on the mutagenicity of poly-
chlorinated terphenyls was found in the searched literature.
The Committee recommends that mutagenicity tests be conducted,
Teratogenicity: No information on the teratogenicity of
polychlorinated terphenyls was found in the searched
literature. The Committee recommends that teratogenicity
tests be conducted.
Other Chronic Effects: Liver, skin and hematopoietic effects
have been observed at high level exposures. Effects at lower
levels cannot be characterized from existing data. Chronic
studies to evaluate the effects of prolonged exposures are
recommended.
Environmental Effects: The limited available data indicate
a potential for bioaccumulation. No adequate information is
available on the ecological effects of these chemicals.
3.2.G PYRIDINE
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
Epidemiology
SUBSTANCE IDENTIFICATION: CAS No. 110-86-1
REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure: The annual production
of pyridine is estimated to be in excess of 60 million
pounds, based on production amounts for 1976. Although the
amount of pyridine released into the environment is unknown,
its production volume and variety of uses raise concern with
respect to human exposure. NIOSH estimates that 249,000
workers may be exposed to pyridine.
16
-------
Carcinogenicity: Only one limited carcinogenicity study was
found in the searched literature. By current standards, the
study is judged inadequate as an evaluation of the carcinogenic
potential of pyridine. The Committee, therefore, recommends
that appropriate carcinogenicity testing be undertaken on
pyridine.
Mutagenicity; No mutagenicity studies on pyridine were found
in the searched literature. Given its known biological activ-
ity, production volume, and human exposure, it is recommended
that appropriate mutagenicity testing be undertaken on pyridine.
Teratogenicity: Only one limited teratogenicity study was
found in the searched literature on pyridine. It indicated
that pyridine produced abnormalities in chicken embryos. An
evaluation of teratogenic effects should be undertaken in
other species.
Other Chronic Effects: The carcinogenicity study cited above
is the only investigation lasting one year or longer found in
the searched literature on the possible chronic effects of
pyridine. Short-term studies indicate that pyridine affects
the central nervous system and causes degeneration in the
liver and kidneys. Chronic effects on these and other systems
should be evaluated in appropriate long-term studies.
Environmental Effects; The environmental release of pyridine
may pose a hazard to aquatic biota and terrestrial life.
Residues have been detected in water and uptake in plants has
been reported. Although a wide range of toxicity has been
measured for plant and animal life in short-term bioassay
tests, the results of one longer-term exposure to Daphnia
magna indicates a potential for chronic toxicity. More test-
ing is needed to determine the biological significance of
residues and the potential effects of long-term exposures on
both plant and animal life.
Epidemiology: Pyridine has been reported to have an effect
on the central nervous system in humans, .as well as to
produce injury to the liver and kidney. Given the large
number of workers exposed, epidemiological studies should be
undertaken.
17
-------
3.2.H 1,1,1-TRICHLOROETHANE
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Epidemiology
SUBSTANCE IDENTIFICATION: CAS NO. 71-55-6
REASON FOR RECOMMENDATIONS:
Production, Release, and Exposure: This compound is produced
primarily for use as a cleaning solvent for metals and other
materials. 1,1,1-Trichloroethane (methyl chloroform) has the
potential to replace the chlorinated ethylenes in a variety
of solvent formulations used commercially. The U.S. produc-
tion of this compound totaled approximately 630 million pounds
in 1976. Current release rates are not known; however, it is
estimated that over 300 million pounds of this compound are
employed in dispersive uses which would principally result
in releases to the atmosphere. The significant adverse
effects on the upper atmosphere have been evaluated. Minor
amounts may also enter the aquatic and terrestrial environ-
ment. NIOSH estimates that about 3,000,000 persons may be
exposed to this material in the workplace.
Careinogenicity: The currently available information, includ-
ing recent results from the NCI carcinogenesis bioassay pro-
gram, indicates that data are not adequate to make a judgment
on the carcinogenic potential of 1,1,1-trichloroethane. The
Committee recommends that this chemical be evaluated with
respect to carcinogenicity.
Mutagenicity: The absence of information on the mutagenicity
of this compound indicates that such studies should be under-
taken.
Teratogenicity: The Committee concludes that the current
available information on teratogenic effects is insufficient
to judge the hazard potential of this material. Consequently,
it is recommended that appropriate teratogenesis studies be
undertaken on 1,1,1-trichloroethane.
18
-------
Other Chronic Effects: There is insufficient evidence
regarding the impact of chronic, low-level exposure to
1,1,1-trichloroethane. Chronic effects, with specific atten-
tion to neurological, cardiovascular and renal systems,
should be evaluated in appropriately designed studies.
Epidemiology; No investigations of health effects in occu-
pational workers exposed to 1,1,1-trichloroethane were found
during the Committee's review of this material. Given the
large population of workers exposed to this compound, it is
recommended that appropriate epidemiological investigations
be conducted.
19
-------
REFERENCES
1. Preliminary List of Chemical Substances for
Further Evaluation, Toxic Substances Control
Act Interagency Testing Committee, July 1977.
2. Initial Report to the Administrator, Environmental
Protection Agency, TSCA Interagency Testing Committee,
October 1, 1977. Published in the Federal Register,
Vol. 42, No. 197, Wednesday, October 12, 1977,
pp. 55026-55080. The report and the supporting
dossiers also were published by the Environmental
Protection Agency, EPA 560-10-78/001, January 1978.
3. Human Health and the Environment - Some Research Needs,
A report of the Second Task Force for Research
Planning in Environmental Health Sciences, DHEW
Publication No. NIH 77-127, Chapter 16, 1977.
20
-------
INFORMATION DOSSIERS ON SUBSTANCES
DESIGNATED BY
TSCA INTERAGENCY TESTING COMMITTEE
(April 1978)
Prepared by
Clement Associates, Inc.
1010 Wisconsin Avenue, NW
Washington, DC 20007
June 1978
Contract No. NSF-C-ENV77-15417
Prepared for
TSCA Interagency Testing Committee
Washington, DC
-------
Clement Associates, Inc.
Technical Support Team
Mukund J. Shah, Ph.D.
Yugal Luthra, Ph.D.
Morton Beroza, Ph.D.
Nan S. Gray
John F. Guy
Alfred E. Pinkney
Barbara Turnham
Ian C.T. Nisbet, Ph.D., Project Director
Jay Turim, Ph.D., Project Manager
-------
TABLE OF CONTENTS
Foreword
Acrylamide
Aryl Phosphates
Chlorinated Naphthalenes
Dichloromethane
Halogenated Alkyl Epoxides
Polychlorinated Terphenyls
Pyridine
1,1,1-Trichloroethane
General References
Key to Abbreviations
Section
I
II
III
IV
V
VI
VII
VIII
Appendix A
Appendix B
111
-------
FOREWORD
This document has been prepared for the Toxic Substances
Control Act (TSCA) Interagency Testing Committee by its
technical contractor, Clement Associates, Inc. The Committee
is charged with making recommendations to the Administrator
of the Environmental Protection Agency (EPA) with respect to
which chemicals EPA should give priority for testing to
determine adverse effects on man or the environment.
The dossiers in this document were originally drafted by
Clement and were reviewed in detail by the Committee, which
.in certain instances added information. Conclusions made by
Clement scientists about specific studies were also reviewed
by the Committee. The information in the dossiers reflects the
collective knowledge and judgment of the Committee and its
technical contractor. These dossiers have been used by the
Committee as the primary basis for recommending the chemicals
for priority testing.
The dossiers were designed to provide the Committee with
information on the chemicals' physical and chemical properties,
exposure characteristics, and biological properties that was
in sufficient detail to support an informed judgment on whether
they should be given priority for testing.
The dossiers are not comprehensive critical reviews. They
contain information from the National Library of Medicine's
TOXLINE and the Environmental Mutagen Information Center (EMIC)
automated data banks. Standard secondary sources (see Appendix A-
General References), monographs, criteria documents, reviews,
and reports available from government agency files and trade
association libraries were also consulted. Material received
in response to the Committee's request in the July 1977
Federal Register for information on certain substances was also
reviewed. Clement scientists and Committee members also relied
upon their own knowledge of the literature to supplement the
data derived from these sources. Secondary sources and abstracts
were consulted first in preparing the dossiers. When an article
was judged to contain information of major significance or to
require a critical review, the primary source was consulted.
Except when indicated otherwise, the information cited in these
dossiers was derived from the primary sources.
IV
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ACRYLAMIDE
TABLE OF CONTENTS
Page
Overview I~l
Part I General Information I-3
Part II Biological Properties
2.1 Bioaccumulation I~5
2.2 Impurities and Environmental Degradation
or Conversion Products 1-5
2.3 Acute Toxicity 1-5
2.4 Other Toxic Effects 1-8
2.5 Carcinogenicity 1-16
2.6 Mutagenicity I~16
2.7 Teratogenicity 1-17
2.8 Metabolic Information 1-17
2.9 Environmental Release and Ecological 1-19
Effects
2.10 Current Testing 1-20
References 1-21
I-i
-------
ACRYLAMIDE
AN OVERVIEW
Acrylamide occurs as colorless, odorless crystals and is
stable at room temperature, but it may polymerize violently on
melting. It is insoluble in benzene and heptane, soluble in
alcohol, ether, and acetone, and very soluble in water and chloro-
form.
NIOSH reported that 70 million pounds of acrylamide were
produced in the United States in 1974. According to an EPA report,
64 million pounds were produced in 1976. The compound has a wide
range of uses, the major ones being as a crosslinking agent in
polymer manufacture and in sewage and waste water treatment. It
is also used in permanent press fabrics; in adhesives, paper,
and textile sizes; in chemical grouting; and in soil conditioning
agents. Small quantities are used for flocculation of ores and
in synthesis of dyes.
According to the NIOSH. criteria document, approximately
20,000 workers in the United States are potentially exposed to
acrylamide.
Due to its high water solubility, 'the compound is likely to
enter rivers and other waters if released into the environment.
This may be significant in ground water and in deep bedrock
aquifers where biodegradation is absent. However, in surface
water it is expected to be hydrolyzed to acrylic acid and ammonia,
to be biodegraded by microorganisms, or to react through its
1-1
-------
double bond with chlorine, bisulfite, or ammonia.
In experimental studies with acrylamide, rats excreted
approximately 60% of an administered dose in the urine, either
as metabolites or unchanged.
The neurotoxic effects of acrylamide are well known and
have been extensively documented. In animal studies, incoordina-
tion, convulsions, behavioral and EEC changes, peripheral neuro-
pathies, sensory loss, and paralysis have been reported. Signs
of acrylamide poisoning in workers include polyneuritis, sensory
loss, muscle weakness, absence of tendon reflexes, imbalance,
numbness, and positive Romberg's sign. There have been two
reports of negative results in the Ames test, and one report of
no adverse effects in the offspring of pregnant rats exposed to
acrylamide.
Acrylamide may pose major hazards to human and aquatic life
as a result of several factors, including the leaching of residual
monomer from polyacrylamides in soil grouts, in waste-treatment
sludge and ore-tailing deposits, and in polyacrylamide flocculants
used in clarifying and purifying waste waters.
1-2
-------
ACRYLAMIDE
PART I
GENERAL INFORMATION
1-1 Identification CAS No.: 000079061
NIOSH No.: AS33250
1-2 Synonyms and Trade names
Acrylic amide; propenamide; propenoic acid amide (G16, G22)
1.3 Chemical Formula and Molecular Weight
0
II
H2C=C - C - NH2 C3H5NO Mol. wt. 71.08 (G22)
H
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless, odorless crystals; the
solid is stable at room temperature
but may polymerize violently on melt-
ing. (G21)
1.4.2 Boiling Point: 125°C (25 mm) (G21)
1.4.3 Melting Point; 84-85°C (G22)
1.4.4 Absorption Spectrometry;
No information was found in the sources searched.
1.4.5 Vapor Pressure: 1.6 mm at 84.5°C (G15)
1.4.6 Solubility; Insoluble in benzene, heptane;
soluble in alcohol, ether, acetone;
very soluble in water, chloroform
(G21, G22)
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched.
1-3
-------
1.5 Production and Use
1.5.1 Production; 15-20 million Ib (.1966)
32 million Ib (.1972)
70 million Ib (1974)
(1, as cited in 2)
64 million Ib (1976) (3)
1.5.2 Use; As a cross-linking agent; in adhesives, paper
and textile sizes, soil grouting and condition-
ing agents, and flocculants; in sewage and
waste water treatment; in ore processing; in
permanent press fabrics; in the synthesis of
dyes, etc.; in secondary and tertiary oil
recovery
tG21,3)
1.6 Exposure Estimates
1.6.1 Release Rate;
No information was found in the sources searched.
1.6.2 NIOSH Estimates of Occupational Exposure;
NOHS Rank: 2987
Estimated no. of persons exposed: 7,000*
*rough estimate
(G29)
In its criteria document, NIOSH estimated that
20,000 workers are potentially exposed to
acrylamide in the United States (2).
1.7 Manufacturers and Suppliers
American Cyanamid Co.
Cemco, Inc.
Conray Chemicals, Inc.
Eastman Kodak Co.
Polysciences, Inc.
Vistron Corp.
(G37)
1-4
-------
ACRYLAMIDE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
No specific evidence for or against the bioaccumulation of
acrylamide was found in the sources searched, and its octanol/
water partition coefficient was not available. Although acryl-
amide is highly soluble in water (215.5 g/100 ml water at 30°C
(G23)), it is also soluble in chloroform, and therefore probably
has a potential for slight bioaccumulation.
2.2 Impurities and Environmental Degradation or Conversion
Products
Acrylamide is available commercially in solid state (G17)
and as a 50% aqueous solution by weight (3). As a solid, acryl-
amide is stable and requires no stabilizers, but in solution it
is unstable and tends to polymerize. Polymerization inhibitors
added to commercial solutions of the chemical are hydroquinone,
tert-butyl pyrocatechol (G23), cupric and ferrous salts, N-phenyl-
2-naphthylamine, cupferron, and tetramethylthiuram monosulfide
(bis(dimethylthiocarbamoyl)sulfide) (G17). Ammonium and calcium
sulfate, acrylic acid, sulfuric acid, acrylonitrile, beta-
hydroxyproprionamide, and water are other possible contaminants,
depending on the mode of synthesis (G17,3). One solid product
in a "technical" grade is reported to be 97% pure (G21) and
another in a "commercial" grade to be 98% pure (G17). Specifica-
1-5
-------
tions for the commercial product allow 0.8% water, 0.0015% Fe,
0.02% water insolubles, and 1.5% butanol insolubles (G17). Speci-
fications for a 50% aqueous solution were 50+2% water by weight,
pH 5.2-6.0, a boiling point of 105.5°C, a specific gravity of
1.04, and a crystallization point of 12-13°C (3).
Ammonia, bisulfite, and chlorine (from water treatment), all
present in the environment, are known to react with the double
bond of the compound (.3). The chlorination product, 2,3-dichloro-
proprionamide, is a vesicant (.3). The ammonia and bisulfite
adducts are reported to have potential uses as acrylamide scaven-
gers (.3) .
Fatty acid amides are generally metabolized to the correspond-
ing acid and amine (.G38). Environmental degradation of acrylamide
is expected to follow a similar course: it will probably hydrolyze
to ammonia and acrylic acid, both of which may be toxic to fish
and other organisms. Acrylamide is also readily biodegraded in
several days by sewage, soil, and river microorganisms; the degra-
dation products were not specified (.3) .
2.3 Acute Toxicity
The acute toxicity of acrylamide, as reported in the NIOSH
Registry of Toxic Effects of Chemical Substances (G16), is given
in Table 1-1.
1-6
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TABLE 1-1
ACUTE TOXICITY OF ACRYLAMIDE
Parameter
LD50
ii
"
LDLO
ii
ti
Dose (mg/kg)
170
170
170
126
1,000
252
Species
Rat
Mouse
H
Rabbit
ii
Guinea pig
Route
Oral
"
i.p.
Oral
Skin
Oral
Paulet and Vidal (4) determined LD50 values of 124 and 90
mg/kg for acrylamide given to Wistar rats by the oral and intra-
peritoneal routes, respectively. Spencer and Schaumburg (5)
reviewed the literature on the effects of acrylamide in animals,
focusing on its neurotoxicity. Unpublished studies cited in this
review have demonstrated a sequence of clinical findings in dogs,
cats, mice, rats, rabbits, and frogs given 100-5,000 mg/kg of the
chemical. Depending on the route of administration and the dose,
neurologic and circulatory manifestations became apparent. Some
animals died, and the suspected cause was respiratory failure.
EEC changes were also seen in decerebellate, decerebrate, and
decorticate cats exposed to acrylamide (23). A convulsive episode,
with recovery within 24 hours, in a cat given a single treatment
with 100 mg/kg was reported.
1-7
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2.4 Other Toxic Effects
Spencer and Schaumburg (5) stated that the induction of
neuropathies by exposure to acrylamide was the most consistent
finding. In a review article, these authors mentioned the
higher susceptibility of older animals and the absence of sex-
specific reactions. Cats given 0.3-1 mg/kg and monkeys given
1-3 mg/kg daily for 1 year were stated to have shown no toxic
symptoms. Doses of 10-50 mg/kg/day, by all routes, elicited
peripheral neuropathy. Hind limb signs (not specified) were
seen by 2 weeks in suckling rats given 50 mg/kg/day of acryl-
amide intraperitoneally for 6 days and in 40-100 days in baboons
fed 10 mg/kg/day in fruit. Cats given 20 mg/kg/day showed adverse
signs in 4-6 days, while those receiving 10 mg/kg/day showed
none until the 13th-15th day.
Bradley and Asbury (27) reported that mice given acrylamide
in their drinking water at 250 ppm for 45 days lost weight and
hair and had difficulty in using their hind legs. After the
treatment had ended, weight gain and improved gait were observed
within five days. In animals autopsied on day 23 of the treat-
ment, histopathological examination revealed degeneration of
myelinated fibers.
To evaluate the safety of the commercial use of polymers or
copolymers, which might contain small amounts of residual acryl-
amide, McCollister et al. (22) gave rats polymer samples contain-
ing 0.07-0.81% residual acrylamide. The authors mixed the poly-
mer samples with rat feed to give acrylamide concentrations of
3, 9, 30, 70, 90, 110, 300, and 400 ppm. The rats were dosed for
1-8
-------
90 days by dietary and intragastric feeding. In animals receiving
acrylamide at 300 ppm, loss of the use of hindquarters and loss
of proprioception were reported.
McCollister et al. (22) fed cats and monkeys acrylamide 5
days/week at 0.83-10 mg/kg for 1 year. The authors observed
weakness and loss of control of the hindquarters in both species.
Hopkins (18) reported that the main features of clinical
illness in seven baboons given acrylamide (injected into fruit
as a 10% solution in water) at 10, 15, or 20 mg/kg/day for 29-192
days were weakness of the jaw and facial muscles, paralysis, and
extensive damage to peripheral nerves.
Leswing and Ribelin (6) determined the effects of acrylamide
on 11 cats and 4 Cebus monkeys. The animals were given the chem-
ical orally at 20 mg/kg/day, but the daily dose for the monkey
was increased to 30 mg/kg by about the 8th week. In 2-3 weeks,
all of the cats showed clinical signs of hind limb weakness,
unsteadiness of the posterior part of the body, and eventually
paralysis. Anorexia, weight loss, rhinitis, and eye infection
were also noted.
Monkeys were reported to have been less sensitive than cats
to the chemical's toxicity (6). They received doses 50% larger
before they showed similar adverse signs. Pathological examina-
tions revealed abnormalities in the nerves of the caudal limbs.
Degeneration of myelin and axons was more severe distally than
proximally. The authors stated that all the animals showed
marked clinical improvement several weeks after returning to an
acrylamide-free diet but that conduction velocity was depressed.
1-9
-------
Barnes (.7). reported that doses of acrylamide given to young
rats by mouth at 100 mg/kg/day for 2 days was lethal for most
rats. When acrylamide was given at 400 ppm in the diet, signs
of disability were apparent within 4 weeks, and the effects were
more severe by 8 weeks. Full information on data was not pro-
vided.
Female rats given acrylamide at 50 mg/kg/day were reported
to have shown alterations in ambulatory and rearing behavior,
but those given 20 mg/kg/day did not (10). Rats given acrylamide
for 9-22 days at 20, 30, and 50 mg/kg/day were said to have had
depressed body weight increase, food intake, and fecal and urin-
ary output.
Drees et al. (9) found no neurotoxicity in newborn rabbits
given subcutaneous injections of acrylamide in 0.5 and 5 mg/kg
doses daily for 12 weeks. In 17 of 23 rabbits given 50 mg/kg/day
for 5 weeks, neurotoxic effects were first observed on the 24th
day- When the rabbits were taken off the treatment for 7 weeks,
all but one were said to have returned to normal. No changes
were detected in hematological and biochemical tests or in gross
and histopathological examinations.
Edwards (8) studied the neurotoxic effects of acrylamide in
nine hens given 50 mg/kg of acrylamide orally, three times a week.
Ataxia was observed in two hens after four doses, in five after
six doses, and in the other two after nine doses. Four hens
recovered 2-3 months after treatment was stopped. Histopatholog-
ical alterations were seen in the peroneal and sciatic nerves
from some of the hens with marked ataxia.
1-10
-------
Edwards (8) reported that three doses in one week of acryl-
amide at 50 vg/g injected into the dorsal sac of five frogs was
lethal in three and a 2-hour exposure to a 2% (w/v) solution
killed two out of three frogs. Surviving frogs were said to have
been free of toxic signs.
Sharma et al. (11) incubated in vitro cultures of nerve
fibers, neuroglia, and neurons from dorsal chick ganglia with
acrylamide at 37°C for 72 hours. Light and phase microscopic
evaluation revealed that acrylamide at 2.1 x 10~4 and 3.8 x 10~ M
had a half-maximal inhibitory effect on the fibers and the neuro-
glia, respectively. The authors reported complete inhibition of
— 2 — 5
cell growth at 10 M, whereas acrylamide at 10 M was noninhibi-
tory.
Several studies have reported instances of toxicity in workers
exposed to acrylamide. Six persons in two factories in England
were reported to have had severe polyneuropathy, and it took 1
year for complete recovery from the symptoms (13). Kesson et al.
(12) reported acrylamide poisoning in six construction workers.
The patients were between 26 and 57 years old and were exposed
to the chemical for 19-36 weeks. Signs and symptoms included
sweating, peeling skin, abnormal skin sensations, sensory loss,
muscle weakness, absence of tendon reflexes, and positive Romberg's
sign. The less affected patients recovered, but little recovery
occurred in two patients after 1 year.
Auld and Bedwell (14) reported the case of a New Brunswick
miner who worked 35 hours/week loading hoppers with a 10%
aqueous solution of acrylamide. The first symptoms, noted af-
1-11
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TABLE 1-2
SUMMARY OF EFFECTS OF ACRYLAMIDE EXPOSURE ON HUMANS
Number of
Subjects
Duration and Route of
Exposure
Observed Effects
References
i
M
NJ
17
10
3-24 mo, dermal and
possible inhalation
3-13 mo, dermal and
possible inhalation
4-7 mo, dermal and
possible inhalation
2 mo-8 yr, dermal and
possible inhalation
1 mo, ingestion
7-12 mo, dermal and
possible inhalation
3-24 mo, dermal and
possible inhalation
1 mo-8 yr, dermal and
possible inhalation
1-15 mo, dermal and
possible inhalation
Erythema, excessive sweating, muscular
weakness
Loss of weight, anorexia
Eye irritation, skin rash, fatigue,
confusion
Gastrointestinal upset
Rhinorrhea, urinary and fecal retention,
ecchymoses
Vertigo, abnormal reflexes, emotional
changes
Ataxia, hypoesthesia
Pain, tremor, desquamation, sensory
loss
Positive Romberg's sign
14-16
Brinkley*
13,15-17,
19
14 ,17
20
21
14,15,
17,19
14-16
13,14,
15,20
13,15
17,19
*From D.R. Brinkley (written communication, June 1976)
Adapted from the NIOSH Criteria for a Recommended Standard—Occupational Exposure to Acrylamide(2)
-------
TABLE 1-3
SUMMARY OF EFFECTS OF ACRYLAMIDE EXPOSURE ON ANIMALS
Routes of
exposure Animal
Dose and Duration
Observed Effects
References
Dermal
Rabbit
Ocular
Oral
i
M
U)
Rat
Mouse
0.5-1.0 g/kg, 24 hr
10% solution, 3 days
10% solution, 2 wk
10 and 40%, 24-48 hr
203-277 mg/kg,.
1 dose
50-126 mg/kg,
1-15 days
100 mg/kg, 2-3 days
0.3-11 mg/kg,
55-189 days
200-400 ppm, 1-6 mo
100 ppm, 6-40 wk
10-50 ppm, 6 wk
170 mg/kg, 1 dose
250 ppm, 45 days
Edema, death 1/5
On abraded skin, slight reddening,
edema
On shaved skin, no effects
Pain, conjunctival irritation
LD50, death 5/5
Lethargy, weakness, bladder
distension
Death of most animals
No effects
Loss of motor control, ataxia, leg
weakness, progressive paralysis
Growth retardation, leg weakness
No effects
LD50
Weight loss, ataxic gait
22
22
22
23
22,24,25
7,24,26
22,24
7,8,22,24,26
22,24
26
26
27
-------
TABLE 1-3 (continued)
Routes of
Exposure
Animal
Dose and Duration
Observed Effects
References
Oral
l.p.
1. V,
s.c.
Rabbit
Guinea pig
Cat
Dog
Monkey
Rat
Monkey
Cat
252 mg/kg, 1 dose
126 mg/kg, 1 dose
252 mg/kg, 1 dose
126 mg/kg, 1 dose
1-20 mg/kg,
53-367 days
0.03-0.3 mg/kg,
367 days
5-100 mg/kg, 4-5 wk
1-8 mg/kg, 4-19 wk
10-30 mg/kg, 8-10 wk
0.03-3 mg/kg, 51 wk
50-100 mg/kg, 4-6 wk
100 mg/kg, 2 days
50 mg/kg, 4 days
10 mg/kg,
21-61 days
Death 4/4 22
Death 1/4; tremors, pupil dilation 22
Death 4/4 22
No deaths, slight weight loss 22
Weakness, paralysis, twitching 6
No effects 22
Ataxia, sedation, weakness 20,26
No effects 26
Weakness, decreased nerve conduction 6,22
velocity, myelin and axonal
degeneration
No effects 22
Weight loss, paralysis, bladder dis- 28,29
tension, myelin and axonal destruction
Lung and kidney congestion, liver 22
necrosis, severe weakness, death
Death within 4 days 22
Ataxia, absent Achilles tendon jerks, 30
interruption of nerve function
-------
TABLE 1-3 (continued)
Routes of
Exposure Animal Dose and Duration Observed Effects References
Oral, i.p., Cat 1-50 mg/kg Ataxia, progressive weakness, gradual 17
i.v., i.m., (duration not blood-pressure drop to shock level;
s.c. specified) death of some animals
Adapted from the NIOSH Criteria for a Recommended Standard—Occupational Exposure to
Acrylamide (2)
-------
ter 7 weeks, included dermatitis, weakness in the legs and
hands, and poor balance. Later signs were blueness, coldness,
and profuse sweating of the extremities, numbness, and tender-
ness. At the time the worker was hospitalized, his bluish-red
forearms, hands, lower legs, and feet dripped perspiration and
were cold to touch. Temperature and vibration sensations were
slightly impaired, tendon reflexes were absent, and the patient
showed general weakness and unsteadiness. The man's condition
had returned to normal 14 weeks after he was removed from ex-
posure to acrylamide.
The effects of acrylamide exposure on humans and animals
are summarized in Tables 1-2 and 1-3, which were adapted from
the NIOSH criteria document on acrylamide (2).
The ACGIH Threshold Limit Value (TLV) for acrylamide
is 0.3 mg/m , with a "skin" notation (Gil), and NIOSH has
recommended a limit of 0.3 mg/m , as a TWA, for occupational
exposure to the substance (2). The OSHA limit for skin ex-
posure is 300 yg/m (G16).
2.5 Carcinogenicity
No information was found in the sources searched.
2.6 Mutagenicity
Acrylamide was reported to have given negative results in
Ames assays run independently by NIOSH (31) and American Cyanamid
(36). In the NIOSH study, bacteria were exposed to 25-500 pi of
acrylamide in DMSO (1 vg/]il DMSO) , in the presence and absence
1-16
-------
of rat liver homogenate (0-50 yl of S-9 fraction/plate) (31).
No evidence of mutagenicity was apparent in the Salmonella tester
strains TA 98, TA 100, TA 1535, and TA 1537. American Cyanamid
tested acrylamide at 1,000 yg in Salmonella typhimurium strains
TA 98, TA 100, TA 1530, TA 1535, and TA 1538 without rat liver
homogenate.
2.7 Teratogenicity
Edwards (32) evaluated the teratogenic effects of acrylamide
by giving it to pregnant rats either in the diet at levels of
200 and 400 ppm from the day of mating until parturition or by
single intravenous injections at 100 mg/kg (in water) on day 9
of gestation, which according to the author is when the nervous
system is most susceptible to teratogenic effects. No macroscopic
skeletal or organ abnormalities were observed in the offspring,
even at doses that produced neuropathy in the mothers. However,
it is possible that acrylamide in utero causes reversible damage
to fetal nerves.
2.8 Metabolic Information
The metabolic fate of acrylamide was extensively reviewed by
Spencer and Schaumburg (5) and in a NIOSH criteria document (2).
Spencer and Schaumburg (5) cited two unpublished studies in
14
which C-labeled acrylamide became widely distributed in the
body and showed the highest affinity for vascular organs (doses,
exposure, and species not specified). In another study cited by
Spencer and Schaumburg, tadpoles totally immersed in a solution
of labeled acrylamide showed distribution in the brain, nerves,
1-17
-------
and other unspecified organs. Ando and Hashimoto (37, as re-
ported in 5) reported that, in mice given labeled acrylamide by
injection, 2.5 times more radioactivity was detected in the distal
half of the sciatic nerve than in the proximal part and 4 times
more radioactivity was found in the distal half of the sciatic
nerve than in the brain. This finding was considered significant
because of the reported damage to the distal peripheral nerve.
Hashimoto and Aldridge (28) injected two male rats intra-
14
venously with a single C-labeled dose of acrylamide at 100 mg/kg.
About 6% of the dose was exhaled as carbon dioxide in the first
8 hours, followed by very slow excretion afterward. Forty per-
cent of the dose was excreted in urine within the 1st day and
more than 60% by day 3. The urinary metabolites were not identi-
14
fied. On the 1st, 4th, and 14th day after treatment, C was
detected in whole blood, plasma, brain, spinal cord, sciatic
nerve, liver and kidney, with the highest activity in the blood.
The large amount of activity present on the 14th day was presumed
to be protein-bound.
Data noted by Spencer and Schaumburg (5) indicated that in
rats 40-65% was excreted in 24 hours and 60-85% in 3-4 days. From
80-89% of the urinary label was thought to be in metabolites,
but some investigators have maintained that acrylamide is excreted
unchanged.
The half-life of acrylamide in the blood of rats given
100 mg/kg intravenously was reported to be 1.9 hours (33,
as reported in 2).
1-18
-------
It has also been suggested that acrylamide might be
metabolized in the liver, because rats pretreated with either
phenobarbitol or DDT showed 100% failure in rotarod performance
(a measure of neurological deficit) only after they were given
520 and 600 mg/kg of acrylamide, respectively, in a single
intraperitoneal injection, while rats that were not pretreated
showed 100% failure when given, a 360 mg/kg dose (34, as re-
ported in 2) .
2.9 Environmental Release and Ecological Effects
Acrylamide may enter the environment from a number of sources.
It is released at manufacturing sites, at polymer-application
sites as residual monomer, and in transportation and handling.
High environmental concentrations of acrylamide may result from
its use in chemical grouting, for example in the sealing of sewage
collection systems to prevent groundwater infiltration and in soil
stabilization at construction sites. In soil grouting, residual
acrylamide monomer may come in direct contact with surface or
ground waters. It could potentially travel great distances in
ground water or aquifers where biodegradation is reported to be
absent. Leaching of residual monomer from polyacrylamide in
waste-treatment sludge and ore-tailing deposits as well as run-
off and seepage from irrigation sites where acrylamide-containing
waste water is used are other sources of contamination. Poly-
acrylamide flocculants are widely used in clarifying and purifying
industrial and municipal waste waters. Monomeric residues from
these flocculants may contaminate the environment (3).
1-19
-------
One ecological incident has been described (3). A road in
Japan 2.5 meters from a well was chemically grouted—a process
that involves incomplete in situ polymerization. All members of
a family of five who used the well became ill, exhibiting a number
of neurological signs. They recovered after they stopped using
the well, which was found to contain acrylamide at 400 ppm.
Edwards (.8) reported that seven goldfish exposed to acryl-
amide at 100 ppm died in 5-7 days, but that exposure at 50 ppm
for 30 days caused no toxic effects. Paulet and Vidal (4) re-
ported a 72-hour LC50 of 140 ppm for goldfish. Edwards (8)
reported that exposure to acrylamide was fatal to frogs (see
Section 2.4, Other Toxic Effects).
2.10 Current Testing
Tox-Tips (35) reported that the Environmental Protection
Agency (J.P. Lewkowski et al., Health Effects Research Labora-
tory, Cincinnati, Ohio) is conducting pathological examinations
on Sprague-Dawley rats. The animals were exposed to unspecified
doses of acrylamide in drinking water for 14 weeks in a behavioral
toxicity study. An identical experiment is planned in which
tissues from exposed animals will be examined for neurophysio-
logical effects.
1-20
-------
REFERENCES
1. Blackford, J.L. Acrylonitrile. In Chemical Economics
Handbook. Stanford Research Institute, Menlo Park,
California. Pp 607.5031A-607.5022G (1974)
2. National Institute of Occupational Safety and Health
(NIOSH) . Criteria for a Recommended Standard—Occupational
Exposure to Acrylamide (October 1976)
3. Peterson, R.J., Colingsworth, R.F., Conway, E.J., and
Graca, J.G. Assessment of the need for, and character of,
limitations on acrylamide and its compounds. Draft Re-
port prepared for Office of Toxic Substances, U.S. Environ-
mental Protection Agency, Washington, D.C. MRI Project No.
4308-N (July 1977)
4. Paulet, G., and Vidal, M. Toxicity of some acrylic and
methylacrylic esters of acrylamide and polyacrylamides.
Arch. Mai. Prof. Med. Trav. Secur. Soc. 36:58-60 (1975)
5. Spencer, P.S., and Schaumburg, H.H. A review of acrylr^ide
neurotoxicity: Part I. Properties, uses and human expos ~e;
Part II. Experimental animal neurotoxicity and patholog
mechanisms. Can. J. Neurol. Sci. 1:152-169 (1974)
6. Leswing, R.J., and Ribelin, W.E. Physiologic and patho ic
changes in acrylamide neuropathy. Arch. Environ. Healtr 18:
23-29 (1969)
7. Barnes, J.M. Observations on the effects on rats of com-
pounds related to acrylamide. Br. J. Ind. Med. 27:147-
149 (1970)
8. Edwards, P.M. Neurotoxicity of acrylamide and its analogues
and effects of these analogues and other agents on acryla-
mide neuropathy. Br. J. Ind. Med. 32:31-38 (1975)
9. Drees, D.T., Crago, F.L., Hopper, C.R., and Smith, J.M.
Subchronic percutaneous toxicity of acrylamide and meth-
acrylamide in the newborn rabbit. Toxicol. Appl. Pharmacol.
37:190 (1976)
10. Gipon, L., Schotman, P., Jennekens, F.G.I., and Gispen, W.H.
Polyneuropathies and CNS protein metabolism: I. Description
of the acrylamide syndrome in rats. Neuropathol. Appl.
Neurobiol. 3:115-123 (1977)
11. Sharma, R.P., and Obersteiner, E.J. Acrylamide cytotoxicity
in chick ganglia cultures. Pharmacologist 18:243 (1976)
1-21
-------
12. Kesson, C.M., Baird, A.W., and Lawson, D.H. Acrylamide
poisoning. Postgrad. Med. J. Volv. 53:16-17 (1977)
13. Garland, T.O., and Patterson, M.W.H. Six cases of acrylamide
poisoning. Brit. Med. J. 4:134-138 (1967)
14. Auld, R.B., and Bedwell, S.F. Peripheral neuropathy with
sympathetic overactivity from industrial contact with
acrylamide. Can. Med. Assoc. J. 96:652-654 (1967)
15. Graveleau, J., Loirat, P., and Nusinovici, V. Polyneuritis
caused by acrylamide. Rev. Neurol. (Paris) 123:62-65 (1970)
16. Cavigneaux, A., and Cabasson, G.B. Acrylamide poisoning.
Arch. Mai. Prof. Med. Trav. Secur. Soc. 33:115-116 (1972)
17. Morviller, P- An industrial poison little known in France—
acrylamide. Arch. Mai. Prof. Med. Trav. Secur. Soc. 30:
527-530 (1969)
18. Hopkins, A.P. The effects of acrylamide on the peripheral
nervous system of the baboon. J. Neurol. Neurosurg. Psy-
chiatry 33:805-816 (1970)
19. Fujita, A., Shibata, J., Kato, H. , Amami, Y., Itomi, K.,
Suzuki, E., Nakazawa, T., and Takahashi, T. Clinical obser-
vations of three cases of acrylamide poisoning. Nippon
Ijo Shimpo 1869:37-40 (1961)
20. Takahashi, M., Ohara, T., and Hashimoto, K. Electrophysio-
logical study of nerve injuries in workers handling acryl-
amide. Int. Arch. Arbeitsmed. 28:1-11 (1971)
21. Igisu, H., Goto, I., Kawamura, Y., Kato, M., Izumi, K., and
Kuroiwa, Y. Acrylamide encephaloneuropathy du'e to well water
pollution. J. Neurol. Neurosurg. Psychiatry 38:581-584
(1975)
22. McCollister, D.D., Oyen, F., and Rowe, V.K. Toxicology of
acrylamide. Toxicol. Appl. Pharmacol. 6:172-181 (1964)
23. Kuperman, A.S. Effects of acrylamide on the central nervous
system of the cat. J. Pharmacol. Exp. Ther. 123:180-192
(1958)
24. Fullerton, P.M., and Barnes, J.M. Peripheral neuropathy
in rats produced by acrylamide. Br. J. Ind. Med. 23:210-
221 (1966)
25. Keeler, P.A., Betso, J.E., and Yakel, H.O. Toxicological
Properties of a 50.7% Aqueous Solution of Acrylamide. Toxi-
cology Research Laboratory, Dow Chemical Co., Midland,
Mich. (1975)
1-22
-------
26. Hamblin, D.O. The toxicity of acrylamide--a preliminary
report. In Hornmage au Doyen Rene" Fabre (Paris) . Pp 195-
199 (1956)
27. Bradley, W.G., and Asbury, A.K. Radioautographic studies
of Schwann cell behavior: I. Acrylamide neuropathy in the
mouse. J. Neuropathol. Exp. Neurol. 29:500-506 (1970)
28. Hashimoto, K. , and Aldridge, W.N. Biochemical studies on
acrylamide, a neurotoxic agent. Biochem. Pharmacol. 19:
2591-2604 (1970)
29. Suzuki, K. , and Pfaff, L.D. Acrylamide neuropathy in rats —
an electron microscopic study of degeneration and regenera-
tion. Acta Neuropathol. (Berlin) 24:197-213 (1973)
30. Sumner, A. J. , and Asbury, A.K. Physiological studies of
the dying-back phenomenon--muscle stretch afferents in
acrylamide neuropathy. Brain 98:91-100 (1975)
31. Taylor, G. (Associate Director, Appalachian Laboratory for
Occupational Safety and Health, National Institute for
Occupational Safety and Health) Memorandum: Mutagenicity
testing--acrylamide (April 13, 1977)
32. Edwards, P.M. The insensitivity of the developing rat foetus
to the toxic effects of acrylamide. Chem. Biol. Interact.
12:13-18 (1976)
33. Edwards, P.M. The distribution and metabolism of acrylamide
and its neurotoxic analogues in rats. Biochem. Pharmacol.
24:1277-1282 (1975)
34. Kaplan, M.L., Murphy, S.D., and Gilles, F.H. Modification
of acrylamide neuropathy in rats by selected factors. Tox-
icol. Appl. Pharmacol. 24:564-579 (1973)
35. Tox-Tips. National Library of Medicine, Bethesda, Md.
(November 1977)
36. Culbreth, W. (American Cyanimid Company). Mutagenicity test
report: Acrylamide. Personal communication (October 12, 1976)
37. Ando, K., and Hashimoto, K. Accumulation of dJ-C)-
acrylamide in mouse nerve tissue. Proceeding of the Osaka
Prefectural Institute of Public Health 10:7-12 (1972)
1-23
-------
ARYL PHOSPHATES
TABLE OF CONTENTS
Page
Overview II-l
Part I General Information
Cresyl Diphenyl Phosphate II-3
Triphenyl Phosphate II-5
Trisisopropylphenyl Phosphate II-7
Tritolyl Phosphate II-9
Part II Biological Properties
Aryl Phosphate Group
2.1 Bioaccumulation 11-13
2.2 Impurities and Environmental
Degradation or Conversion
Products 11-13
2.3 Acute Toxicity 11-14
2.4 Other Toxic Effects 11-14
2.5 Carcinogenicity 11-15
2.6 Mutagenicity 11-16
2.7 Teratogenicity 11-16
2.8 Metabolic Information 11-16
2.9 Environmental Release and
Ecological Effects 11-16
2.10 Current Testing 11-17
Cresyl Diphenyl Phosphate
2.1 Bioaccumulation 11-18
2.2 Impurities and Environmental
Degradation or Conversion
Products 11-18
2.3 Acute Toxicity 11-18
Il-i
-------
Page
2.4 Other Toxic Effects 11-18
2.5 Carcinogenicity 11-18
2.6 Mutagenicity 11-18
2.7 Teratogenicity 11-18
2.8 Metabolic Information 11-19
2.9 Environmental Release and
Ecological Effects 11-19
2.10 Current Testing 11-19
Triphenyl Phosphate
2.1 Bioaccumulation 11-20
2.2 Impurities and Environmental
Degradation or Conversion
Products 11-20
2.3 Acute Toxicity 11-20
2.4 Other Toxic Effects 11-21
2.5 Carcinogenicity 11-23
2.6 Mutagenicity 11-23
2.7 Teratogenicity 11-24
2.8 Metabolic Information 11-24
2.9 Environmental Release and
Ecological Effects 11-24
2.10 Current Testing 11-24
Trisisopropylphenyl Phosphate
2.1 Bioaccumulation 11-25
2.2 Impurities and Environmental
Degradation or Conversion
Products 11-25
2.3 Acute Toxicity 11-25
2.4 Other Toxic Effects 11-25
2.5 Carcinogenicity 11-25
2.6 Mutagenicity 11-25
2-7 Teratogenicity 11-25
Il-ii
-------
Page
2.8 Metabolic Information 11-26
2.9 Environmental Release and
Ecological Effects 11-26
2.10 Current Testing 11-26
Tritolyl Phosphate
2.1 Bioaccumulation 11-27
2.2 Impurities and Environmental
Degradation or Conversion
Products 11-27
2.3 Acute Toxicity 11-27
2.4 Other Toxic Effects 11-29
2.5 Carcinogenicity 11-31
2.6 Mutagenicity 11-31
2.7 Teratogenicity 11-31
2.8 Metabolic Information 11-31
2.9 Environmental Release and
Ecological Effects 11-32
2.10 Current Testing 11-32
References 11-33
-------
ARYL PHOSPHATES
AN OVERVIEW
Four different aryl phosphate compounds are included in
this dossier: cresyl diphenyl phosphate, triphenyl phosphate,
trisisopropylphenyl phosphate, and tritolyl phosphate. A
number of other aryl phosphates, including some containing alkyl
as well as aryl ester linkages, are also manufactured. Aryl
phosphates are either liquids or solids that are generally solu-
ble in organic solvents but insoluble in water.
Six different manufacturers of the aryl phosphates discussed
in this dossier have been identified in the United States. No
data are available on the manufacturers or the production volume
of trisisopropylphenyl phosphate; the latest available produc-
tion figures for the other three compounds reviewed in this
dossier range from 4.5 to 51 million pounds per year.
Aryl phosphates are used as components of high pressure
lubricants and hydraulic fluids and as plasticizers, gasoline
additives, and flame retardants. EPA regulations aimed at pre-
venting damage to automotive catalysts allow only trace concen-
trations of phosphorus in additives in unleaded gasoline. As
a result, the use of aryl phosphates as gasoline additives will
decline as unleaded gas assumes a larger share of the market.
Occupational exposure estimates by NIOSH range from less
than 1,000 workers for trisisopropylphenyl phosphate to more
than 2,000,000 for tritolyl phosphate.
Data on the bioaccumulation of aryl phosphates are limited.
Because of the aryl phosphates' high stability and their low
II-l
-------
solubility in water compared to their solubility in organic
solvents, some biostorage is likely. Uptake and storage of
aryl phosphates by fish and other aquatic food-chain organisms
have been reported.
Certain aryl phosphates are known to produce degenerative
damage to the peripheral (motor) nervous system, which results
in flaccid paralysis. One of these, tri-ortho-tolyl phosphate,
is highly toxic and has been implicated in numerous incidents
of human poisoning that have resulted in varying degrees of
paralysis. Subchronic feeding studies with triphenyl phosphate
have been reported, but long-term carcinogenicity studies are
lacking. No information was found on the mutagenicity or terato-
genicity of the aryl phosphates.
Commercial triaryl phosphate mixtures have been reported
to produce toxic effects in rainbow trout after prolonged
exposure. Several aryl phosphates have been found to potentiate
the effects of organophosphate pesticides on insects, and tri-
ortho-tolyl phosphate has been shown to produce such' potentiation
in other organisms, including mammals.
II-2
-------
ARYL PHOSPHATES
PART I
GENERAL INFORMATION
CRESYL DIPHENYL PHOSPHATE
1.1 Identification CAS No.: 026444495
NIOSH No.:
1.2 Synonyms and Trade Names
CDP; cresylphenyl phosphate; phosphoric acid, cresyl
diphenyl ester; Phosflex 122; Santicizer 140; Kronitex MX;
Kronitex K-3
(1,31,G21)
1.3 Chemical Formula and Molecular Weight
Mol. wt. 340.32
1.4 Chemical and Physical Properties
1.4.1 Description; Probably appears seldom as a pure com-
pound; usually as a mixture of ortho-,
meta-, and para-cresyl diphenyl phos-
phates; clear transparent liquid; very
slight color
(G21)
1.4.2 Boiling Point: 390°C (1)
1.4.3 Melting Point; -38°C (1)
1.4.4 Absorption Spectrometry;
No information was found in the sources searched.
1.4.5 Vapor Pressure; 0.08 mm at 200°C (1)
1.4.6 Solubility; Insoluble in water; soluble in most
organic solvents except glycerol
(G21)
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched.
II-3
-------
1.5 Production and Use
1.5.1 Production; 14.6 million lb (1972) (G28)
14.1 million lb (1973) (1)
7-8 million lb (1975) (G41)
4.5 million lb (1976) (G24)
1.5.2 Use; As a plasticizer; as an extreme pressure lubri-
cant; in hydraulic fluids; in food packaging;
as a gasoline additive
(G21)
Use of phosphorus-containing additives in
unleaded gasoline is limited by the EPA to
trace quantities (0.005 g phosphorus/gal,
maximum); use of aryl phosphate as addi-
tives should decline as use of unleaded
gasoline increases.
(2)
1.6 Exposure Estimates
1.6.1 Release Rate:
No information was found in the sources searched.
1.6.2 NOHS Occupational Exposure;
Rank: 1176
Estimated no. of persons exposed: 89,000*
*rough estimate
(G29)
1.7 Manufacturers
IMC Chem. Group
Stauffer Chemical Co.
Monsanto Industrial Chemicals Co.
Sobin Chemicals Co.
FMC Corp.
II-4
-------
TRIPHENYL PHOSPHATE
1.1 Identification CAS No.: 000115866
NIOSH No. : TC84000
1.2 Synonyms and Trade Names
Celluflex TPP; phosphoric acid, triphenyl ester; TPP;
Phosflex TPP
1.3 Chemical Formula and Molecular Weight
r w pn Mol. wt. 326.29
°18 15^U4
3 (G22)
1.4 Chemical and Physical Properties
1.4.1 Description: Colorless, odorless, crystalline
powder
(G21)
1.4.2 Boiling Point; 370°C (1)
1.4.3 Melting Point; 49.2°C (1)
1.4.4 Absorption Spectrometry;
No information was found in the sources searched.
1.4.5 Vapor Pressure;
No information was found in the sources searched.
1.4.6 Solubility; Insoluble in water; soluble in alcohol
and chloroform; very soluble in ether,
benzene, and carbon tetrachloride
(G22)
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched.
1.5 Production and Use
1.5.1 Production: 10.6 million Ib (1970) (G28)
II-5
-------
1.5.2 Use: At present, used exclusively as a plasticizer,
primarily with cellulosics such as cellulose
acetate and cellulose nitrate, but also in
newer rigid thermosetting materials, such
as polyphenylene oxide, and in synthetic rub-
bers
(1)
1. 6 Exposure Estimates
1.6.1 Release Rate:
No information was found in the sources searched.
1.6.2 NOHS Occupational Exposure;
Rank: 1154
Estimated no. of persons exposed: 95,000*
*rough estimate
(G29)
1.7 Manufacturers
Eastman Kodak
Monsanto Industrial Chemicals Co.
(G24)
II-6
-------
TRISISOPROPYLPHENYL PHOSPHATE
1.1 identification CAS No.r
NIOSH NO.:
1-2 Synonyms and Trade Names
No information found in sources searched
I-3 Chemical Formula and Molecular Weight
CH3CHCH3
0-- PO
C27H33P04 Mo1- wt- 452.53
1.4 Chemical and Physical Properties
1.4.1 Description; Probably a mixture of phenyl and
isopropylphenyl ester isomers;
liquid
(G25)
1.4.2 Boiling Point; 250°C at 4 mm (G25)
1.4.3 Melting Point; <-25°C (G25)
1.4.4 Absorption Spectrometry;
No information was found in the sources searched.
1.4.5 Vapor Pressure;
No information was found in the sources searched.
1.4.6 Solubility;
No information was found in the sources searched.
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched.
1.5 Production and Use
1.5.1 Production;
No information was found in the sources searched.
1.5.2 Use; In late 1970, FMC Corp. introduced trisisopro-
pylphenyl phosphate as a substitute for tritolyl
phosphate (see uses for tritolyl phosphate)
(G25)
II-7
-------
1.6 Exposure Estimates
1.6.1 Release Rate;
No information was found in the sources searched.
1.6.2 NOHS Occupational Exposure:
Rank: 5167
Estimate no. of persons exposed : <1,000*
*rough estimate
(G29)
1.7 Manufacturers
FMC Corp.
(G25)
II-8
-------
1•1 Identification
TRITOLYL PHOSPHATE
CAS No.: 001330785
NIOSH No.: TD01750
I-2 Synonyms and Trade Names
Phosphoric acid, tris(methylphenyl) ester; tricresyl
phosphate; TCP; PX-917; Celluflex; Kronitex; Lindol
(G23)
!«3 Chemical Formula and Molecular Weight
C21H21P04 Mo1' wt* 368-36
(G23)
1.4 Chemical and Physical Properties
1.4.1 Description; A mixture of isomeric tritolyl
phosphates, usually excluding the
very toxic ortho isomer as much as
possible; oily, flame-resistant
liquid
(G23)
1.4.2 Boiling Point; 420°C (G21)
1.4.3 Melting Point; -20°C ("congealing point") (G25)
1.4.4 Absorption Spectrometry;
No information was found in the sources searched.
1.4.5 Vapor Pressure;
No information was found in the sources searched.
1.4.6 Solubility; Insoluble in water ( <0.002% at
85°C); soluble in all proportions
in common organic solvents and thin-
ners, linseed oil, china wood oil,
castor oil
(G23)
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched.
II-9
-------
1.5 Production and Use
1.5.1 Production; 50.2 million Ib (1972) (G28)
50.6 million Ib (1973) (G25)
56 million Ib (1974) (G28)
51 million Ib (1975) (G41)
1.5.2 Use; As a plasticizer in vinyl plastics manufactur-
ing; as a flame retardant; as a solvent for
nitrocellulose; in cellulosic molding compo-
sition; as an additive to extreme pressure
lubricants; as a nonflammable fluid in hydrau-
lic systems; as a lead scavenger in gasoline;
to sterilize certain surgical instruments
(G23)
Use of phosphorus-containing additives in
unleaded gasoline is limited by the EPA to
trace quantities (0.005 g phosphorus/gal,
maximum); use of aryl phosphates as additives
should decline as use of unleaded gasoline
increases
(2)
Quantitative Distribution; Percentage
Functional fluids and lubricants
Plasticizers, flame retardants
Air filter adhesive mediums
Gasoline additive, automotive chemicals
Miscellaneous
100
(G25)
Consumer Product Information;
No. of tritolyl phos-
phate products
No. of products in category inn
containing Total no. of products x
Category tritolyl phosphate in category
Paints, varnishes, 22 0.2%
shellac, rust
preventatives,
etc.
Flame-retardant 9 1.5%
chemicals
Household aerosols 1 0.03%
Adhesives and adhesive 1 0.19%
products including glue
11-10
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The 33 products surveyed contained an average of 8.3% tritolyl
phosphate.
(G27)
1.6 Exposure Estimates
1.6.1 Release Rate; 43.4 million Ib
(G28)
1.6.2 NOHS Occupational Exposure;
Rank: 32
Estimated no. of persons exposed: 2,282,000*
(G29)
*rough estimate
1.7 Manufacturers
FMC Corp.
Monsanto Co.
Sobin Chemicals, Inc.
Stauffer Chemical Co.
IMC Chemical Group, Inc. (G24 G25)
11-11
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TABLE II-I
CHARACTERISTICS OF ARYL PHOSPHATES
Name
Cresyl
diphenyl
phosphate
Triphenyl
phosphate
H
H
i
H-<
Trisiso-
propyl-
phenyl
phosphate
Tritolyl
phosphate
Estimated
Environmental
Solubility Log P . Release
r (million Ib)
i in H2O; * *
s in most os
i in H2O; s * *
in ale, chl;
vs in eth, bz,
and CC14
* * *
i in H2O; °° in * 43.5
oos, linseed
oil, china wood
oil, castor oil
Production
(million Ib)
14.6
14.1
7-8
4.5
10.6
*
50.2
50.6
56
51
(1972)
(1973)
(1975)
(1976)
(1970)
(1972)
(1973)
(1974)
(1975)
Estimated No.
of Persons
Exposed
(Occupational )
^89,000
m
^95,000
<1,000
^2,300,000
Use
Plasticizer,
lubricant
gasoline additive,
in food packaging
Plasticizer
See Tritolyl
phosphate
Plasticizer,
f lame-retardant ,
solvent, additive
to lubricants and
hydraulic fluids,
lead scavenger in
gasoline
*No information was found in the sources searched.
Key to Abbreviations: i — insoluble
s — soluble
os — organic solvents
ale — alcohol
chl — chloroform
vs
eth
bz
00
oos
— very soluble
— ether
— benzene
— soluble in all proportions
— ordinary org
anic solvents
-------
ARYL PHOSPHATES
PART II
BIOLOGICAL PROPERTIES
ARYL PHOSPHATE GROUP
2.1 Bioaccumulation
Few data were found on the bioaccumulation of the particular
aryl phosphates discussed in this dossier. Some aryl phosphates
are likely to biostore because they are highly stable and are less
soluble in water than in organic solvents. One study provided
indirect evidence of the uptake of a commercial aryl phosphate
mixture from water by trout. Hydrolysis of muscle tissue from fish
exposed for 4 months to IMOL S-140 aryl phosphate at 0.9 mg/liter
in a flow-through system yielded cresols not detected before
hydrolysis. These cresols were not detected before or after
hydrolysis of tissue from unexposed fish (3). Preliminary
findings in another study indicated that aryl phosphates were
taken up by fish in their natural environment (4). In model
ecosystem studies, tri-p-cresol phosphate has been found to accu-
mulate and persist in all the aquatic test organisms used (30).
2.2 Impurities and Environmental Degradation or Conversion
Products
Aryl phosphate products are generally mixtures. For example,
some tricresyl phosphate, dicresyl phenyl phosphate, and triphenyl
phosphate can be expected in cresyl diphenyl phosphate. The cresyl
(same as tolyl) moiety in tricresyl phosphate is a mixture of
11-13
-------
ortho, meta, and para isomers. The relative amount of each isomer
depends on the nature of the cresol raw material (G25). The
concentration of the ortho-tolyl moiety is deliberately kept low
during synthesis to favor synthesis of the meta and para isomers
and thus avoid formation of the highly toxic ortho-tolyl phos-
phates (7). In air, triphenyl and tritolyl phosphates react with
hydroxyl radical with an estimated half-life of 4 days (G14). In
water, hydrolysis is moderately rapid at pH 10 (half-life 30 days)
and extremely slow at pH 7 (half-life many years) (G14). Phos-
phates generally hydrolyze with loss of ester groups to give
phosphoric acid, the corresponding phenols, and their degradation
products, e.g., quinones. Hydrolysis of the diester is usually
the slowest step (4). One report indicated that an aryl phosphate
was metabolized by a soil microorganism (G14).
2.3 Acute Toxicity
See Section 2.3 for each aryl phosphate.
2.4 Other Toxic Effects
In man and other species, certain aryl phosphates may
produce damage to central or peripheral nerves, leading to paral-
ysis. Aryl phosphates may also produce inhibition of cholines-
terases in erythrocytes and plasma. The tris(alkylphenyl) phos-
phates specifically depress intestinal and hepatic phenylbutyrate
esterases (G10). Several aryl phosphates, such as tri-ortho-tolyl
phosphate, have been found to produce delayed neurotoxic ef-
fects (8).
11-14
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Accidental poisoning of cattle was reportedly caused by
triaryl phosphates (TAP's) escaping from a gas pipeline compressor
station. The clinical signs were posterior motor paralysis, dysp-
nea, diarrhea, and agalactia (absence or 'failure of milk secretion)
This incident prompted a study in which cattle were given oral
doses of TAP at 0.5-1 g/kg. The cattle exhibited axonal degen-
eration of the spinal cord and cholinesterase depression (9, from
TOXLINE abstract).
The relationship between the delayed neurotoxicity of aryl
phosphates and their chemical structures has been reviewed (8).
The neurotoxic aryl phosphates include those with one or more
ortho-alky1-substituted aryl groups having at least one hydrogen
on the alpha carbon. Para-alkyl-substituted aryl phosphates can
also be neurotoxic if the alpha carbon of the substituent has at
least two hydrogen atoms.
Tri-ortho-tolyl phosphate has caused severe human poisoning.
(See 2.4 for tritolyl phosphate.)
A NIOSH criteria document on organophosphates is to be
submitted to the Department of Labor in 1980 (G16).
2.5 Carcinogenicity
No tumors were reported in two short studies with animals
exposed to triphenyl phosphate. See Triphenyl Phosphate,
Section 2.5. No additional information on the carcinogenicity
of the aryl phosphates discussed in this dossier was found in the
sources searched.
11-15
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2.6 Mutagenicity
No information was found in the sources searched.
2.7 Teratogenicity
No information was found in the sources searched.
2.8 Metabolic Information
The results of a metabolism study of tri-ortho-tolyl phos-
phate have been reported (see Tritolyl Phosphate, Section 2.8),
but no metabolic information was found on the other aryl phosphates
discussed in this dossier.
2.9 Environmental Release and Ecological Effects
A synthetic triaryl phosphate lubricating oil (IMOL S-140)
was reported not to be acutely toxic to rainbow trout; the fish,
however, slowly developed signs of poisoning during prolonged
exposure. They refused food, their fatty tissues became dis-
colored, and SCOT and LDH activities increased (3). At concen-
trations as low as 0.25 mg/liter, a triaryl phosphate hydraulic
fluid (Pydraul 50E) was reported to produce toxic effects in
rainbow trout (27). These observations suggest that triaryl phos-
phates could have long-term effects on ecological systems. Several
aryl phosphates have been found to potentiate the effects of
organophosphate pesticides on insects (28, as reported in 4).
Tri-ortho-tolyl phosphate has been shown to produce such potenti-
ation in other organisms, including mammals (29).
(See also Tritolyl Phosphate, Section 2.9.)
11-16
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2.10 Current Testing
See Section 2.10 for each aryl phosphate,
11-17
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CRESYL DIPHENYL PHOSPHATE
2.1 Bioaccumulation
See Aryl Phosphate Group/ Section 2.1.
2.2 Impurities and Environmental Degradation or Conversion
Products
See Aryl Phosphate Group, Section 2.2.
2.3 Acute Toxicity
Reported oral LD50 values for cresyl diphenyl phosphate
are 6,4-12.8 g/kg for rats and mice and 1.6-3.2 g/kg for
guinea pigs (G38). No paralysis occurred at these doses,
although there was some dyspnea at the higher doses. In guinea
pigs, neither skin irritation nor absorption through skin was
observed.
The Stauffer Chemical Company (10) reported that the oral
LD50 for cresyl diphenyl phosphate was >4,640 mg/kg in rats.
The dermal LD50 in rabbits also was reported to be >4,640 mg/kg.
In rabbits, the substance was nonirritating in a 4-hour dermal
exposure, and a single dose caused no eye irritation.
2.4 Other Toxic Effects
See Aryl Phosphates Group, Section 2.4.
2.5 Carcinogenicity
No information was found in the sources searched.
2.6 Mutagenicity
No information was found in the sources searched.
2.7 Teratogenicity
No information was found in the sources searched.
11-18
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2.8 Metabolic Information
No information was found in the sources searched.
2.9 Environmental Release and Ecological Effects
See Aryl Phosphate Group, Section 2.9.
2.10 Current Testing
Stauffer Chemical Company plans to conduct neurotoxicity
tests on cresyl diphenyl phosphate (10).
11-19
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TRIPHENYL PHOSPHATE (TPP)
2 .1 Bioaccumulation
See Aryl Phosphate Group, Section 2.1
2.2 Impurities and Environmental Degradation or Conversion
Products
See Aryl Phosphate Group, Section 2.2
2.3 Acute Toxicity
The acute toxicity of triphenyl phosphate (TPP), as re-
ported in the NIOSH Registry of Toxic Effects of Chemical
Substances (G16) and by Sutton et al. (11), is given in Table
II-2.
TABLE II-2
ACUTE TOXICITY OF TRIPHENYL PHOSPHATE
Parameter
Dosage
Animal
Route
LDLo
LD50
3,000 mg/kg
6.1 g/kg
2.0 g/kg
100 mg/kg
0.1-0.2 g/kg
Rat
Cat
Chicken
Oral
Subcutaneous
TPP has low acute toxicity for rats, mice, and guinea
pigs (11). In cats, it produced delayed generalized illness <•
paralysis. It was slowly absorbed when administered orally o:
11-20
-------
injected in alcohol solution, and it was poorly absorbed through
the skin and produced no dermal irritation. Although TPP inhib-
ited cholinesterase in vitro and in vivo, it was not a potent
anticholinesterase agent in rats, mice, guinea pigs, and cats (11),
Hine et al. (7) reported that TPP administered subcuta-
neously at 0.5 g/kg and orally at 1.0 g/kg failed to produce
paralytic effects in white leghorn cockerels. There was no eyi-
dence of degeneration in the brain, spinal cord, or sciatic nerve.
TPP given orally at 2 g/kg caused severe depression of plasma
cholinesterases 24 hours after administration. Studies with fowl
plasma in vitro showed no anticholinesterase activity for TPP.
Triphenyl phosphate (dosage unspecified) apparently produced
erythrocyte cholinesterase inactivation (G10).
Acute toxicity data from the literature on TPP are summarized
in Table II-3. (See also Table II-2.)
2.4 Other Toxic Effects
A secondary source (G26) reported that triphenyl phosphate
was more neurotoxic than tritolyl phosphate in cats but probably
not in humans. TPP was said to have caused a delayed but periph-
eral neuritis involving motor neurons, which resulted in a
flaccid paralysis, particularly of the distal muscles. No
sensory disturbances were observed. Signs of cholinesterase
inhibition also were detected. A later review (8), however,
reported that pure TPP was not neurotoxic in the hen and the cat
and suggested that other aryl phosphates present as impurities
might have been responsible for earlier observations of neuro-
toxicity.
11-21
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TABLE II-2
SUMMARY OF ACUTE TOXICITY DATA ON TRIPHENYL PHOSPHATE (11)
Route
Animal
Dose
Effect
Reference
Cited
Oral
Fowl (unspecified)
Inhala-
tion
Dermal
Subcu-
taneous
Mouse
Monkey
Cat
Fowl (unspecified)
Intraperi- Cat
toneal
25 g/kg (total)
0.5-2 g/kg
1.0 g/kg
757 mg/m3 for 2 hr
0.5 ml (70% in
ethanol) for 24-
72 hr
1.0 g/kg
0.5 g/kg
0.3-1 g/kg
0.2 g/kg
0.1 g/kg
0.5 g/kg
0.1-0.4 g/kg
No death or paralysis in 2/2 12
No death or paralysis in 4/4 13
No paralysis in 4/4 7
Significantly reduced cho- 11
linesterase activity
Absorption but no irritation 11
Rapid paralysis 14
Paralysis 14
Death in 4/4 13
Paralysis and death in 3/3 13
No paralysis in 2/2 13
No paralysis in 4/4 7
Paralysis in 2/6 in 16-18 days, 13
followed by anorexia, weakness,
weight loss, exaggerated deep
tendon reflex
T-n 1 /<; no
13
-------
_2
TPP at 10 M showed no neurotoxic effects on sympathetic
ganglia from chick embryos (15).
Rats fed 0.5% TPP for 35 days showed a slightly depressed
growth rate. No hematological or gross pathological change's were
observed, although the liver weights were significantly- increased
(11). These effects were not observed in rats fed 0.1% TPP for
35 days (11).
TPP administered orally to rats and mice at one-tenth to
one-half of the LD50 for 3 months had no significant toxic
effects, nor were there any irritating effects on rat skin (16,
from TOXLINE abstract).
One person developed dermatitis after dermal exposure to
carbon paper containing TPP (17, from TOXLINE abstract).
The 1976 ACGIH Threshold Limit Value (TLV) for triphenyl
phosphates was 3 mg/m (Gil).
2.5 Carcinogenicity
Hierholzer et al. (18, as reported in G18) observed no
tumors in 12 rats fed TPP at 1 g/kg for 90 days. The same
investigators also obtained negative results for carcinogenicity
in shorter feeding studies with cats and rats. Button et al. (11)
detected no tumors in cats given TPP by single intraperitoneal
injections at up to 0.4 g/kg or in rats fed 0.5% TPP in their
diet for 35 days.
2.6 Mutagenicity
No information was found in the sources searched.
11-23
-------
2.7 Teratogenicity
No information was found in the sources searched,
2.8 Metabolic Information
No information was found in the sources searched,
2.9 Environmental Release and Ecological Effects
See Aryl Phosphate Group, Section 2.9-
2.10 Current Testing
No information was found in the sources searched.
11-24
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TRISISOPROPYLPHENYL PHOSPHATE
2.1 Bioaccumulation
See Aryl Phosphate Group, Section 2.1.
2.2 Impurities and Environmental Degradation or Converstion
Products
See Aryl Phosphate Group, Section 2.1.
2.3 Acute Toxicity
No data were found on the acute toxicity of trisisopro-
pylphenyl phosphate. However, the toxic effects of iso-
propylphenyl diphenyl phosphate have been studied by Stauffer
Chemical Company, which reported that the substance was
nonirritating (10) and had low toxicity. The LD50 of the
substance is greater than 2,000 mg/kg in rabbits given a sir e
dose by either the dermal or oral route (10). Rabbits expos der-
mally for 4 hours showed no irritation, and a single dose caused
no eye irritation (10).
2.4 Other Toxic Effects
See Aryl Phosphate Group, Section 2.4.
2.5 Carcinogenicity
No information was found in the sources searched.
2.6 Mutagenicity
No information was found in the sources searched.
2.7 Teratogenicity
No information was found in the sources searched.
11-25
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2 . 8 Metabolic Information
No information was found in the sources searched,
2.9 Environmental Release and Ecological Effects
See Aryl Phosphate Group, Section 2.9.
•2.10 Current Testing
No information was found in the sources searched.
II'-2 6
-------
TRITOLYL PHOSPHATE
2.1 Bioaccumulation
See Aryl Phosphate Group, Section 2.1.
2-2 Impurities and Environmental Degradation or Conversion
Products
See Aryl Phosphate Group, Section 2.2.
2.3 Acute Toxicity
The acute toxicity of tritolyl phosphate, as reported in
the NIOSH Registry of Toxic Effects of Chemical Substances
(G16), is given in Table II-4.
TABLE II-4
ACUTE TOXICITY OF TRITOLYL PHOSPHATE
Parameter Dosage Animal Route
LDLo 4,680 rag/kg Rat Oral
" 500 mg/kg Dog
100 mg/kg Rabbit
The Stauffer Chemical Company (10) evaluated the acute
toxicity of this compound (isomer unspecified). The oral
LD50 in rats and the dermal LD50 in rabbits were stated to be
greater than 4,640 mg/kg. In rabbits, the substance was non-
irritating in a 4-hour dermal exposure, and a single dose
caused no eye irritation. The LC50 for a 1-hour inhalation
exposure was greater than 8.6 mg/liter in rats.
11-27
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Cells from the spinal cords of chickens given 0.5 ml of
tritolyl phosphate in a single dose showed cytoplasmic fibrilli-
zation, mitochondrial degeneration, and a variety of large
osmiophilic masses in the cell body and processes (19). Neither
the isomer used nor the route of exposure was specified.
Dollahite and Pierce (20) administered Cellulube 220, a
mixture of triphenyl phosphate, tritolyl phosphate (isomer
unspecified), trixylenyl phosphate, and trialkylphenyl phosphate,
by stomach tube to rats, rabbits, chickens, goats, and calves
in single doses of 2-60 g/kg. Calves, goats, and rabbits were
apparently most susceptible, chickens were less affected, and
rats showed no signs of toxicity. The data are summarized in
Table II-5. The signs of toxicity included dyspnea, tympanites,
lack of coordination, and paralysis, and some animals died. Red
blood cell cholinesterase levels were reported to have decreased
in calves, goats, and rabbits but not in chickens.
TABLE II-5
REPORTED SINGLE DOSE ORAL TOXICITY OF CELLULUBE 220 (20)
Animal
Rat
Rabbit
ii
Dosage
10-20 g/kg
2 g/kg
5 g/kg
Observations
No toxic effects
Healthy
Signs of illness
in 1/5, 1 death
" 6 g/kg Anorexia, saliva-
tion, diarrhea,
trembling, and
paralysis
Chicken 20 g/kg No toxic effects
11-28
-------
TABLE II-5 (continued)
Animal Dosage Observations
Chicken 20-40 g/kg Paralysis in 3/11
" 60 g/kg No toxic effects
Goat 5 g/kg Anorexia, incoor-
10 g/kg dination, dyspnea,
and paralysis in
19-36 days
Calf 7.7 g/kg Signs on the 19th
day similar to those
in goats, death on
the 30th day
2.4 Other Toxic Effects
Brown et al. (G14) summarized the chronic toxicity of
tritolyl phosphate (isomer unspecified) in studies with experi-
mental animals as follows: "Repeated dose effects include
gastrointestinal disturbances, ataxia, paralysis, adrenal hyper-
trophy, cretinuria (sic), nerve degeneration, and EEC alternations
Effects reported in the rat, cat, guinea pig, rabbit and unspec-
ified primate."
Saito et al. (21, from TOXLINE abstract) reported that oral
administration of tritolyl phosphate (isomer unspecified) at
30-1,000 mg/kg/day to rats for 3 months produced no deaths and no
signs of toxicity except temporary salivation. However, serum
albumin levels were significantly decreased in male and female
rats, and the level of serum urea nitrogen was increased in
females. Females had increased relative liver weights. Hyper-
trophy of the zona fasticulata in the adrenal gland of some rats
was also noted.
11-29
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Degenerative changes seen in spinal ganglion mitochondria
of prosimians poisoned with tritolyl phosphate (isomer unspec-
ified) indicated mitochondrial involvement in TTP poisoning
(22, from TOXLINE abstract).
The ortho isomer (tri-ortho-tolyl phosphate or tri-ortho-
cresyl phosphate) has been implicated in many cases of human
poisoning. Sax (G4) summarized epidemiological data on these
incidents, as follows:
Most of the cases of tri-o-cresyl phosphate poison-
ing have followed its ingestion. In 1930, some 15,000
persons were affected in the United States, and of these,
10 died. The responsible material was found to be an
alcoholic drink known as Jamaican ginger, or "jake."
This beverage had been adulterated with about 2% of tri-
o_-cresyl phosphate. The affected persons developed a
polyneuritis, which progressed, in many cases, with de-
generation of the peripheral motor nerves, the anterior
horn cells and the pyramidal tracts. Sensory changes
were absent. Since 1930 there have been several other
outbreaks of poisoning following ingestion of the material.
Recently 3 cases of polyneuritis occurring in England in
connection with the manufacture of the tri-o-cresyl phos-
phate have been reported. Absorption was probably through
the respiratory tract, though there may have been some
absorption through the skin. All three men made a good
recovery-
From ingestion experiments with cockerels, it appears
that tri-o-cresyl phosphate is more toxic than the m form,
and much more so than tri-p-cresyl phosphate or triphenyl
phosphate.
Irrespective of whether absorption has been by in-
gestion or by inhalation or skin absorption, the history
is usually one of early, transient gastrointestinal upset,
with nausea, vomiting, diarrhea and abdominal pain. These
clear up, and are followed in 1 to 3 weeks by soreness of
the lower leg muscles, "numbness" of the toes and fingers,
and a few days later by weakness of the toes and bilateral
foot-drop. After another week or so, weakness of the
fingers and bilateral wrist-drop follow. There are no
sensory changes. Recovery is slow, and the degree of
residual paralysis depends upon the extent of damage to
the nervous system. Many cases recover completely. In
1958 several thousand persons in Morocco were poisoned
11-30
-------
with this material which was present in lubricating oil
which had been mixed with edible oils by dishonest mer-
chants. Many of the victims suffered a permanent para-
lysis .
Liver biopsies from six patients affected with poly-
neuritis after exposure to tri-ortho-tolyl phosphate showed
changes in hepatocytes, which were characterized by vacuolar
swelling of the cytoplasm with abnormalities of the nuclear
membrane and lipofuscin pigment accumulation (23, from TOX-
LINE abstract).
The 1976 ACGIH Threshold Limit Value (TLV) for tri-ortho-
tolyl phosphate was 0.1 mg/m (Gil).
2.5 Carcinogenicity
No information was found in the sources searched.
2.6 Mutagenicity
No information was found in the sources searched.
2.7 Teratogenicity
No information was found in the sources searched.
2.8 Metabolic Informatioji
To determine the metabolic fate of tri-ortho-tolyl phosphate,
Sharma and Watanabe (5,6) administered an oral dose (0.77 g/kg) of
the substance to chickens. They found that 26.5% of the dose was
excreted in 72 hours. The metabolites were not fully character-
ized, but at least one was considered to be hydroxylated on the
phenyl ring in at least one position. Almost all (99%) of the
chemical excreted during the first 72 hours of the experiment
was unchanged material.
11-31
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2.9 Environmental Release and Ecological Effects
Tritolyl phosphate (isomer unspecified) was moderately
toxic to fish, with an Aquatic Toxicity Rating (96-hr TLm,
species unspecified) of 10-1 ppm (G16). Stauffer Chemical
Company (10) reported that tritolyl phosphate had an LD50
greater than 1,000 ppm and less than 5,000 ppm in sticklebacks
exposed for 96 hours.
Tri-ortho-tolyl phosphate inhibited esterases in house-
flies, mosquitoes, and lepidopteran larvae, slowing the metab-
olism of insect growth regulators and phthalate esters (24,
25, from TOXLINE abstract). It has been reported to have
potentiated the effects of organophosphate pesticides on
other organisms, including mammals (29).
Tritolyl phosphate (isomer unspecified) is reportedly
used at a concentration of 2% in a fish-net preservative that
is of low toxicity to fish but prevents fouling by other marine
organisms. The other components of the preservative are methyl
isobutyl ketone (81%), copper oleate (5%) , polyvinyl chloride
(5%), beta-pyrene (5%), and tributyl tin oxide (2%) (26, from
TOXLINE abstract). (See also Aryl Phosphate Group, Section
2.9.)
2.10 Current Testing
No information was found in the sources searched.
11-32
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REFERENCES
1. U.S. Environmental Protection Agency, Office of Toxic
Substances. The Manufacture and Use of Selected Aryl and
Alkyl Phosphate Esters. EPA 560/6-76-008 (February 1976)
2. Code of Federal Regulations (40 CFR 80.2) (July 1, 1975)
3. Lockhart, W.L., Wagemann, R., Clayton, J.W., Graham, B.,
and Murray, D. Chronic toxicity of a synthetic triaryl
phosphate oil to fish. Environ. Physiol. Biochem. 5:
361-369 (1975)
4. Midwest Research Institute. Assessment of the need for,
the character of and the impact resulting from limitations
on aryl phosphates. Draft Final Report prepared for Office
of Toxic Substances, U.S. Environmental Protection Agency,
Washington, D.C. MRI Project No. 4309-L (June 17, 1977)
5. Sharma, R., and Watanabe, P. Metabolism aid elimination of
tri-o-tolyl phosphate (TOTP), a neurotoxic organophosphate,
in the chicken. Toxicol. Appl. Pharmacol. 25:483 (1973)
6. Sharma, R., and Watanabe, P. Time related disposition of
tri-o-tolyl phosphate (TOTP) and metabolites in the chicken.
Pharmacol. Res. Commun. 6:475-484 (1974)
7* Hine, C.H., Dunlap, M.K., Rice, E.G., Coursey, M.M., Gross,
R.M., and Anderson, H.H. The neurotoxicity and anticholin-
esterase properties of some substituted phenyl phosphates.
J. Pharmacol. Exper. Ther. 116:227 (1956)
8. Johnson, M.K. The delayed neuropathy caused by some organ-
ophosphorous esters: Mechanism and challenge. CRC Grit.
Rev. Toxicol. 3:289-316 (1975)
9. Beck, B.E., Wood, C.D., and Whenham, G.R. Triarylphosphate
poisoning in cattle. Vet. Pathol. 14:128-137 (1977) (Abstract)
10. Molitor, J.T. (Stauffer Chemical Company). Comments on
the preliminary list (August 1977)
11. Button, W.L., Terhaar, C.J., Miller, F.A., Scherberger,
R.F., Riley, E.G., Roudabosh, R.L., and Fasset, D.W.
Studies on the industrial hygiene and toxicology of tri-
phenyl phosphate. Arch. Environ. Health 1:33-46 (1960)
12. Hunter, D., Perry, K.M.A., and Evans, R.B. Toxic poly-
neuritis arising during the manufacture of tricresyl
phosphate. Brit. J. Ind. Med. 1:227 (October 1944)
13. Smith, M.I., Engel, E.W., and Stohlman, E.F. Further
studies on the pharmacology of certain phenol esters with
11-33
-------
special reference to the relation of chemical constitution
and physiologic action. NIH Bulletin 160. P 1 (1932)
14. Lillie, R.D., and Smith, M.D. The histopathology of some
neurotoxic phenol esters. NIH Bulletin 160. P 54 (1932)
15. Obersteiner, E.J., and Sharma, R.P- Cytotoxicity of selec-
ted organophosphates in chick ganglia cell cultures. Fed.
Proc. 35:504 (1976)
16. Antonyuk, O.K. Hygienic evaluation of the plasticizer
triphenyl phosphate added to polymer compositions. Gig.
Sanit. 8:98-99 (1974) (Abstract)
17. Calnan, C.D., and Connor, B.L. Carbon paper dermatitis due
to nigrosine. Berufsdermatosen 20:248-254 (1974) (Abstract)
18. Hierholzer, K., Noetzel, H., and Schmidt, L. Arzneim.
Forsch. 7:585-588 (1957)
19. Ahmed, M.M. A note on the neuroglia in normal and tri-
cresylphosphate (TCP) poisoned hen. Acta Anat. 77:120-
130 (1970)
20. Dollahite, J.W., and Pierce, K.R. Neurologic disturbances
due to triaryl phosphate toxicity. Am. J. Vet. Res. 30:
1461-1468 (1969)
21. Saito, C., Kato, T., Taniguchi, H., Fujita, T., Wada, H.,
Mori, Y., Lockhart, W.L., Wagemann, R., Clayton, J.W.,
Graham, B., and Murray, D. Subacute toxicity of tricresyl-
phosphate in rats. Oyo Yakuri 8:107-118 (1974) (Abstract)
22. Ahmed, M.M., and Glees, P. Mitochondrial degeneration
after organic phosphate poisoning in prosimian primates.
Cell Tissue Res. 175:455-465 (1977) (Abstract)
23. Rozwoda, J. A clinical picture of triorthocresyl phosphate
poisoning. Wiadomoscki Lekar 21:1497-1499 (1968) (Abstract)
24. Quistad, G.B., Staiger, L.E., and Schooley, D.A. Environ-
mental degradation of the insect growth regulator metho-
prene: V. Metabolism by houseflies and mosquitoes. Pestic.
Biochem. Physiol. 5:233-241 (1975) (Abstract)
25. Sanborn, J.R., Metcalf, R.C., Yu, C., and Lu, P. Plastici-
zer s in the environment: Fate of di-n-octyl phthalate
(DOP) in two model ecosystems and uptake and metabolism
of DOP by aquatic organisms. Arch. Environ. Contam.
Toxicol. 3:244-255 (1975) (Abstract)
26. Oda, S., and Yada, H. Fish net preservatives with low
toxicity to fish. (CA 78-001051) (Abstract)
11-34
-------
27. Nevins, M.J., and Johnson, W.W. Acute toxicity of phosphate
ester mixtures to invertebrates and fish. Bull. Environ.
Contam. Toxicol. 19:250-256 (1978)
28. Plapp, F.W., Jr., and Tong, H.H.C. Synergism of malathion
and parathion against resistant insects: Phosphorus esters
with synergistic properties. J. Econ. Entomol. 59:11-15
(1966)
29. Cohen, S.D., and Murphy, S.D. Comparative potentiation of
malathion by triorthotolyl phosphate in four classes of
vertebrates. Toxicol. Appl. Pharmacol. 16:701-708 (1970)
30. Metcalf, F.L. Evaluation of the Utility of the Model
Ecosystem for Determining the Ecological Fate of Substances
Subject to FDA Regulatory Authority. Final Report on
Contract FDA 74-127 (December 1976)
31. CHEMLINE. National Library of Medicine, Bethesda, Md. Data
Base (1978)
11-35
-------
CHLORINATED NAPHTHALENES
TABLE OF CONTENTS
Page
Overview III-l
Part I General Information III-3
Part II Biological Properties
2.1 Bioaccumulation III-6
2.2 Impurities and Environmental Degradation
or Conversion Products III-7
2.3 Acute Toxicity III-9
2.4 Other Toxic Effects III-9
2.5 Carcinogenicity 111-19
2.6 Mutagenicity 111-19
2.7 Teratogenicity 111-19
2.8 Metabolic Information 111-19
2.9 Environmental Release and Ecological
Effects 111-21
2.10 Current Testing 111-23
References 111-24
Ill-i
-------
CHLORINATED NAPHTHALENES
AN OVERVIEW
Chlorinated naphthalenes are oily liquids or waxy solids,
insoluble in water but soluble in most organic solvents. The
commercial products are mixtures of chloronaphthalenes and are
defined by their chlorine content and approximate melting point.
Halochem, Inc., reported to be the only manufacturer of
chlorinated naphthalenes in the world, produces mixtures contain-
ing monochloro, dichloro, trichloro, and tetrachloro derivatives
for a world market of 700,000 pounds a year. Overall production
has declined in recent years; production of the pentachloro
through octachloro derivatives has been discontinued recently.
These products are used in the manufacture of capacitors,
as engine oil additives, in electroplating, and in fabric dyeing.
According to the NOHS, approximately 5,000 persons are occupation-
ally exposed to them in the United States.
Data on occupational toxicity and cattle poisoning incidents
in the 1940's and 1950's suggest that chlorinated naphthalenes
are hazardous pollutants. While the physical and chemical
properties of the chlorinated naphthalenes suggest that they
have a high potential for bioaccumulation, this has not been
verified experimentally. The high thermal stability of chlorinated
naphthalenes and their resistance to chemical attack indicate
that they will persist in the environment, with their persistence
increasing as chlorine content becomes greater. No reports of
their effects were found, and the extent of their distribution
III-l
-------
in the environment is not known. Few data are available on their
toxicity to fish and wildlife.
Chlorinated naphthalenes are strong irritants. As their
chlorination increases from monochloronaphthalene to hexachloro-
naphthalene, their toxicity generally increases as well. Few
data are available on the toxicity of the heptachloro and octa-
chloro derivatives. The most common toxic effects in humans,
generally as a result of occupational exposure, are chloracne
and liver damage. No information on the carcinogenicity, muta-
genicity, and teratogenicity of the compounds was found in the
sources searched.
III-2
-------
CHLORINATED NAPHTHALENES
PART I
GENERAL INFORMATION
1.1 Identification (see Section 1.8, Table III-l)
1.2 Synonyms and Trade Names
Chloronaphthalene, oil; chloronaphthalene, wax; N-oil;
N-wax; Halowax (production discontinued) (G21,l)
1.3 Chemical Formula and Molecular Weight
C-,AH0 , ^ >C1 ^ Mol. wt. 162.62 to
10 8-(x+y) x+y 403.74
(G22)
(x + y = 1 through 8}
1.4 Chemical and Physical Properties
1.4.1 Description; The technical grade monochloronaphthalenes
and dichloronaphthalenes are liquids at
room temperature; the higher chlorinated
compounds are solids. Industrial
chlorinated naphthalenes are liquid or
solid mixtures of chloronaphthalenes
defined by their chlorine contents,
approximate melting points, and often
also by their color.
The oils are almost colorless, thin
mobile liquids and are combustible.
The waxes are varied in color.
Chloronaphthalene crudes, darker in
color than the refined products, are
also commercially available. They may
contain impurities such as chlorinated
biphenyls, fluorenes, pyrenes, anthra-
cenes, and dibenzofurans.
(G17,G21,2)
1.4.2 Boiling Point; (see Section 1.8, Table III-2)
1.4.3 Melting Point; (see Section 1.8, Table III-2)
1.4.4 Solubility: Insoluble in water; soluble in
practically all organic solvent liquids
and oils (wax must be heated)
(G21,G22)
III-3
-------
1.5 Production and Use
1.5.1 Production:
<5 million Ib (1972)
Declined slightly from 1972-1974
(1)
1.5.2 Use:
The current total world market is
reported to be 700,000 Ib/yr (3)
In the manufacture of electronics mater-
ials (capacitors) and as an engine oil
additive; less commonly in electroplating
and fabric dyeing
1.6 Exposure Estimates
1.6.1 NOHS Occupational Exposure;
Rank: 3439
Estimated no. of persons exposed to chlorinated
naphthalenes: 5,000*
*rough estimate (G29)
(see also Section 1.8, Table III-l)
1.7 Manufacturers
Halochem, Inc. (now the only manufacturer; trade name:
N-Oil and N-Wax) (3)
Koppers Company (formerly a producer; trade name: Halowax)
1.8 Data on Specific Chlorinated Naphthalenes
TABLE III-I
IDENTIFICATION AND EXPOSURE DATA FOR MAJOR CONSTITUENTS OF
CHLORINATED NAPHTHALENE MIXTURES
NOHS Occupational Exposure
Name
1-Chloronaphthalene
Dichloronaphthalene
Trichloronaphthalene
Tetrachloronaphthalene
Pentachloronaphthalene
Hexachloronaphthalene
Octachloronaphthalene
NIOSH No.
QJ21000
-
QK40250
QK37000
QK03000
QJ73500
QK02500
CAS No.
000090131
028699889**
001321659**
001335882**
001321648**
001335871**
002234131**
Rank
3760
6443
5056
5458
-
-
-
No. of Persons
Exposed*
3,000
150
1,700
1,000
-
-
-
*Rough estimate
**Generic CAS number (assigned when isomer is not specified)
III-4
-------
TABLE III-2
CHARACTERISTICS OF COMMERCIALLY AVAILABLE CHLORONAPHTHALENE MIXTURES (1,2)
Halochem Inc.
Product
Monochloro-
naphthalene
N-Oil 12
N-Wax 34
(and 34S)
£ N-Wax 43
H (and 43B)
in
N-Wax 45**
Koppers Co.
Product*
Halowax
Halowax
1031
1000
Halowax 1001
(and 1001S)
Halowax
1099
(and 1099B)
Halowax
1013
Derivatives
Present (approx. Chlorine
percentage) Content
95%
5%
70%
30%
7%
30%
63%
2%
15%
83%
10%
50%
40%
mono 22%
di
mono 26%
di
di 50%
tri
tetra
di 52%
tri
tetra
tri 56%
tetra
penta
Boiling Melting
Point Point Uses
250°C -25°C Engine oil addi-
tive; proprietary
uses in fabric
250°C -33°C
308°C 93°C Impregnating
automobile
capacitors
315°C 102°C
328°C 120°C Electroplating
stopoff compounds;
impregnating carbon
electrodes used in
chlorine production
N-Wax 56**
(and 56B)
N-Wax 80**
Halowax
Halowax
1014
1051
20%
40%
40%
10%
90%
tetra 62%
penta
hexa
hepta 70%
octa
344°C 137°C
370°C 185°C Unknown
**No longer produced (3)
-------
CHLORINATED NAPHTHALENES
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
Based on their low water solubility, low volatility, and re-
sistance to degradation, the chlorinated naphthalenes have a high
potential for storage and persistence in living matter (4). As
their chlorine content increases, their chemical and thermal
stability increase while their water solubility decreases, thereby
raising their potential for bioaccumulation. The reported pres-
ence of traces of chlorinated naphthalenes in dead birds in the
Netherlands (5) also indicates a potential for bioaccumulation.
The highest accumulation factor for algae exposed to chlorinated
naphthalenes for 24 hours, however, was 140, a figure that is con-
sidered low for algae (6).
Green and Neff (7) studied the effects of three Halowax
chlorinated naphthalenes on grass shrimp (Palaemonetes pugio).
After the aquatic LCSO's had been determined, the shrimp were ex-
posed to the test compound at 40 ppb for up to 15 days. Most
of the bioaccumulation occurred in the first 3 days. The
levels of accumulated chlorinated naphthalenes were greatly
reduced after the shrimp were exposed to clean sea water for
5 days. The bioconcentration factor and LC50's for the three
substances are given in Table III-3.
III-6
-------
TABLE II1-3
ACUTE TOXICITY AND BIOCONCENTRATION OF THREE CHLORINATED NAPHTHALENES (7)
Bioconcentra-
Substance Approximate Composition 96-hr LC50 tion Factor
Halowax 1000
Halowax 1013
Halowax 1099
2.2 Impurities
60%
40%
10%
50%
40%
40%
60%
and
mono
di
tri
tetra
penta
tri
tetra
Environmental
325 ppb 63
187
90 ppb 257
Degradation or Conversion
Products
Possible impurities in chlorinated naphthalenes are chlorin-
ated derivatives of biphenyl, fluorene, pyrene, anthracene, and
dibenzofuran (G17). Vos and Beems (8) have reported that commer-
cial chlorinated naphthalenes were contaminated with chlorinated
dibenzofurans and that at least some of the toxic effects (chlor-
acne and liver damage) might be attributable to the contaminants.
Chlorinated naphthalenes have been found in PCB's produced in
foreign countries (2). In PCB's manufactured in the United States,
they were found at lower levels (9, as reported in 2).
Chlorinated naphthalenes have high thermal stability, are
stable to oxidizing agents, and are resistant to chemical attack
at ordinary temperatures (G17). Their low vapor pressure limits
their entry into the atmosphere by direct volatilization. Because
the photolysis of polychlorinated naphthalenes in methanol at
300 nm caused carbon-chlorine bond fission and dimerization, Ruzo
III-7
-------
et al. (10) concluded that environmental degradation of chloro-
aroraatics may be more efficient through photochemical pathways
than through metabolic routes, although exposure of 1,5-dichloro-
naphthalene and 2-chloronaphthalene as a solid film to sunlight
irradiations led to an insoluble polymeric material.
Environmental decomposition of chlorinated naphthalenes has
received little attention. Microbial degradation studies of the
monochlorinated naphthalenes have shown that these compounds are
degraded by bacteria in soil and sewage sludge (.11, 12 from abstract,
13). Blodegradation of chlorinated naphthalenes in the rabbit
has been reported by Cornish and Block (14) and is described in
Section 2.8. The monochloro and dichloro compounds are metabol-
ized to hydroxy derivatives. The tetrachloro compounds are much
less extensively metabolized, and those with five or more chlorines
are metabolized at a rate too low to be detected, indicating that
they are stored or poorly absorbed. Persistence in the environ-
ment, therefore, appears to increase as the degree of chlorination
increases.
Two thirds of the reported (21 production of chlorinated
naphthalenes is in the form of less chlorinated naphthalenes for
use in temporarily closed systems (.automobile capacitors) . Pollu-
tion from this source depends on the extent of leaching from the
capacitors when disposed of in sanitary landfills.
2.3 Acute Toxicity
Chlorinated naphthalenes are strong irritants. They may
cause death or permanent injury after very brief exposures to
III- 8
-------
small quantities (G4). A single oral dose of 1 g octachloro-
naphthalene was fatal to rabbits in 7 days (14). Chloracne has
been experimentally induced in humans by applications of Halowax
1014, pentachloronaphthalene, and hexachloronaphthalene (15, as
reported in 16).
2.4 Other Toxic Effects
Outbreaks of hyperkeratosis QC disease) in cattle in the
1940"s and 1950's in the United States and Germany, according to
a review by Crow (18), were the result of the accidental inges-
tion of chlorinated naphthalenes in wood preservatives and lubri-
cating oils.
Hansel et al. (41) induced hyperkeratosis in calves by
feeding them a wood preservative containing chlorinated naphthal-
enes. The authors did not describe the dosage regimen but reported
that doses of 7-11 ml were fatal to 300-pound calves. Lacrimation,
depression, and emaciation were observed in 3-6 weeks, and severe
vitamin A deficiency occurred. From 30 ml of the preservative,
fractionation procedures isolated 0.5 g of what the authors described
as active material probably containing trichloronaphthalene and
more highly chlorinated naphthalenes. A calf wearing a blanket
that contained an unspecified amount of the same preservative
developed severe lesions after 3 weeks.
Bell (42) gave one calf an oral dose of pentachloronaphthal-
ene (.as a 3% solution in vegetable oil) at approximately 22.0 mg/
kg, a second calf an oral dose of hexachloronaphthalene (as a 3%
solution in vegetable oil) at approximately 11.0 mg/kg, and a
III- 9
-------
third calf an oral dose of unspecified chlorinated naphthalenes
(as a 3% content of a lubricant) at 17.6 mg/kg. The doses were
administered in gelatin capsules. Lacrimation, excessive saliva-
tion, and nasal discharge were observed in all three calves 3 days
after treatment. The calf exposed to hexachloronaphthalene died
on day 14 and the calf exposed to the unspecified chlorinated
naphthalenes died on day 46. The calf exposed to pentachloronaph-
thalene was killed on day 57. Autopsies revealed hyperkeratosis,
enlarged kidneys, bile duct proliferation and fibrosis of the
liver, papillary proliferations of the oral mucosa, and squamous
metaplasia of the epididymis. Link (43), reviewing the literature
on bovine hyperkeratosis, described similar lesions as common
signs of the disease; in addition, he listed squamous metaplasia
of the seminal vesicles, Gartner's ducts, and salivary glands;
mucoid papillary proliferation in the gall bladder; thickening
of the gall bladder; and fibrosis in the pancreas.
Sikes et al. (19) reported that a 2-month-old calf nursing
from a cow given octachloronaphthalene orally in capsules at
approximately 12 mg/kg for 18 days developed hyperkeratosis.
The authors concluded that either octachloronaphthalene or a
toxic metabolite was excreted in milk.
Brock et al. (44) reported that the lowest concentration of
chlorinated naphthalene (Halowax 1014) fatal to sheep was approx-
imately 116 mg/kg. (The sheep were fed for an average of 106
days). This concentration was more than 100 times greater than
the lowest fatal concentration for cows, which was reported as
approximately 1 mg/kg, given for one week (the route of adminis-
111-10
-------
tration and the chlorine content of the chlorinated naphthalene
were not specified) (.45, as reported in 44) . Affected animals
showed nasal discharge, weakness, and weight loss. Pathological
changes were apparently due to toxic effects on the cardiovascular
system, the liver, and the kidneys. Myocardial damage, liver
necrosis and cirrhosis, and degeneration of the nephrons were
reported. Cardiac insufficiency and increased resistance to the
flow of blood through the liver resulted in congestion of the
spleen, kidneys, intestinal tract, and lungs.
Hyperkeratosis has been produced by oral administration of
hexachloronaphthalene to rats and hamsters. In rats, mild to
moderate fatty degeneration with centrilobular vacuolation of the
hepatic cells was observed. Kidneys exhibited degenerative
changes and necrosis of the tubules (17) .
Pigs given hexachloronaphthalene orally at 22 mg/kg for 8-9
days exhibited depression, anorexia, and ataxia, but they did not
develop other signs characteristic of bovine hyperkeratosis. Also
observed were degenerative changes of the liver and kidneys, sub-
acute interstitial duodenitis, and hyperplasia of the stratified
squamous epithelium of the vaginal tissue accompanied by the for-
mation of keratin on the mucosal surface (17).
The addition of 0.05 to 0.30% of octachloronaphthalene to
the diet of rats accelerated the loss of vitamin A from the liver
(20). Pentachloronaphthalenes and hexachloronaphthalenes fed to
chickens led to chick-edema disease (21, as reported in 16).
Chlorinated naphthalenes interfere with the biotransformation of
carotene to vitamin A, an effect that is reported to be highly
III-ll
-------
variable and subject to species-specific variation. Goats, sheep,
swine, mice, chickens, and rats are much less susceptible than
cattle (.2).
Schwartz et al. (.22, as reported in 16) indicated that in
humans the most potent chloracne-producing agents were the chlor-
inated naphthalenes, chlorodiphenyls, and chlorodiphenyl oxides.
Persons who worked with chlorinated naphthalenes usually developed
acne after a month or more of exposure.
Chronic exposure to chlorinated naphthalenes generally
produces both dermatological and systemic effects in humans.
Among the former are acneform eruptions with pustules, papules,
and large comedones; vesiculo-erythematous eruptions; simple
erythematous eruptions with pruritis; and the appearance of derma-
tological lesions characterized by cysts that developed because
the orifices of the sebaceous glands had been plugged (23).
Mixtures both of monochloronaphthalenes and dichloronaphthal-
enes and of trichloronaphthalenes and tetrachloronaphthalenes at
500 mg/g in a mineral oil suspension applied to the ears of humans
led to no response during a 30-day period. A mixture of penta-
chloronaphthalene and hexachloronaphthalene caused acne, but hepta-
chloronaphthalene and octachloronaphthalene, applied under the
same conditions, did not (24, as reported in 2). Pentachloro-
naphthalene and hexachloronaphthalene at 30 mg/g in acetone (25,
as reported in 2) also caused acne in humans.
Chlorinated naphthalenes have been reported to produce
chloracne and, less frequently, systematic effects. These include
jaundice produced by either an acute or subacute necrosis of the
111-12
-------
liver, acute hepatitis, anorexia, nausea, vomiting, or abdom-
inal pain (23). Death after exposure to chlorinated naphthal-
ene fumes has also been reported (26, 27). The liver is usually
the only organ showing damage (.25). Kleinfeld et al. (23), in a
description of an incident in which workers were exposed to a
mixture of tetrachloronaphthalene and pentachloronaphthalene,
could make no definitive pronouncement on whether hepatic injury
occurred.
Cotter (28, as reported in 16) reported seven cases of penta-
chloronaphthalene poisoning in workers engaged in the manufacture
of insulated cable. Four of the workers developed jaundice and
two died. Microscopic examination of the livers of the dead men
showed complete loss of cells in some areas. Also the centri-
lobular areas were hemorrhagic, and prominent bile duct prolifera-
tion was observed in the periphery.
Toxic effects depend on the degree of chlorination.
A summary of toxicity data on individual chloronaphthalenes
and mixtures from a recent EPA report (2) are given in Table
III-4.
The following Threshold Limit Values (TLV's) for skin
exposure have been set for certain chlorinated naphthalenes (Gil)
Trichloronaphthalene—5 mg/m
Tetrachloronaphthalene--2 mg/m
Pentachloronaphthalene— 0.05 mg/m
Hexachloronaphthalene--0.2 mg/m
Octachloronaphthalene—0.1 mg/m
111-13
-------
TABLE III-4
TOXICITY OF CHLORONAPHTHALENES (2)
Compound
Animal
Exposure and Route
Response
Reference Cited
Monochloronaphthalene Rabbit
Mixture of monochloro- Human
naphthalene and
dichloronaphthalene
H
M
i Dichloronaphthalene
Trichloronaphthalene
Rabbit
Rat
Mouse
Mixture of trichloro- Human
naphthalene and
tetrachloronaphthalene
90 mg/g in acetone,
applied to ear for
5-7 days
590 mg/g in acetone,
applied to ear
500 mg/g in mineral
oil suspension, ap-
plied to ear for 30
days
45 mg/g and 290 mg/g
in acetone
5 g/kg, fed for 15
days
2.5 mg/day, fed for
20 days
500 mg/kg in solvent,
applied to ear for
30 days
Mild reddening
Severe reddening
No effect
Reddening
Increase in liver
weight; growth
impaired; coat
texture roughened
No dermatitis**
No effect
24
25
25
25
29
30
24
-------
TABLE III-4 (continued)
Compound
Animal
Exposure and Route
Response
Reference Cited
Mixture of trichloro- Rat
naphthalene and
tetrachloronaphthalene
Rabbit
Rat
H
H
H
I
M
Ul
Mixture of tetra-
chloronaphthalene
and pentachloro-
naphthalene
Rabbit
3 g*, fed for 9-136
days
15 mg/kg/day fed for
60 days
1.31 mg/m , by inhala-
tion for 16 hrs/day
for 134 days
10.97 mg/m , by in-
halation for 16 hrs/
day for 102 days
500 mg/kg/day*, fed
for 63 days
15 mg/kg/day, injected
subcutaneously for
12-26 days
Fatty accumulation
in liver cells
No effect
No effect
Slight liver dis-
coloration, swollen
cells with slightly
increased granular-
ity and vacuoliza-
tion of the cyto-
plasm**
Fatal intoxication;
jaundice and fatty
degeneration of the
liver
Fatal intoxication
31
32
31
31
31
32
-------
TABLE III-4 (continued)
Compound
Animal
Exposure and Route
Response
Reference Cited
Pentachloronaphthalene Pig
Pentachloro-
naphthalene
Pig**
H
H
6% solution in light-
weight lubricating
oil, sprayed daily
6 days/week for 4
weeks (total approxi-
mate treatment volume:
3,000 ml of oil)*
Total oral doses over
8-10 days:
50 mg/lb**
70 mg/lb**
90 mg/lb**
Slight hyperkera-
tosis
33
No vitamin A
depression**
Marked vitamin A
depression**
3/3 deaths**
33 **
Pentachloronaphthalene
Guinea pig
(one animal)
2.5 mg/kg/day, orally
6 days/wk** for 48
days
Fatal
34
Mixtures of penta-
chloronaphthalene and
hexachloronaphthalene
Human**
50% solution in mineral
oil applied to skin at
various locations for
35 days**
Acne**
24 **
-------
TABLE III-4 (continued)
Compound
Animal
Exposure and Route
Response
Reference Cited
Mixtures of penta-
chloronaphthalene and
hexachloronaphthalene
Rat
Poult
H
I
Rat
Rabbit
Hexachloronaphthalene Rat
300 mg/day, orally for
33 days or less (maxi-
mum dose of 9.9 g) or
100 mg/day, orally for
55 days (total dose
of 5.5 g)
100 ppm in diet
5 ppm in diet
8.88 mg/m *, by in-
halation 16 hr/day
for 52 days
15 mg/kg, orally for
12-26 days (total dose
180-390 mg/kg)
30 mg/kg in acetone,
applied to skin daily
for 5 days
20 and 63 mg/kg, in
diet for 84 days
Fatal; livers 31
markedly yellow
with fatty
degeneration
16/18 deaths 21
Some deaths; de- 21
crease in weight
gain by 1/3
Jaundice; enlarged, 31
yellow liver; fatal
to 69%
Death; liver damage 32
Mild dermatitis with 25
follicular attentua-
tion
Weight loss 35
200 mg/kg, in diet
Some deaths
35
-------
TABLE III-4 (continued)
Compound
Animal
Exposure and Route
Response
Reference Cited
Hexachloronaphthalene Rabbit
30 mg/kg in acetone,
applied to ear for 5
days
Decrease in seba-
ceous gland tis-
sue
25
Heptachloronaphthalene
No chronic studies reported in EPA Report (2)
Octachloronaphthalene Human
Applied to ear
No effects
24
H
H
H
I
00
Rat
0.5, 2, or 5 g/kg,
in diet for 22 days
Decrease in vitamin
A in liver but not
in plasma
* Corrected to agree with reference cited
**Added from reference
20
fl
fl
Rabbit 1 g, single oral dose Death in 7 days 14
Poult - No effect 35
-------
2.5 Carcinogenicity
No information was found in the sources searched.
2.6 Mutagenicity
No information was found in the sources searched.
2.7 Teratogenicity
No information was found in the sources searched.
2.8 Metabolic Information
Cornish and Block (.14) investigated the metabolism of 1
doses of chlorinated naphthalenes in rabbits. They reported 1 t
1-chloronaphthalene and dichloronaphthalene were metabolized
readily and that tetrachloronaphthalene was metabolized to a some-
what lesser extent over a 4-day period. Pentachloronaphthalene,
heptachloronaphthalene, and octachloronaphthalene did not undergo
metabolic reactions that could be detected in this particular
study.
Highly chlorinated naphthalenes were found to be excreted in
the milk of cows suffering from X-disease (see Section 2.4) (19).
In rabbits, the major excretory product was a glucuronide; small
amounts of mercapturic acid derivatives, sulfates, and phenolic
compounds were also excreted. For data on urinary metabolites in
rabbits, see Table III-5. An inverse correlation existed between
the extent to which chlorinated naphthalenes (from monochloro
through pentachloro) were metabolized and excreted and the known
toxicity of these compounds (14).
111-19
-------
TABLE III-5
NAPHTHALENE AND LESS CHLORINATED NAPHTHALENES*
ACCOUNTED FOR IN URINARY METABOLITES IN RABBITS (14)
H
Compound Accounted for
Compound Fed (1 g)
Naphthalene
1-Chloronaphthalene
Dichloronaphthalene
Tetrachloronaph-
thalene
Ethereal
Sulfate (mg)
64
101
55
40
Mercapuric
Acid (mg)
192
131
177
32
in Various Metabolites
Glucuronic Free Phenolic
Acid (mg) Compounds (mg)
390 23
537 20
686
379
Total
Compound
Excreted
669
789
918
451
Percentage
of Compound
Excreted
67%
79%
92%
45%
*No pentachloronaphthalene, heptachloronaphthalene, or octachloronaphthalene fed to the rabbits
could be accounted for in any of the four metabolites.
-------
1-Chloronaphthalene, when metabolized by certain soil
bacteria, may give D-6-chloro-l,2-dihydro-l,2-dihydroxynaph-
thalene and 3-chlorosalicylic acid, as diagrammed below (10)
"OH ^^^ 0
OH ^ - COH
(a)
(b)
(c)
(a) 1-Chloronaphthalene
(b) D-6-Chloro-l,2-dihydro-l,2-dihydroxynaphthalene
(c) 3-Chlorosalicylic acid
2.9 Environmental Release and Ecological Effects
Except for monochloronaphthalenes, few reports on the toxici-
ty of chlorinated naphthalenes to aquatic and terrestrial wildlife
were found in th^ sources searched, and none were found on their
ecological effects. Little is known about the distribution of
chlorinated naphthalenes in the environment. Goerlitz and Law
(27) have noted that chlorinated naphthalenes, particularly those
with three to six chlorine atoms, interfere in analyses of environ-
mental samples for chlorinated pesticides and PCB's and that there-
fore they may be mistaken for them. The most reliable technique
for analysis is gas chromatography/mass spectrometry. The detec-
tion of chlorinated naphthalenes in routine analyses for chlorinated
hydrocarbons is unlikely unless they are specifically sought (2).
The FDA, in monitoring agricultural products, can determine chlor-
inated naphthalene residues, but none were found from 1970-1975
(2). Chlorinated naphthalenes have been detected in the ppb range
III-21
-------
in fish in Lake Ontario (46).
Crump-Wiesner et al. (.37, as reported in 2) found water
samples containing chlorinated naphthalenes at 5.7 yg/liter in a
South Florida drainage ditch near an airport overhaul hangar
(their source may have been capacitors); sediment samples con-
tained chlorinated naphthalenes at 5-rag/kg. Law and Goerlitz
(38, as reported in 2) found chlorinated naphthalenes in the yg/kg
range in material from the bed of the Guadalupe River in Cali-
fornia, although there appeared to be no industrial activity in
the vicinity.
From the foregoing, it appears that chlorinated naphthalenes
have generally not been identified in the environment; it is not
known, however, whether they are in fact absent or whether analyt-
ical capabilities for detecting them are unavailable.
Goldfish were rapidly intoxicated when exposed to chloro-
naphthalene at less than 1 ppm in water (39). The frog (Rana
pipiens) had an LD50 of 900 mg/kg for 1-chloronaphthalene injected
intraperitoneally in solution with peanut oil (39). Halowax 1000
(60% monochloronaphthalene and 40% dichloronaphthalene) had a 96-
hour LC50 of 325 ppb in adult grass shrimp (Palaemonetes pugio).
The LC50 for Halowax 1099 (40% trichloronaphthalene and 60% tetra-
chloronaphthalene) was 90 ppb (7). Chlorinated naphthalene mix-
tures were tested on four species of unicellular marine algae at
concentrations from 0.1-1.0 ppm (6). Judged by the growth of the
algae, toxicity appeared to be inversely proportional to the degree
of chlorine substitution—an effect that is the reverse of what
can be expected in mammals--while uptake was directly related to
III- 22
-------
chlorine content. The 1- and 2-chloronaphthalenes were found to
be very toxic to eggs of the sea urchin (Paracentrotus lividus)
(40).
2.10 Current Testing
No information was found in the sources searched.
111-23
-------
REFERENCES
1. Halochem, Inc. Data Sheets: Chlorinated Naphthalene
Products. Boonton, N.J.
2. U.S. Environmental Protection Agency, Office of Toxic
Substances. Environmental Hazard Assessment Report:
Chlorinated Naphthalenes. EPA 560/8-75-001 (December
1975)
3. Cuozza, R. (Halochem, Inc., Boonton, N.J.). Personal
Communication (April 18, 1978)
4. Howard, P.H., and Durkin, P.R. Preliminary Environmental
Hazard Assessment of Chlorinated Naphthalenes, Silicones,
Fluorocarbons, Benzenepolycarboxylates and Chlorophenols.
EPA 560/2-74-001, NTIS PB-238 074/AS (1973)
5. Koeman, J.H., Van Velzen-Blad, H.C.W., DeVries, R. , and
Vox, J.G. Effects of PCB and DDE in cormorants and eval-
uation of PCB residues from an experimental study- J. Re-
prod. Fert., Suppl. 19:353-364 (1973)
6. Walsh, G.E., Ainsworth, K.A., and Faas, K. Effects and uptake
of chlorinated naphthalenes in marine unicellular algae. Bull,
Environ. Contam. Toxicol. 18:297-302 (1977)
7. Green, F.A., Jr., and Neff, J.M. Toxicity, accumulation
and release of three polychlorinated naphthalenes (Halo-
wax 1000, 1013, and 1099) in postlarval and adult grass
shrimp (Palaemonetes pugio). Bull. Environ. Contam. Toxic-
ol. 17:399-407 (1977)
8. Vos, J.G., and Beems, R.B. Dermal toxicity studies of
technical polychlorinated biphenyls and fractions thereof
in rabbits. Toxicol. Appl. Pharmacol. 19:617-633 (1971)
9. Bowes, G.W., Simoneit, B.R.T., Burlingame, A.C., and Rise-
broug, R.W. Identification of chlorinated dibenzofurans
in American polychlorinated biphenyls. Nature 256:305-
307 (1975)
10. Ruzo, L.O., Bunce, N.W., Safe, S., and Hutzinger, D.
Photodegradation of polychloronaphthalenes in methanol
solution. Bull. Environ. Contam. Toxicol. 14:341-345
(1975)
11. Walker, N., and Wiltshire, G.H. The decomposition of
1-chloro- and 1-bromonaphthalene by soil bacteria. J. Gen.
Microbiol. 12:478-483 (1955)
12. Canonica, L., Fiecchi, A., and Treccani, V. Products of mi-
crobial oxidation of some substituted naphthalenes. Rend.
1st. Lombardo Sci. 91:119-129 (1959) (Abstract)
111-24
-------
13. Okey, R.W., and Bogan, R.H. Apparent involvement of elec-
tronic mechanisms in limiting microbial metabolism of
pesticides. J. Water Pollut. Contr. Fed. 37:692-712
(1965)
14. Cornish, H.H., and Block, W.D. Metabolism of chlorinated
naphthalenes. J. Bio. Chem. 231:583-588 (1958)
15. Plewig, G. Zur Kinetik der Comedonen-Bildung bei Chlor-
acne (Halowax acne). Arch. Klin. Exp. Dermatol. 238:
228 (1961)
16. Kimbrough, R.D. The toxicity of polychlorinated poly-
cyclic compounds and related chemicals. CRC Crit. Rev.
Toxicol. 445-498 (1974)
17. Huber, W.G., and Link, R.P. Toxic effects of hexachloro-
naphthalene on swine. Toxicol. Appl. Pharmacol. 4:257-
262 (1962)
18. Crow, K.D. Chloracne. Trans. St. John Hosp. Der-
matol. S. 56:79-99 (1970)
19. Sikes, D., Wise, J.C., and Bridges, M.E. The experi-
mental production of "X-disease" (hyperkeratosis) in
cattle with chlorinated naphthalenes and petroleum
products. J. Am. Vet. Med. Assoc. 121:337 (1952)
20. Deadrick, R.E., Bieri, J.G., and Cardenas, R.R., Jr.
Effects of octachloronaphthalene on vitamin A metabol-
ism in the rat. J. Nutr. 57:286-295 (1955)
21. Pudelkiewicz, W.J., Boucher, R.V., Callenbach, E.W.,
and Miller, R.C. Some physiological responses of New
Hampshire chickens to a mixture of penta- and hexa-
chloronaphthalenes. Poultry Sci. 38:424-430 (1959)
22. Schwartz, L., Tulipan, L., and Birmingham, D.J.
Occupational Diseases of the Skin. 3rd ed. Lea and
Febinger, Philadelphia. P 336 (1957)
23. Kleinfeld, M., Messite, J., and Swencicki, R. Clini-
cal effects of chlorinated naphthalene exposure. J.
Occup. Med. 14:377-379 (1972)
24. Shelley, W.B., and Kligman, A.M. The experimental
production of acne by penta- and hexachloronaphthalenes.
Arch. Dermatol. 75:689-695 (1957)
25. Hambrick, G.W. The effect of substituted naphthalenes
on the pilosebaceous apparatus of rabbit and man.
J. Invest. Dermatol. 28:89-103 (1957)
26. Collier, E., and Glasg, M.B. Poisoning by chlorinated
naphthalene. Lancet 1:72-74 (1943)
111-25
-------
27. Goerlitz, D.F., and Law, L.M. Chlorinated naphthalenes
in pesticide analysis. Bull. Environ. Contain. Toxicol.
7:243-251 (1972)
28. Cotter, L.H. Pentachlorinated naphthalenes in industry.
J. Am. Med. Assoc. 125:173 (1944)
29. Wagstaff, D.J. Detoxification of lead acetate and
other trace substances. In D.D. Hemphill (ed.), Trace
Substances in Environmental Health—V, Proceedings of
the U. of Missouri Conference. Pp 363-371 (1971)
30. Shakhnovaskaya, F.B. Toxicology of chlorinated naph-
thalenes. Farmakol. Toksikol. 16:43 (1953) (.Abstract)
31. Bennett, G.A., Drinker, C.K., and Warren, M.F. Morpho-
logical changes in the liver of rats resulting from
exposure to certain chlorinated hydrocarbons. J. Ind.
Hyg. Toxicol. 20:97-123 (1939)
32. Greenburg, L., Mayers, M.R., and Smith, A.R. The
systemic effects resulting from exposure to certain
chlorinated hydrocarbons. J. Ind. Hyg. Toxicol. 21:
29-38 (1939)
33. Link, R.P., Smith, J.C., and Newton, D.I. Toxic effect
of chlorinated naphthalenes in pigs. J. Am. Vet. Med.
Assoc. 133:83-85 (1958)
34. Bentz, H., and Herdman, I. The suitability of the
guinea pig as a test animal for the determination of
poisoning by chlorinated naphthalenes. Arch. Exp.
Veterinarmed. 10:50-57 (1955)
35. Weil, C.S., and Goldbe,rg, M.E. Toxicological and phar-
macological criteria of repeated doses of a he'patotoxic
agent. Acta Pharmacol. Toxicol. 19:129-138 (1962)
36. Pudelkiewicz, W.J., Boucher, R.V., Callenback, E.W.,
and Miller, R.C. Some physiological responses of broad
breasted bronze poults to chlorinated naphthalene.
Poultry Sci. 37:185-187 (1958)
37. Crump-Wiesner, H.J., Feltz, H.R., and Yates, M.L.
A study of the distribution of polychlorinated biphenyls
in the aquatic environment. U.S. Geol. Surv. J. Res. 1:
603-607 (1973)
38. Law, L.M., and Goerlitz, D.F. Selected chlorinated
hydrocarbons in bottom material from streams tributary
to San Francisco bay. Pestic. Monit. J. 8:33-36 (1974)
39. Sundstrom, G., Hutziner, O., Safe, S. et al. Methods
for the study of metabolism of toxic and persistent
111-26
-------
chemicals in aquatic organisms as exemplified by chloro-
naphthalenes. Proc. Swedish Netherland Symp. 177-178 (1975)
40. Gavaudan, P., and Gavaudan, N. Narcosis of batrachians and
inhibition of the cleavage of sea urchin eggs by cyclic
hydrocarbons which modify karyokinesis and plant cytodier-
esis. C. Rend. Soc. Biol. 136:237-239 (1942)
41. Hansel, W. , Olafson, P., and McEntee, K. Bovine hyperkera-
tosis: Studies on a German wood preservative. Cornell Vet.
43:311-324 (1953)
42. Bell, W.B. The production of hyperkeratosis (X disease) by
a single administration of chlorinated naphthalenes. J. Am.
Vet. Med. Assoc. 124:289-290 (1954)
43. Link, R.P. Bovine hyperkeratosis (X disease). J. Am. Vet.
Med. Assoc. 123:427-430 (1953)
44. Brock, W.E., Jones, E.W., MacVicar, R., and Pope, L.S.
Chlorinated naphthalene intoxication in sheep. Am. J. Vet.
Res. 18:625-630 (1957)
45. Bell, W.B. Further studies on the production of bovine hyper-
keratosis by the administration of a lubricant. Virginia J.
Sci. 3.'169-177 (1952)
46. Annual Report of Surveillance Subcommittee of the Implementa-
tion Committee of the Great Lakes Water Quality Board (June
1977)
47. Schoettle, C.E., Reber, E.F., Morrill, C.C., and Link, R.P.
Experimental production of hyperkeratosis in rats and ham-
sters. Am. J. Vet. Res. 16:183-188 (1955)
111-27
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DICHLORQMETHANE
TABLE OF CONTENTS
Page
Overview IV-1
Part I General Information IV-3
Part II Biological Properties
2.1 Bioaccumulation IV-6
2.2 Impurities and Environmental Degradation
or Conversion Products IV-6
2.3 Acute Toxicity IV-7
2.4 Other Toxic Effects IV-9
2.5 Carcinogenicity IV-11
2.6 Mutagenicity IV-11
2.7 Teratogenicity IV-18
2.8 Metabolic Information IV-18
2.9 Environmental Release and Ecological
Effects IV-20
2.10 Current Testing IV-21
References IV-23
IV-i
-------
DICHLQROMETHANE
AN OVERVIEW
Dichloromethane, also known as methylene chloride, is a
colorless, volatile liquid with a penetrating, ether-like odor.
It is slightly soluble in water and soluble in all proportions
in alcohol and ether.
Production of dichloromethane has steadily increased to an
excess of 500 million pounds in 1976. Demand for the chemical
is expected to increase as it substitutes for other compounds
coming under regulation.
The compound is most commonly used as a paint remover.
Other uses are as a propellant for aerosol sprays, a blowing
agent in foams, and a degreasing agent.
NOHS reports that nearly 2,500,000 workers are exposed to
dichloromethane in their places of employment.
An estimated 367 million pounds of dichloromethane are re-
leased annually into the environment. The chemical is nontoxic
to sewage microorganisms and its Aquatic Toxicity Rating is in
the nontoxic range. No reports of adverse ecological effects
have been.found, although some concern has been expressed about
possible inhibition of natural fermentation processes.
In animals, acute exposure to dichloromethane has produced
adverse effects on the heart and lungs; long-term exposure has
produced toxic effects on the liver, lungs, eyes, and brain, as
well as death. In humans, acidosis, hemoglobinuria, unconscious-
ness, elevated carboxyhemoglobin levels, increased pulse rate,
IV-1
-------
paresthesia, sensations of heat, eye irritation, and nausea have
been reported after acute exposure to the chemical. Long-term
effects include sonorous breathing, cyanosis, rapid weak pulse,
and biochemical changes in serum.
Metabolism of dichloromethane is thought to occur by enzy-
matic activation of the microsomal heme-oxygenase system. Car-
bon monoxide and carbon dioxide have been identified as meta-
bolites. When inhaled or administered intraperitoneally, the
chemical is largely eliminated unchanged in the breath.
No information on the carcinogenicity or mutagenicity of
the chemical was found. One source reported an increased in-
cidence of extra or split sternebrae in the offspring of mice
exposed to it.
The chemical is being tested for its toxicity, carcino-
genicity, and tissue-binding characteristics.
IV-2
-------
DICHLOROMETHANE
PART I
GENERAL INFORMATION
1.1 Identification CAS No.: 000075092
NIOSH No. : PA80500
1.2 Synonyms and Trade Names
Methane dichloride; methylene bichloride; methylene chloride;
methylene dichloride; Solaesthin
(G16)
1. 3 Chemical Formula and Molecular Weight
CH Cl Mol. wt. 84.93
£• £
(G22)
1 . 4 Chemical and Physical Properties
1.4.1 Description; Colorless, volatile liquid;
penetrating ether-like odor
(G23,G21)
1.4.2 Boiling Point: 40°C (G22)
1.4.3 Melting Point; -95.1°C (G22)
1.4.4 Absorption Spectrometry ;
(G22)
1.4.5 Vapor Pressure; 400 mm at 24.1°C (G22)
1.4.6 Solubility; Slightly soluble in water;
soluble in all proportions in
alcohol, ether
(G22)
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched,
IV-3
-------
1.5 Production and Use
1.5.1 Production:
1.5.2 Use:
471.3 million Ib (1972)
537.7 million Ib (1976)
(G28)
(G24)
As a solvent for cellulose acetate; in degreasing
and cleaning fluids; in paint removers; as a pro-
pellant for aerosol sprays; in plastics processing;
as a blowing agent in foams; food extraction
applications
Quantitative Distribution;
Paint remover
Exports
Aerosol sprays
Chemical specialties (mainly
solvent degreasing)
Plastics processing
All other
(G23,G21,45)
Percentage
40
20
17
10
6
7
100
(G25)
Category
Consumer Product Information:
No. of products
containing
dichloromethane
Cleaning agents and com-
pounds
Paints, varnishes, shellac,
rust preventatives, etc.
Household aerosols
Solvent-based cleaning and
sanitizing agents
Caustics, lyes and drain
cleaners
Adhesives and adhesive pro-
ducts, including glue
Paint and varnish removers
3
41
1,298
8
No. of dichloromethane
products in category ,..
Total no. of products x
in category
0.17%
0.37%
34.55%
3.67%
0.87%
0.75%
18.18%
The 1,358 products surveyed contained an average of 30.0% dichloromethane.
(G27)
IV-4
-------
1.6 Exposure Estimates
1.6.1 Release Rate; 367.0 million Ib (G28)
1.6.2 NOHS Occupational Exposure;
Rank: 5 7
Estimated no. of persons exposed: 2,499,000
(G29)
1.7 Manufacturers
Allied Chemical Corp.
Diamond Shamrock Corp.
Dow Chemical Corp.
Stauffer Chemical Co.
Vulcan Materials Co.
(G24)
IV-5
-------
DICHLOROMETHANE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
Dichloromethane1s high vapor pressure (440 mm at 25°C (G38))
facilitates its excretion unchanged via the lungs. In addition,
its stability and water solubility (13 g/liter (G14)) promote
excretion in the urine. Experiments verify that the compound is
largely excreted unchanged by the lungs (G38), especially when
subjects are exposed under occupational conditions (to dichloro-
methane at about 200 ppm).
DiVincenzo and Hamilton (38) reported no accumulation of
radioactivity in rats administered labeled dichloromethane intra-
peritoneally.
Only minor portions of an intraperitoneal dose are metabo-
lized to carbon dioxide, carbon monoxide, and an unidentified
urinary metabolite (38). Pearson and McConnell (14) found no
evidence for the bioaccumulation of C,/C2 chlorinated hydro-
carbons in food chains in a marine environment.
2.2 Impurities and Environmental Degradation or Conversion
Products
Impurities found in commercial dichloromethane include
chloroform (up to 2,500 ppm), methyl chloride, cyclohexane,
water (up to 200 ppm), acid (HCl, up to 5 ppm), and trans-
dichloroethene (G14,G17). A sample of dichloromethane used in
a Russian cellulose acetate factory was stated to contain 0.25%
IV-6
-------
methyl chloride, 0.25% chloroform, and 1% ethanol (3, as reported
in 15). The commercial chemical often contains a small amount
(0.0001%) of an additive such as phenol, hydroquinone, p-cresol,
resorcinol, thymol, and 1-naphthol, or small quantities of amines
to stabilize it during contact with air and moisture (G17).
Methylene chloride is stated to be one of the most stable
of the chloroparaffins (G17). It is only slightly reactive
toward the hydroxyl radical (half-life about 1 year) and much
less so toward the peroxy radical and ozone; it is also highly
resistant to hydrolysis (half-life about 700 years) (G14). Spence
et al. (24) reported that the photo-oxidation of the compound in
the troposphere probably proceeds with a half-life of several
months. They irradiated 20 ppm dichloromethane at 1 atmosphere
pressure and obtained carbon dioxide and carbon monoxide as the
major carbon-containing products. They also observed hydrochloric
acid and a small amount of phosgene. In similar experiments,
Pearson and McConnell (14) obtained the same products, with the
exception of phosgene. They estimated the tropospheric half-life
of dichloromethane, based on outdoor exposure in quartz flasks,
to be 33 weeks.
No information on biodegradation was found (G14).
2.3 Acute Toxicity
The acute toxicity of dichloromethane, as reported in the
NIOSH Registry of Toxic Effects of Chemical Substances (G16),
is given in Table IV-1.
IV-7
-------
TABLE IV-1
Acute Toxicity of Dichloromethane
Parameter
Dosage
Species
Route
TCLo
LD50
500 ppm/8 hr
2,136 mg/kg
1,500 mg/kg
6,460 mg/kg
3,000 mg/kg
950 mg/kg
2,700 mg/kg
200 mg/kg
1,900 mg/kg
2,700 mg/kg
5,000 ppm/2 hr
Human
Rat
Mouse
it
Dog
Rabbit
Guinea Pig
Inhalation
Oral
Intraperitoneal
Subcutaneous
Oral
Intraperitoneal
Subcutaneous
Intravenous
Oral
Subcutaneous
Inhalation
Svirbely et al. (13, as cited in 15) determined the LC50
in mice for a 7-hour inhalation exposure to be 16,188 ppm.
Gradiski et al. (25) found an LD50 of 1,900 mg/kg in female
mice treated intraperitoneally.
Kimura et al. (26) reported oral LDSO's of <1.00 ml/kg in
newborn rats and 1.8, 1.6, and 2.3 ml/kg in 14-day-old, young
adult, and older rats, respectively.
Aviado and Smith (32) reported that guinea pigs exposed to
this chemical for 6 hours had mortality rates of 15% at 8,700
ppm, 40% at 11,100 ppm, and 100% at 16,000 ppm. Increased levels
IV-8
-------
of triglycerides and carboxyhemoglobin were also observed.
Aviado (27) classified dichloromethane as a highly toxic,
low pressure propellant. Its inhalation at concentrations of
0.5-5% by monkeys and dogs and'at 1-10% by rats and mice was
reported to cause major adverse effects on the lungs and heart,
including cardiac arrhythmia and tachycardia.
In humans, accidental ingestion of dichloromethane pre-
parations, such as paint remover, has reportedly caused uncon-
sciousness, acidosis, and hemoglobinuria (28). Stewart and
cowo.rkers reported finding elevated carboxyhemoglobin levels
in human subjects exposed by inhalation for 2 hours to dichloro-
methane at 500-1,000 ppm (29,30) and in humans exposed to paint
removers containing dichloromethane (31). Humans exposed to
dichloromethane at 1,000 ppm for 2 hours showed carboxyhemoglobin
saturation levels in excess of those permitted from occupational
exposure to carbon monoxide (30).
Other experiments have demonstrated that exposure at 25,000
ppm for 2 hours was not lethal (G4). Exposure at 7,200 ppm
caused paresthesia of the extremities in 8 minutes and increased
pulse rate, congestion in the head, a sensation of heat, and
mild eye irritations. Exposure at 2,300 ppm for 1 hour caused
nausea after 30 minutes.
2.4 Other Toxic Effects
Dichloromethane was described as an irritant and weak
narcotic (G3). When used as an anesthetic in humans, it caused
stertorous breathing, cyanosis, dilated pupils, and a rapid
IV-9
-------
weak pulse. Hyperbilirubinemia and reduced albumin-globulin
ratio after mild occupational poisoning with dichloromethane
have been reported (G10). Rats, rabbits, and dogs, but not
guinea pigs tolerated exposure by inhalation at 5,000 ppm
(17 mg/liter), 7 hours/day, 5 days a week, for 6 months (G3).
Reported toxic effects of repeated exposure to mammals in-
cluded liver damage in mice, dogs, monkeys, and rats; reduced
growth rates in monkeys and rats; brain damage in mice; liver
enzyme alterations in rats; and death in mice and dogs (G14,G15)
Weinstein et al. (17) observed that continuous inhalation
of dichloromethane at 5,000 ppm by female mice induced poly-
ribosomal dissociation and swelling of hepatocyte rough endo-
plasmic reticulum, which showed partial reversal after 2 days.
Other findings were transient fatty changes (increase in tri-
glycerides) and partial inhibition of leucine incorporation in
liver protein.
Aviado and Smith (32) reported that exposure to dichloro-
methane as an aerosol propellant did not alter respiratory
minute volume in monkeys but affected pulmonary resistance and
compliance.
Balmer et al. (33) detected increased triglyceride levels
in guinea pigs exposed at 552-679 ppm for 5 days. Guinea pigs
exposed once at 11,100 ppm were said to have congestion and
hemorrhage in the lungs and centrilobular patchy fat vacuolation,
Five days of exposure at 552-679 ppm induced fatty changes in
the liver and some pneumonitis. Not all the guinea pigs were
IV-10
-------
affected. Ballantyne et al. (34) reported transient effects
such as inflammation of the conjunctiva and eyelids and increased
corneal thickness and intraocular tension in rabbits exposed to
dichloromethane as a liquid or vapor.
Johnson (35) detected 100% increases in glutathione levels
in female rats given 11.8 millimoles/kg of dichloromethane orally
and killed 2 hours later.
Gamberale et al. (36) investigated the effect of dichloro-
methane on reaction time, short-term memory, and numerical
ability in 14 healthy men exposed at 870-3,470 mg/m . Irregu-
larity of response was evident in subject reaction time only
at the highest concentration. Other toxicity data are summarized
in Tables IV-2 and IV-3, which were adapted from the NIOSH
criteria document (15) .
The ACGIH Threshold Limit Value (TLV) for dichloromethane
is 200 ppm (Gil).
2.5 Carcinogenicity
It has been reported that no tumors developed in dogs,
rabbits, guinea pigs, and rats exposed by inhalation for up to
6 months at 5,000 ppm (17 mg/liter) for 7 hours/day, 5 days a
week, and at 10,000 ppm (34 mg/liter) for 4 hours/day, 5 days a
week (G18).
2.6 Mutagenicity
No information on mutagenicity was found in the sources
searched.
IV-11
-------
TABLE IV-2
EFFECTS OF ACUTE INHALATION EXPOSURE TO DICIILOROMETHANE
Animal
Concentration (ppm)
Duration
Effects
Reference
Cited
Human
H
<
i
M
NJ
Mouse
317 and 751
317, 470, and
751
Unknown
14,500
10,000
5,000
100
4 hr
3-5 hr
4 hr
2 hr
2 hr
7 days
Up to 10 wk
continuous
Depressed critical 8
flicker frequency (CFF),
auditory vigilance per-
formance
Decreased performance 9
of CFF, auditory vigi-
lance, psychomotor tasks
Oppressive odor, eye ir- 11
ritation, excessive fa-
tigue, weakness, sleepi-
ness, lightheadedness,
chilly sensations, nausea,
shortness of breath, sub-
sternal pain, weakness,
dry rales in chest, pul-
monary edema
Death 12
Narcosis 12
Initial increase in phys- 17
ical activity followed
by decrease in food and
water intake, lethargy,
increased liver-to-body
weight ratio and liver fat,
mild fatty infiltrations,
hydropic degeneration of
centrilobular cells
Elevated liver fat, de-
creased hepatocyte glyco- 18
gen, centrilobular fatty
infiltration
-------
TABLE IV-2 (continued)
EFFECTS OF ACUTE INHALATION EXPOSURE TO DICIILOROMETHANE
Animal
Mouse
Concentration (ppm)
25
Duration
14 wk
continuous
Effects
Increased activity
Reference
Cited
16
Rat
Dog
25,000 to 28,000
16,000-18,000
5,000 to 9,000
3,000, 1,000, and
500
2,800
100 or 1,000
40,000
1.5 hr
6 hr
8 hr
24 hr
14 hr
3 hr
Cessation of elec- 22
trical activity after
1.5 hr
Initial excitement 22
followed by deep
narcosis, decreased
EMG tonus, decreased
EEC activity, breath-
ing difficulties, tremor,
cessation of electrical
activity after 6 hr
Long sleeping phase lack- 22
ing desynchronization
phases
Suppressed REM sleep, in- 8
creased time between two
REM periods, linear rela-
tion between dose and
response
Decreased proportion of 22
REM sleep to total sleep
Increased blood CO 23
Loss of pupillary and 21
corneal reflexes after
10-20 min, complete
muscular relaxation af-
ter 16 min, death from
progressive heart failure
due to cardiac injury in
3 of 5 dogs
-------
TABLE VI-2 (continued)
EFFECTS OF ACUTE INHALATION EXPOSURE TO DICHLOROMETHANE
Animal
Concentration (ppm)
Duration
Effects
Reference
Cited
Dog
M
<
Mouse, rat,
monkey, dog
15,000 and 20,000
6,000
4,000
5,000
1,000
100
25
6 hr
14 wk
continuous
2-8 wk
continuous
Loss of pupillary and 21
corneal reflexes after
10-20 min, complete
muscular relaxation after
25-35 min, reduction
in blood pressure and
rapid narcosis at
20,000 ppm
Light narcosis in 2 hr 12
Light narcosis after 12
2.5 hr
High mortality, pneu- 20
monia, fatty liver, ic-
terus, splenic atrophy,
edema of meninges, renal
tubule vascular changes
Increased hematocrit, 20
Hgb, RBC, bilirubin,
weight loss; mild cen-
trilobular fat
Altered cytochromes 19
P-450, P-420, and b5;
fatty infiltration of
the liver; nonspecific
tubular degenerative and
regenerative changes; ele-
vated COHb
No overt toxicity, non- 19
specific tubular degener-
ative and regenerative
changes
-------
TABLE IV-2 (continued)
EFFECTS OF ACUTE INHALATION EXPOSURE TO DICHLOROMETHANE
Animal Concentration (ppm) Duration Effects Reference
Cited
Rabbit 6,000
4,000
Guinea pig 6,000
£ Cat 6,000
i
i-1
6 hr Light narcosis in
45 min
" Light narcosis after
6 hr
" Light narcosis in 2.5 hr
" Light narcosis in 45 min
12
12
12
12
Adapted from NIOSH Criteria for a Recommended Standard—Occupational Exposure to Methylene
Chloride (15)
-------
TABLE IV-3
EFFECTS OF REPEATED INHALATION OF DICHLOROMETHANE
<
)-•
CTi
Animal
Human
Concentration Duration
(ppm)
50-500 7.5 hr/day
5 days/wk
Observations Reference
Cited
Increased affinity of Hgb for
oxygen in proportion to exposure
1
Human
(1 subject)
Human
(1 worker)
Human
(33 workers)
100 and 500
Unknown
Unknown
28-4,896
concentration
" Slightly increased blood
lactic acid from exercise at
500 ppm,
13 yr Irregular, severe leg and arm
intermittent pains, hot flashes, vertigo,
stupor, poor night vision,
anorexia, precordial pain, rapid
pulse, shortness of breath,
fatigue, attacks of rapid
heartbeat
20 yr Drowsy, pains in head, tingling
intermittent in hands and feet
Average of
2 yr
exposure
Headache, fatigue, irritation of
upper respiratory tract, con-
junctiva, neurasthenic disorders,
mild acute poisoning in 3 with
unconsciousness in 1, sweet taste,
heart palpitations
-------
TABLE IV-3 (continued)
EFFECTS OF REPEATED INHALATION OF DICHLOROMETHANE
<
Animal Concentration
(ppm)
Human 660-3,600
(1 worker)
Human 159-219
(4 workers) (average 183)
Rat 5,000
Dog, rabbit, 5,000
guinea pig,
rat
Dog, monkey, 10,000
rabbit, guinea
pig, rat
Duration
Several
hr/day
for 5 yr
8 hr/day, 6
days/wk for
several yr
30 min/day
on 5 alter-
nate days
7 hr/day
5 days/wk
up to 6 mo
4 hr/day
5 days/wk
for 8 wk
_. . . Reference
Observations _. . ,
After 3 yr, burning pain around
heart, restlessness, feeling
of pressure, palpitations, for-
getfulness, insomnia, and feeling
of drunkerxness; after 5 yr
auditory and visual hallucina-
tions, slight erythema of hands
and underarms, encephalosis
diagnosed
Increased alveolar CO at end
of workday
Decreased running activity
No effect
Incoordination, conjunctival
irritation, shallow respiration,
pulmonary congestion, edema with
focal extravasation of blood,
some fatty degeneration
4
5
6
7
7
Adapted from NIOSH Criteria for a Recommended Standard —Occupational Exposure to
Methylene Chloride (15)
-------
2.7 Teratogenicity
Schwetz et al. (37) reported finding no fetal toxicity or
teratogenicity when pregnant rats and mice were exposed to
dichloromethane at 2,450 ppm for 7 hours/day during gestation.
However, they did find an increased incidence of extra or split
sternebrae in offspring from mice and rats exposed at 1,250 ppm.
2.8 Metabolic Information
DiVincenzo and Hamilton (38) studied the metabolic fate of
14
dichloromethane. In 24 hours, about 91% of C-dichloromethane
administered to rats intraperitoneally at 412-930 mg/kg was
eliminated in the breath unchanged, 2% as carbon monoxide, 3%
as carbon dioxide, and 1.5% as unidentified metabolite. Urine
contained 1% and the carcass 2% of the radioactivity. The
highest tissue activity was found in liver, kidney, and adrenals.
Formaldehyde levels were increased in serum but decreased in
tissue, and there was no evidence that dichloromethane was meta-
bolized to formaldehyde. The authors suggested that formation
of carbon monoxide might occur by enzymatic action of the micro-
somal heme-oxygenase system.
Kassebart and Angerer (49, as reported in 15) have proposed
a mechanism for the metabolism of dichloromethane. They sug-
gested that the parent compound might be converted into formalde-
hyde by hydrolytic dehydrochlorination. The formaldehyde would
be oxidized to formic acid, which would be oxidized to carbon
dioxide and water and dehydrated to carbon monoxide and water.
IV-18
-------
Carlson and Hultengren (39) investigated the relationship
between methylene chloride exposure and the concentration of
carboxyhemoglobin and carbon monoxide in the blood. Rats were
14 3
exposed to C-dichloromethane at 1,935 mg/m in inspiratory
air. The results showed that the level of carboxyhemoglobin
was increased due to carbon monoxide derived from methylene
chloride. The highest concentrations of dichloromethane or its
metabolites per gram of tissue were detected in the white adipose
tissue. The concentration in adipose tissue declined by 90% in
2 hours, whereas in the liver and brain, the levels dropped by
25% and 75%, respectively, during the same time.
In preliminary in vitro and in vivo metabolism studies,
Hogan et al. (40) also have reported microsomal conversion of
dichloromethane to carbon monoxide.
Recently Rodkey and Collison (41) reported biological
14
oxidation of C-dichloromethane to carbon monoxide and carbon
dioxide in the rat. The authors suggested that this halogenated
hydrocarbon acted as a direct substrate and was metabolized to
carbon monoxide. Settle (42) had suggested earlier that in-
creased carboxyhemoglobin levels seen in vivo are due to a
change in carbon monoxide affinity rather than dichloromethane
metabolism.
Ratney et al. (43) reported that dichloromethane was con-
verted to carbon monoxide and blood carboxyhemoglobin levels
were elevated in humans exposed to about 280 ppm for 8 hours.
Stewart et al. (29) reported the same findings in studies with
humans exposed to 500-1,000 ppm for 1-2 hours.
IV-19
-------
Stewart and Dodd (44) reported that immersion of a human
thumb in dichloromethane resulted in a mean peak breath concen-
tration of 3.1 ppm in 30 minutes and mean breath concentration
of 0.69 ppm after 2 hours.
2.9 Environmental Release and Ecological Effects
An extroardinarily large volume of dichloromethane enters
the environment on a regular basis. Indeed, the Stanford Research
Institute estimated that in 1972 95% of its uses were dispersive.
Because of the pattern of its uses (paint remover, aerosol spray,
etc.), much of the chemical is released into the home and the fac-
tory (G14). It is also reported to be used as a food additive (G4).
The compound has been detected at 8 ppb in water by gas
chroinotography/mass spectrometry (G14). EPA has reported dichloro-
methane concentrations in waste water effluents in the 100 ppm
range. In a survey of municipal water in sites in EPA Region V
(upper Midwest), 7 of 83 sites tested contained dichloromethane
at levels as high as 7 ppb (45).
The compound is reported to be nontoxic to sewage infusoria
and flagellates at concentrations up to 2,000 mg/liter and to
sewage nitrifiers at concentrations up to 2,500 mg/liter (G14).
On the other hand, studies have been cited (45) in which the
interaction of chloromethanes (including dichloromethane) with
anaerobic organisms has resulted in inhibition in various digestive
systems, e.g., sewage, sludge, and rumen of cow.
The Aquatic Toxicity Rating (96-hr TLm, species unspecified)
is 1,000-100 ppm, which indicates that it is ranked as practically
IV-20
-------
nontoxic (G16).
No reports of ecological incidents involving dichloromethane
were found in the sources searched, although some concern has
been expressed about possible inhibition of natural fermentation
processes (45).
Between December 1974 and February 1975, <5 ppt of the
compound were found in the air of a rural area near Pullman,
Washington (46). Analyses of the atmosphere, fresh water, sea
water, marine sediments, algae, invertebrates, fish, and other
aquatic life in the Liverpool Bay area of England were negative
for dichloromethane (14). A 1978 document on halomethanes states
that atmospheric concentrations of methylene chloride are aboi
35 ppt above marine and land areas except urban areas, where
concentrations range from less than 20 to 144 ppt (45).
There are descriptions of the effects that the chemical has
had on the health of workers who were exposed at various concen-
trations (15). In one workplace, air samples taken over a 2-day
period averaged 391 ppm of dichloromethane (43, as reported in
15). In a Russian factory, levels over a 3-year period were re-
ported to range from 30 to 5,000 ppm with an average of 627 ppm
(50, as reported in 15). A survey (45) revealed concentrations
of the chemical in the 4-20 ppb range associated with the indoor
atmosphere of certain business establishments open to the public.
2.10 Current Testing
Dow Chemical Company is currently testing dichloromethane
for carcinogenicity in a 2-year inhalation study at the Toxicol-
IV-21
-------
ogy Research Laboratory- at Midla,ndf Michigan, Rats and hamsters
are being exposed at 500, 1,500, and 3,500 ppm for 6 hours/day,
5 days/week. Results are expected in mid-1978 (47,48).
The National Cancer Institute is sponsoring a 2-year study
with mice and rats (administration by gavage), which began in
June 1976 with prechronic-testing. In addition, NCI has selected
dichloromethane for a 2-year inhalation study with rats and mice.
In both of these studies, all animals will be killed and their
tissues examined histopathologically, but no clinical chemistry,
mutagenic, or teratogenic evaluations will be performed (G12,47).
The University of Arizona is planning to study the bio-
activation of some halogenated alkanes and alkenes, including
dichloromethane, and their covalent binding to tissue macro-
molecules. Tests will be performed in various strains of mice,
rats, and hamsters (101.
IV-2 2
-------
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and Baretta, E.D. Carboxyhemoglobin elevation after expos-
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version of methylene chloride to carbon monoxide. Arch.
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IV-2 6
-------
49. Kassebart, V., and Angerer, J. Influence of dichloromethane
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IV-2 7
-------
HALOGENATED ALKYL EPOXIDES
TABLE OF CONTENTS
Page
Overview V-l
Part I General Information
l-Chloro-2,3-Epoxypropane (Epichlorohydrin) V-3
l,l,l-Trichloro-2,3-Epoxypropane (TCPO) V-6
l-Bromo-2,3-Epoxypropane (Epibromohydrin) V-8
1,4-Dichloro-2,3-Epoxybutane V-10
l,l,l-Trichloro-3,4-Epoxybutane (TCBO) V-ll
Tetrafluoroethylene Epoxide (TFEO) V-l3
Hexafluoropropylene Epoxide (HFPO) V-14
Part II Biological Properties
l-Chloro-2,3-Epoxypropane (Epichlorohydrin)
2.1 Bioaccumulation V-17
2.2 Impurities and Environmental Degradation V-17
or Conversion Products
2.3 Acute Toxicity V-18
2.4 Other Toxic Effects V-19
2.5 Carcinogenicity V-23
2.6 Mutagenicity V-29
2.7 Teratogenicity V-31
2.8 Metabolic Information V-31
2.9 Environmental Release and Ecological V-32
Effects
2.10 Current Testing V-33
V-i
-------
Page
1,1,l-Trichloro-2,S-Epoxypropane (TCPO)
2.1 Bioaccumulation V-34
2,2 Impurities and Environmental Degradation V-34
or Conversion Products
2.3 Acute Toxicity V-34
2.4 Other Toxic Effects V-34
2.5 Carcinogenicity V-36
2.6 Mutagenicity V-36
2.7 Teratogenicity V-36
2.8 Metabolic Information V-36
2.9 Environmental Release and Ecological V-36
Effects
2.10 Current Testing V-37
l-Bromo-2,3-Epoxypropane (Epibromohydrin)
2.1 Bioaccumulation V-38
2.2 Impurities and Environmental Degradation V-38
or Conversion Products
2.3 Acute Toxicity V-38
2.4 Other Toxic Effects V-38
2.5 Carcinogenicity V-38
2.6 Mutagenicity V-38
2.7 Teratogenicity V-39
2.8 Metabolic Information V-39
2.9 Environmental Release and Ecological V-39
Effects
2.10 Current Testing V-39
1,4-Dichloro-2,3-Epoxybutane V-40
1,1,l-Trichloro-3,4-Epoxybutane (TCBO)
2.1 Bioaccumulation V-41
V-ii
-------
Page
2.2 Impurities and Environmental Degradation V-41
or Conversion Products
2.3 Acute Toxicity V-42
2.4 Other Toxic Effects V-42
2.5 Carcinogenicity V-42
2.6 Mutagenicity V-42
2.7 Teratogenicity V-42
2.8 Metabolic Information V-43
2.9 Environmental Release and Ecological V-43
Effects
2.10 Current Testing V-43
Tetrafluoroethylene Epoxide (TFEO) V-44
Hexafluoropropylene Epoxide (HFPO) V-45
References V-46
V-iii
-------
HALOGENATED ALKYL EPOXIDES
AN OVERVIEW
The seven epoxides included in this dossier are halogenated
noncyclic aliphatic hydrocarbons with one or more epoxy func-
tional groups. The specific substances are l-chloro-2,3-epoxy-
propane (epichlorohydrin), 1,1,l-trichloro-2,3-epoxypropane
(TCPO), l-bromo-2,3-epoxypropane (epibromohydrin), 1,4-dichloro-
2,3-epoxybutane, 1,1,l-trichloro-3,4-epoxybutane (TCBO), tetra-
fluoroethylene epoxide (TFEO), and hexafluoropropylene epoxide
(HFPO). Several of these compounds are liquids that are generally
more soluble in organic solvents than in water.
Over 500 million pounds of epichlorohydrin were produced
in the United States in 1975. No accurate production figures
for epibromohydrin were found, but its estimated annual produc-
tion is between 1 thousand and 1 million pounds. Apparently,
only limited amounts of the other halogenated epoxides are pro-
duced.
Epichlorohydrin is used extensively as an intermediate and
solvent in the manufacture of various products, including
glycerine, epoxy resins, paints, varnishes, shellacs, flame-
retardant chemicals, and household aerosols. TCPO is used in
research laboratories as an inhibitor of the enzyme epoxide hydrase,
TCBO has potential uses as an intermediate in the preparation of
urethane, epoxy resins, phenolic resins, and many other chemicals.
No information on the uses of epibromohydrin and l,4-dichloro-2,3-
epoxybutane was found. TFEO and HFPO are monomers used in the
production of specific polymers.
V-l
-------
NIOSH estimates that between 50,000 and 140,000 workers
in the United States are occupationally exposed to epichloro-
hydrin. No exposure estimates on the other epoxides were found.
No reports on the bioaccumulation and ecological effects
of these epoxides were found in the sources searched.
Severe necrotic lesions have occurred in humans after skin
contact with epichlorohydrin, and humans exposed to the chemical
at a high atmospheric concentration have experienced eye and
throat irritation, nausea, dyspnea, bronchitis with bronchiolar
constrictions, and enlarged livers. TCBO causes skin and eye
irritation in rabbits. Results of carcinogenicity studies on
epichlorohydrin are equivocal. No lesions were observed in ani-
mals exposed by skin application, but subcutaneous injections
induced sarcoma and adenosarcoma. TCPO inhibits detoxifying
enzymes in mammals and potentiates the effect of carcinogens.
Negative results for carcinogenicity were reported for epibromo-
hydrin and TCPO when applied dermally-
Epichlorohydrin has been shown to be mutagenic in mice
and bacteria; positive results were also reported for epibromo-
hydrin and TCBO. Increased embryolethality in animals exposed
to TCPO and antifertility effects in animals exposed to epi-
chlorohydrin have been reported. No reports of teratogenic
effects from these epoxides were found in the sources searched.
V-2
-------
HALOGENATED ALKYL EPOXIDES
PART I
GENERAL INFORMATION
l-CHLORO-2,3-EPOXYPROPANE (EPICHLOROHYDRIN)
1.1 Identification CAS No.: 000106898
NIOSH No. : TX49000
1. 2 Synonyms and Trade Names
3-Chloro-l , 2-epoxypropane; (chloromethyl) ethylene oxide;
chloromethyloxirane; chloropropylene oxide; gamma-chloro-
propylene oxide; 3-chloro-l, 2-propylene oxide; alpha-
epichlorohydrin; epichlorohydrin; glycerol epichlorohydrin;
oxirane, (chloromethyl) -; oxirane, 2- (chloromethyl) -
(G16)
1. 3 Chemical Formula and Molecular Weight
CH^ — CHCH Cl C-.H-OC1 Mol. wt . 92.53
^ l J b (G22)
1. 4 Chemical and Physical Properties
1.4.1 Description; Highly volatile, unstable liquid;
chloroform-like odor
(G23)
1.4.2 Boiling Point: 116. 5°C (G22)
1.4.3 Melting Point: -48°C (G22)
1.4.4 Absorption Spectrometry :
No information was found in the sources searched.
1.4.5 Vapor Pressure; 12.5 mm at 20°C (G22)
1.4.6 Solubility: Slightly soluble in water; soluble
in benzene; soluble in all
proportions in alcohol and ether
(G22)
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched.
V-3
-------
1.5 Production and Use
1.5.1 Production; 340 million Ib (1973) (G41)
495 million Ib (1974) (G15)
550 million Ib (1975) (G19)
1.5.2 Use; Major raw material for epoxy and phenoxy
resins; in the manufacture of glycerol; for
curing propylene-based rubbers; solvent for
cellulose esters and ethers; in high wet-
strength resins for paper industry
(G21)
Consumer Product Information;
No. of products
No. of products containing 1-chloro-
containing 2,3-epoxy propane x
l-chloro-2,3- Total no. of pro-
Category epoxy propane ducts in category
Paints, 4 0.04%
varnishes,
shellac, rust
preventatives,
etc.
Flame-retardant 1 0.17%
chemicals
Household 5 0.13%
aerosols
The 10 products surveyed contained an average of 6.7%
l-chloro-2,3-epoxy propane.
(G27)
Quantitative Distribution (1970):
Glycerin manufacture 55%
Epoxy resins 40
Miscellaneous 5
100%
(G25)
V-4
-------
1.6 Exposure Estimates
1.6.1 Release Rate;
No information was found in the sources searched.
1.6.2 NIOSH Estimates of Occupational Exposure:
NOHS Rank: 882
Estimated no. of persons exposed: 140,000*
*rough estimate
(G29)
In its criteria document, NIOSH estimated
that 50,000 workers are occupationally ex-
posed to epichlorohydrin in the United
States (1).
1.7 Manufacturers
Dow Chemical USA
Shell Chemical Co. (G25)
V-5
-------
1,1,l-TRICHLORO-2,3-EPOXYPROPANE (TCPO)
1.1 Identification CAS No..: 003083236
NIOSH No.:
1.2 Synonyms and Trade Names
1,2 epoxy-3,3,3 trichloropropane;
3,3,3-trichloropropylene oxide; TCPO
(G22,G30)
1.3 Chemical Formula and Molecular Weight
Cl
l
Cl - C - CH - CH_ C-H-Cl-,0 Mol. wt. 161.42
I \ / 2 333
Cl ^0 (G22)
1.4 Chemical and Physical Properties
1.4.1 Description: No information was found in the
sources searched.
1.4.2 Boiling Point: 149°C at 764 mm
(G22)
1.4.3 Melting Point; No information was found in the
sources searched.
1.4.4 Absorption Spectrometry;
No information was found in the sources searched,
1.4.5 Vapor Pressure:
No information was found in the sources searched.
1.4.6 Solubility: Very soluble in ether
(G22)
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched.
1.5 Production and Use
1.5.1 Production; Only known production is as a
laboratory chemical.
1.5.2 Use: Research chemical—an inhibitor of the
enzyme epoxide hydrase
(G30)
V-6
-------
1.6 Exposure Estimates
No information was found in the sources searched.
1.7 Manfacturers
Aldrich Chemical Co., Inc. (G30)
V-7
-------
l-BROMO-2,3-EPOXYPROPANE (EPIBROMOHYDRIN)
1.1 Identification CAS No.: 003132647
NIOSH No.:
1.2 Synonyms and Trade Names
Epibromohydrin
(G22)
1.3 Chemical Formula and Molecular Weight
H0C - CH - CH0 C,HKBrO Mol. wt. 136.98
2 \ \ / 2 3 5
Br ° (G22)
1.4 Chemical and Physical Properties
1.4.1 Description:
No information was found in the sources searched.
1.4.2 Boiling Point; 138-140°C (G22)
1.4.3 Melting Point; -40°C (G30)
1.4.4 Absorption Spectrometry;
No information was found in the sources searched.
1.4.5 Vapor Pressure;
No information was found in the sources searched.
1-4.6 Solubility; Insoluble in water; soluble in hot
alcohol, ether, benzene, and chloro-
form
(G22)
1.4.7 Octanol/Water Partition Coefficient:
No information was found in the sources searched.
1.5 Production and Use
1.5.1 Production; Estimated production is between
1,000'and 1,000,000 Ib (1976).
(G41)
1.5.2 Use:
No information was found in the sources searched.
V-8
-------
1.6 Exposure Estimates
No information was found in the sources searched.
1.7 Manufacturers and Suppliers
Aldrich Chemical Co., Inc.
Freeman Industries, Inc.
Great Lakes Chemical Corp.
(G30, G37)
V-9
-------
1,4-DICHLORO-2,3-EPOXYBUTANE
1.1 Identification CAS No.: 003583479
NIOSH No.: EJ80500
1.2 Synonyms and Trade Names
No information was found in the sources searched.
1.3 Chemical Formula and Molecular Weight
H-C - CH - CH - CH,. C,H,C100 Mol. wt. 141.00
2\ \/ | 2 462
Cl 0 Cl
(G16)
1.4 Chemical and Physical Properties
No information was found in the sources searched.
1.5 Production and Use
No information was found in the sources searched.
1.6 Exposure Estimates
No information was found in the sources searched.
1.7 Manufacturers
No information was found in the sources searched.
V-10
-------
1,1,l-TRICHLORO-3,4-EPOXYBUTANE (TCBO)
1.1 Identification CAS No.: 003088258
NIOSH No.:
1.2 Synonyms and Trade Names
Trichlorobutylene oxide; butane, l,l,l-trichloro-3,4-
epoxy-; oxirane, (2,2,2-trichloroethyl)-; 4 , 4,4-trichloro-
1,2-epoxybutane; 4,4,4-trichloro-l,2-butylene oxide; TCBO
(2)
1.3 Chemical Formula and Molecular Weight
Cl
I
Cl— C — CH_ — CH — CH_ C.H_C1_0 Mol. wt. 175.4 (2,3,4)
I 2 \/ 2 4 5 3
Cl 0
1.4 Chemical and Physical Properties
1.4.1 Description; Dark amber liquid (2,3)
1.4.2 Boiling Point; 174°C (3)
1.4.3 Melting Point; No information was found in the
sources searched.
1.4.4 Absorption Spectrometry; No information was found
in the sources searched.
1.4.5 Vapor Pressure; No information was found in the
sources-searched.
1.4.6 Solubility: Insoluble in water; miscible with
common organic solvents such as
carbon tetrachloride, chloroform, and
benzene
(2,3)
1.4.7 Octanol/Water Partition Coefficient;
No information was found in the sources searched.
V-ll
-------
1.5 Production and Use
1.5.1 Production; No information was found in the sources
searched.
1.5.2 Use; Not known if TCBO is used commercially at this
time, but has potential uses as an intermediate
in the preparation of urethanes, epoxy resins,
and esters; in fire-retarding phenolic resins;
as a neutralizing agent; in insecticides,
fungicides, nematocides; as an olefinic
polymerization activator; in glycols, plasti-
cizers, and modifiers; in textiles; in the
vulcanization of graft polymer rubbers
(2,4)
1.6 Exposure Estimates
No information was found in the sources searched.
1.7 Manufacturers and Suppliers
Olin Chemicals (2,3,4)
V-12
-------
TETRAFLUOROETHYLENE EPOXIDE (TFEO)
1 . 1 Identification CAS No . :
NIOSH No. :
1.2 Synonyms and Trade Names
TFEO
1. 3 Chemical Formula and Molecular Weight
(G21)
F2C CF2
Mol. wt. 116.01
(G21)
1.4 Chemical and Physical Properties
No information was found in the sources searched.
1.5 Production and Use
1.5.1 Production; No information was found in the
sources searched.
1.5.2 Use; In the synthesis of TFEO dimers and polymers
(e.g., Freon E, the trademark for a series
of TFEO polymers used as coolants in electronic
devices)
(G21)
1.6 Exposure Estimates
No information was found in the sources searched.
1.7 Manufacturers
No information was found in the sources searched.
V-13
-------
HEXAFLUOROPROPYLENE EPOXIDE (HFPO)
1.1 Identification CAS No.: 000428591
NIOSH No.:
1.2 Synonyms and Trade Names
HFPO; propane, 1,2-epoxy-l,1,2,3,3,3-hexafluoro-; oxirane,
trifluoro(trifluoromethyl)-; hexafluoropropylene oxide;
hexafluoropropene oxide; perfluoropropylene oxide; propylene
oxide hexafluoride
(G21,48)
1.3 Chemical Formula and Molecular Weight
F-C—CF-CF- C,F,0 Mol. wt. 166.02
2 \ / 3 36
0
1.4 Chemical and Physical Properties
No information was found in the sources searched.
1.5 Production and Use
1.5.1 Production; No information was found in the sources
searched.
1.5.2 Use; In the synthesis of HFPO polymers (e.g.,
Krytox, the trademark for a series of HFPO
polymers used as lubricating oils and greases)
(G21)
1.6 Exposure_Estimates
No information was found in the sources searched.
1.7 Manufacturers
No information was found in the sources searched.
V-14
-------
TABLE V-l
CHARACTERISTICS OF HALOGENATED ALKYL EPOXIDES
Name
Solubility
Log P
oct
Estimated
Environmental
Release
(million Ib)
Estimated No.
of Persons
Exposed
(Occupational)
Use
M
UI
l-Chloro-2, ss in H~O; s in
3-epoxypro- bz; » in ale and
pane (Epi- eth
chloro-'
hydrin)
1,1,1-Tri- vs in eth
chloro-2,3-
epoxypro-
pane (TCPO)
l-Bromo-2, i in H20; s in
3-epoxypro- hot ale, eth, bz,
pane (Epi- and chl
bromohydrin)
1,4-Di- *
chloro-2,3-
epoxybutane
^140,000 In manufacture of
glycerol and epoxy
resins, in paints
and household aero-
sols and as flame
retardant
* Research chemical-—
an inhibitor of the
enzyme epoxide hy-
drase
-------
TABLE V-l (continued)
Name
Solubility
Log P
oct
Estimated
Environmental
Release
(million Ib)
Estimated No.
of Persons
Exposed
(Occupational)
Use
1,1,1-Tri- i in H20; °° in
chloro-3,4- CCl., chl, and
epoxybutane bz
(TCBO)
Tetrafluoro-
ethylene
epoxide
(TFEO)
Hexafluoro-
propylene
epoxide (HFPO)
*No information was found in the sources searched.
Potential uses in
resins, pesticides;
as a neutralizing
agent; in olefinic
polymerization; in
glycols, plasticizers,
textiles; in vulcani-
zation of graft poly-
mer resins
In synthesis of TFEO
dimers and polymers
(e.g. Freon E, the
trademark for a
series of TFEO poly-
mers used as coolants
in electrical devices)
In the synthesis of
HFPO polymers (e.g.
Krytox, the trademark
for a series of HFPO
polymers used as lu-
bricating oils and
greases)
Key to Abbreviations:
i -- insoluble vs —
s — soluble «> —
ss — slightly soluble
very soluble
soluble in all
proportions
ale — alcohol
bz — benzene
chl — chloroform
eth — ether
-------
HALOGENATED ALKYL EPOXIDES
PART II
BIOLOGICAL PROPERTIES
l-CHLORO-2,3-EPOXYPROPANE (EPICHLOROHYDRIN)
2.1 Bioaccumulation
No data on the bioaccumulation of epichlorohydrin were
found in the sources searched. Theoretically, the high
chemical reactivity of the halo substituent and of the epoxy
group lessens the possibility of bioaccumulation.
2.2 Impurities and Environmental Degradation or Conversion
Products
The impurities in l-chloro-2,3-epoxypropane (epichloro-
hydrin) depend on the method of manufacture. In the most common
method, allyl chloride from high-temperature chlorination of
propylene is chlorohydrogenated with chlorine water to give
glycerol chlorohydrin isomers. This mixture is dehydrochlorin-
ated with alkali, and epichlorohydrin is recovered by steam
distillation. In this process, allyl alcohol, 3-chloro-l,2-
propylene glycol, and water are potential impurities. About
47% of the epichlorohydrin produced is immediately used in
crude form to make synthetic glycerine. The remainder is
refined and used as a chemical intermediate, mostly for polymer
production (G41).
The ring of the reactive epoxide group opens when epichloro-
hydrin reacts with acid (G17). Epichlorohydrin also reacts
V-17
-------
with compounds having active hydrogens, e.g. , alcohols, water,
organic acids, phenols, thiols> and amines. The chloro group,
being allylic to the epoxide of -a hetero group (after ring
opening) , will also be' reactive.
2.3 Acute Toxicity
The acute toxicity of epichlorohydrin, as reported in the,
NIOSH Registry of Toxic Effects of Chemical Substances (G16),
is given in Table V-2.
TABLE V-2
ACUTE TOXICITY OF EPICHLOROHYDRIN
Parameter.
TCLo
(eye effects)
LCLo
ii
LD50
n
it
n
Dosage
20 ppm
250 ppm/4 hr
7,400 ppm/30 min
90 mg/kg
238 mg/kg
155 mg/kg
1,300-mg/kg
Animal
Human
Rat
Mouse
Rat
Mouse
n
Rabbit
Route
Inhalation
n
n
Oral
n
Intra-
peritoneal
Skin
Epichlorohydrin has been described as irritating, espec-
ially to the eyes, and moderately systemically toxic by the
inhalation, oral, percutaneous, and subcutaneous routes (G38).
Humans exposed to epichlorohydrin at an unspecified high
atmospheric concentration were reported to have had irritation
V-18
-------
of the eyes and throat, nausea, dyspnea, bronchitis with
bronchiolar constrictions, and enlarged livers (G38).
A summary of acute toxicity data from the NIOSH criteria
document on epichlorohydrin appears in Table V-3 (1).
2.4 Other Toxic Effects
Secondary sources reported that death in animals exposed
to epichlorohydrin (details unspecified) is generally due to
depression of the central nervous system, particularly the res-
piratory center, and irritation of the respiratory tract (G38).
Impairment of kidney function in animals has been attributed
to epichlorohydrin exposure, and the cumulative effects of
repeated exposure are considered to be caused by nephrotoxic
actions (G38,G9).
Epichlorohydrin has been reported to penetrate human skin
and induce systemic effects. Severe necrotic lesions were ob-
served after a latency period of several minutes to several
hours (13, as reported in 1).
Hahn (14)reported that oral administration of epichlorohy-
drin at 15 mg/kg to male rats for 12 days produced reversible
infertility as determined by the decreased number of uterine
implants in females after mating.
Cooper et al. (15, as reported in 1) reported permanent
infertility in male rats fed epichlorohydrin. Five rats fed
100 mg/kg over 5 consecutive days (20 mg/kg/day) were infertile
for the next 2 weeks, but regained their fertility in the
3rd week. Five rats fed a single dose each of epichlorohydrin
at 100 mg/kg developed similar temporary infertility. During
V-19
-------
TABLE V-3
EFFECTS OF ACUTE EXPOSURE TO EPICHLOROHYDRIN IN ANIMALS
Route Animal No. Exposure
Inhalation Mouse 30 16,600 ppm
30 min
20 8,300 ppm
30 min
30 2,370 ppm
1 hr
i " Rat 6 250 ppm
o 4 hr
60 91.0 pom
4 hr
60 5.2 pom
4 hr
60 1.8 ppm
4 hr
Subcutaneous " 120 500 mg/kg
250 mg/kg
125 mg/kg
Observations References
Cited
Nose and eye irritation; 100%
mortality
100% mortality
No deaths
Death of 2-4 rats
Kidney damage, liver function
disrupted
"
Kidney damage and disrupted liver
function less severe than at 91.0
and 5 . 2 ppm
Reduced blood histamine.
activity
5
5
5
6
7
7
7
7
14
23
180 mg/kg
150 mg/kg
Necrotic lesions in nephrons; non-
specific lung, brain, and adrenal
gland damage
-------
TABLE V-3 (continued)
Route Animal No.
Subcutaneous Rat
n » 67
" Mouse 10
10
< Oral " 15
i
N)
(-• » " 15
15
15
n n _
" Rat
Dermal Rabbit
Rat 20
ii " 10
10
Exposure Observations References
Cited
150 mg/kg LD50
125 mg/kg Oliguria, anuria, polyuria, kidney
damage
0.23 ml/kg/day 100% mortality
4 days
0.08 ml/kg/day
21 days
0 . 5 ml/kg
0.23 ml/kg/day
4 days
0.08 ml/kg/day
21 days
0.23 ml/kg No -deaths
0.20 ml/kg LD50
0.22 ml/kg
0.64 ml/kg "
2 ml/kg Local irritation, 30% mortality
1 hr
1 ml/kg Local irritation, 40% mortality
1 hr,3 time?
1 ml/kg Local irritation, 20% mortality
1 hr
10
11
5
5
5
5
5
5
12
12
12
5
5
5
-------
TABLE V-3 (continued)
-------
the 12th week four of the five rats developed spermatoceles,
which were thought to render the rats permanently sterile.
The effects of repeated exposure to epichlorohydrin in
animals are summarized in Table V-4 (1).
Occupational exposure to epichlorohydrin occurs chiefly
by inhalation and skin contact and, to a limited extent, by
ingestion (1). The effects of exposure to epichlorohydrin in
humans which were summarized in the NIOSH criteria document (1)
are tabulated in Table V-5. Eye and nose irritation, lung
edema, kidney lesions, and changes in the voltage of the peaks
of the alpha rhythm in EEC measurements have been observed in
exposed humans.
The ACGIH has adopted a Threshold Limit Value (TLV) of 5
ppm (19 mg/m3) for epichlorohydrin (Gil).
2.5 Carcinogenicity
Van Duuren et al. (24) reported that epichlorohydrin given
by subcutaneous injection was carcinogenic in mice. Fifty mice
received weekly injections of 1 mg of epichlorohydrin in 0.1
ml tricaprylin for 26 weeks. The first sarcoma was noted after
126 days and the second one after 300 days (24). In a similar
study, of 50 mice given weekly subcutaneous injections of 1 mg
epichlorohydrin in 0.05 ml tricaprylin for 580 days, 6 were re-
ported to have developed local sarcomas and 1 a local adeno-
carcinoma (25). Only 1 of 50 tricaprylin-treated controls was
reported to have developed a local sarcoma.
Weil et al.(26) painted one vbrushful" of undiluted epi-
chlorohydrin on the clipped dorsal skin of 40 mice, thrice
V-23
-------
TABLE V-4
EFFECTS OF REPEATED EXPOSURE TO EPICHLOROHYDRIN IN ANIMALS
Route
Animal
No.
Exposure
Observations
Reference
Cited
Inhalation Mouse
ro
Rat
10 2,370 ppm
1 hr/day, up
to 16 days
(until all died)
120 ppm
6 hr/day
5 days/wk
11 exposures
(epichlorohydrin
in propanol
solution)
56 ppm, 6 hr/day
5 days/wk
18 exposures
27 ppm, 6 hr/day
5 days/wk
18 exposures
17 ppm, 6 hr/day
5 days/wk
19 exposures
Nose and eye irritation, followed by
gradual cyanosis, muscular relaxation
of the extremities, stiffening of the
tail, and fine body tremor; respiration
decreased before death and ceased
completely before cardiac arrest; termi-
nal clonic convulsions in some animals
Labored breathing, profuse nasal dis-
charge, weight loss, leukocytosis,
increased urinary protein excretion
(suggesting damage to kidney), and peri-
pheral atrophy of cortical.tubules (in
4 rats); lung congestion, edema, con-
solidation, and inflamed areas with signs
of abscess formation; no effects from the
propanol vehicle alone reported
Respiratory distress, nasal discharge,
weight loss
Mild nasal irritation; hemorrhagic and
consolidated areas in the lungs of one
rat
No effects
16
.16
16
16
-------
TABLE V-4 (continued)
Route
Animal
No.
Exposure
Observations
Reference
Cited
Inhalation Rat
ro
en
Oral
8 9 ppm, 6 hr/day
5 days/wk
18 exposures
15 5.2 ppm
24 hr/day
98 days
15 0.5 ppm
24 hr/day
98 days
15 0.05 ppm
24 hr/day
98 days
10 5.2*-15.6 ppm
3 hr/day for
6.5 mo
- 15 mg/kg/day
for 12 days
Pulmonary infection in two rats
More leukocytes with altered fluores-
cence, increased urine coproporphyrin,
kidney and lung damage, decrease in
blood nucleic acid
Increased modified leukocytes, reduced
blood nucleic acid
No effects
No deaths or signs of intoxication; low
body weight gain
Infertility in male rats within 7
days, reversed when exposure
discontinued for approximately 1 wk;
testes, epididymides, prostate, and
seminal vesicles examined histopatho-
logically on the 12th day no different
from those of untreated controls
16
17
17
17
18
14
Adapted from NIOSH Criteria for a Recommended Standard—Occupational Exposure to
Epichlorohydrin (1)
-------
TABLE V-5
EFFECTS OF EPICHLOROHYDRIN ON HUMANS (1)
Subject and
Exposure
Observations
Comments
Reference
Cited
39-year-old
worker
exposed to
"a gust"
i
NJ
-------
TABLE V-5 (continued)
Subject and
Exposure
Observations
Comments
Reference
Cited
NJ
Four volunteers
in an experiment
on ocular light
sensitivity
exposed at 0.2-
0.75 mg/m3 (about
0.05-0.19 ppm)
Accidental 1-hr
occupational
exposure to epi-
chlorohydrin at
20 and 40 ppm
Study of 48 em-
ployees exposed
at least once to
epichlorohydrin
for periods of
7 days to 13 yr
Retrospective
epidemiological
study based on
medical examina-
tion data for 507
Dow Chemical Co.
employees exposed
to epichlorohydrin
at unknown concen-
trations for at
least 6 mo
No significant ocular changes
17
Transient burning of eyes and
nasal passages in lower concen-
tration; at higher level, eye and
throat irritation lasting 48 hr
Decreased percentage of poly-
morphonuclear leukocytes and
increased percentage of mono-
cytes in total leukocyte count
in the blood
Blood chemistry and liver and
kidney functions in exposed in-
dividuals similar to company
laboratory normal values
Concentration of 100 ppm sug-
gested as intolerable for even
a short period; method of measur-
ing epichlorohydrin concentra-
tions not reported.
NIOSH considered the observed
persistent changes not attribut-
able solely to epichlorohydrin
exposure and suggested that a
detailed study of medical his-
tories of individuals and their
possible exposure to other chem-
icals was necessary for evaluation.
According to NIOSH, the study was
inadequate because it lacked
a control group, its estimates
of exposure were "crude," and
it did not consider individuals
who dropped out because of
illness, retirement, or death.
21
22
23
-------
K>
CO
TABLE V-5 (continued)
Subject and Reference
Exposure Observations Comments Cited
Inhalation of Statistically significant Because the exposure period 17
epichlorohydrin changes in electroencephalo- was unspecified, the total
at 0.05 and graphic (EEG) recordings at dose is impossible to esti-
0.08 ppm by 0.08 ppm (the olfactory thresh- mate.
five volunteers hold); no effects observed at
0.05 ppm
-------
weekly, for life. Thirty mice were still alive after 17
months; the last one died after 25 months. No tumors were ob-
served.
Van Duuren et al. (25) found no tumors in 50 female
mice that received 2 mg epichlorohydrin in 0.1 ml acetone on
their clipped dorsal skin, three times/week, for 580 days. The
median survival time was 506 days. However, 9 skin papillomas
were noted in 30 mice given single skin applications of 2 mg
epichlorohydrin in 0.1 ml acetone followed by thrice weekly
skin applications of phorbol myristate acetate in acetone. Of
30 control mice receiving only the phorbol myristate acetate ap-
plications, 3 were reported to have developed papillomas. No
tumors were found in acetone-treated controls (25).
Van Duuren et al. (25) also reported that weekly intraper-
itoneal injections of 1.0 mg epichlorohydrin in 0.05 ml tri-
caprylin produced papillary lung tumors in 11 out of 30 mice.
No tumors were observed in the tricaprylin controls.
Kotin and Falk (27, as reported in 1) gave 30 mice epichloro-
hydrin (5 pM) in single subcutaneous doses and observed them for
about 2 years. They reported finding a skin papilloma in one
mouse after 11.5 months, a hepatoma in another after 13 months,
and two lung adenomas in a third after 24 months. Except for
the skin papilloma, the tumors were said to have been similar
in type and frequency to those in the control group.
2.6 Mutagenicity
According to an EPA study, epichlorohydrin induced chromo-
some aberrations in bone marrow cells of female mice treated in
V-29
-------
vivo (28, as reported in G41). A dose response was said to have
been observed 24 hours after single intraperitoneal administra-
tions of 1-20 mg/kg and after oral administration of 5 or
20 mg/kg in single doses. Neither the number of animals nor
the statistical analysis was included in the EPA report.
The EPA study also referred to a report by Kucerova (29,
.as reported in G41) that the leukocytes of workers exposed to
epichlorohydrin for 1 year showed chromosome aberrations, but it
considered the data presented by this study to be insufficient
for evaluation. The blood samples were pooled, and the number of
blood cells per worker and the number of workers analyzed were
not reported.
Sram et al. (28, as reported in G41) were reported to have
shown epichlorohydrin to be mutagenic in host-mediated assay
tests with the Salmonella typhimurium strains G-46, TA 100, and
TA 1950 in female mice given injections of epichlorohydrin at
50 and 100 mg/kg. They found a dose-response relationship in
the induction of reversions to histidine prototrophy in the G-46
and TA 100 strains after the host mice were given single intra-
muscular injections and in the TA 1950 strain after single
subcutaneous injections.
Elmore et al. (30; as reported in G41) incorporated epi-
chlorohydrin in agar containing S. typhimurium TA 100 and re-
ported that it produced dose-related reversions to histidine
prototrophy over a range of 25.6-500 pM.
Epichlorohydrin was reported to have induced reversions
to tryptophan prototrophy when 0.6 ml of a 1:1 ethanol solution
of epichlorohydrin was added to a buffered suspension of 7 x
g
10 E. coli B/r (try-) (31, as reported in G41).
V-30
-------
In a study by Koelmark and Giles (32, as reported in
G41) epichlorohydrin was reported to have induced reversions
to adenine prototrophy in Neurospora crassa W.40 "distinctus"
A. The reported mutation frequency was 135.2 revertants per
million survivors 1 hour after treatment of 73.6 million conidia
with epichlorohydrin at 0.15 M in water.
An EPA report (G41) stated that epichlorohydrin induced
chromosome aberrations in root tip meristems of Vicia faba and
mutations at the eceriferum loci in barley but gave no experimen-
tal details.
Epstein et al. (33, as reported in G9) reported no domin-
ant lethal mutations in mice given epichlorohydrin intraperito-
neally at 150 mg/kg.
2.7 Teratogenicity
No information was found in the sources searched.
2.8 Metabolic Information
Jones et al. (34) stated that in rats epichlorohydrin
yielded the same urinary metabolites as alpha-chlorohydrin
(3-chloropropane-l,2-diol). The investigators found that when
alpha-chlorohydrin was administered intraperitoneally or orally
at 50 mg/kg, 2,3-dihydroxypropyl-S-cysteine and the correspond-
ing N-acetate were excreted in the urine along with the unchanged
compound. They concluded that epichlorohydrin was converted to
alpha-chlorohydrin by hydrolysis of the epoxide ring.
V-31
-------
2.9 Environmental Release and Ecological Effects
Most of the epichlorohydrin produced in 1974 was used as
an intermediate in the production of glycerine, polymers, and
a variety of other chemicals. Although only a small percentage
of the amount of the chemical produced is expected to be lost
during production or processing, the total released to the atmos-
phere might be of concern due to its high vapor pressure (12.5 mm
at 20°C (G22)) and the large amount produced annually.
Air concentrations monitored in 1974 and 1975 in a Dow
Chemical Company plant were in the range of 0.01-0.66 ppm in a
unit producing epoxy resin and glycerine (35, as reported in 1).
Environmental monitoring within Russian plants producing
epichlorohydrin and dichlorohydrin-glycerine showed epichlorohy-
drin at about 20 mg/m (5.2 ppm) where employees withdrew quality
control samples and at about 3.5 ppm during filling of tanks
with epichlorohydrin (36, as reported in 1). In another Russian
plant that discharged epichlorohydrin to the atmosphere, the
maximum permissible concentration of 0.2 mg/m was exceeded by
2.5-6 times, and 400 meters from the plant the permissible
limit was exceeded in 5 of 29 samples analyzed. No epichloro-
hydrin was detected 500-600 meters from the plant (17, as re-
ported in 1) .
Epichlorohydrin has an Aquatic Toxicity Rating (96-hour
TLm, species unspecified) of 100-10 ppm (G16).
No reports of ecological damage caused by the chemical were
found.
V-32
-------
2.10 Current Testing
G.J. Van Esch is conducting carcinogenicity studies with
rats given epichlorohydrin orally at Rijks Instituut voor de
Volksgezondheid, Netherlands (G13). According to Tox-Tips,
K. Olson will be studying the effects of epichlorohydrin on
fetal rats and rabbits at Dow Chemical Company, Midland, Michi-
gan (37). Separate groups of Sprague-Dawley rats and New
Zealand white rabbits will be exposed to epichlorohydrin at 0,
5, and 15 ppm in closed inhalation chambers for 6 hours/day on
days 16-18 of the gestation period. All animals will be killed
immediately before term, and fetuses will be examined morpholog-
ically and histopathologically.
Epichlorohydrin (NCI #C07001) has been tentatively selected
by NCI for carcinogenicity studies in hamsters, mice, and rats
exposed by inhalation (G12).
According to an abstract reported in the CANCERPROJ data-
base, the Preventive Medicine and Community Health Department
of the University of Texas School of Medicine at Galveston will
conduct epidemiologic studies of employees of the Texas Division
of Dow Chemical Company involved in the manufacture of epichloro-
hydrin (38) .
V-33
-------
l,l,l-TRICHLORO-2,3-EPOXYPROPANE (TCPO)
2.1 Bioaccumulation
No information was found in the sources searched.
2.2 Impurities and Environmental Degradation or Conversion
Products
No information was found in the sources searched.
2.3 Acute Toxicity
No information was found in the sources searched.
2.4 Other Toxic Effects
TCPO has been characterized as an enzyme inhibitor. Exten-
sive studies have been performed to evaluate its effect on the
pathobiological processes of various toxic substances.
Oesch (39) has reviewed the literature on mammalian epoxide
hydrases, inducible enzymes that catalyze the inactivation of
some carcinogenic and cytotoxic metabolites. TCPO was reported to
be the most potent inhibitor of epoxide hydrase. With H-styrene
oxide as a substrate, TCPO inhibited epoxide hydrase prepared
from guinea pig liver. TCPO at one-fifth the substrate concen-
tration completely inhibited the hydration. Seidegard et al.
(40) reported a similar uncompetitive inhibition of epoxide
hydrase prepared from the rat lung.
Van Duuren and Banerjee (41) demonstrated that the bind-
ing of trichloroethylene (TCE) metabolites to rat hepatic
microsomal protein was increased by 13-91% in the presence of TCPO.
The authors suggested that the covalent binding was via an epox-
V-34
-------
ide or other related electrophilic species.
Kappus et al. (42) demonstrated that TCPO did not affect
the uptake of vinyl chloride by rat liver microsomes but, in its
presence, the irreversible binding of vinyl chloride metabol-
ites to microsomal protein was increased twofold.
Alexandrov and Thompson (43) reported that TCPO (5 x 10~ M)
inhibited aryl hydrocarbon hydroxylase activity in vitro but
increased the binding of benzo(a)pyrene (BP) to liver nuclei
preparations from male rats pretreated with either phenobarbitol
or methylcholanthrene (MCA) and from untreated male rats. TCPO
in the incubation mixture was also reported to selectively in-
hibit metabolism by preventing the formation of diols, phenols,
and to a lesser degree quinones.
In experiments reported by Berry et al. (44), TCPO slightly
enhanced the enzymatic covalent binding of MCA and BP to. DNA
in epidermal homogenates in vitro but did not have a similar
effect on 9,10-dimethyl-l,2-anthracene (DMBA) or dibenz(a,h)-
anthracene (DBA). TCPO also was reported to have increased the
tumorigenic effects of BP and MCA in mice, perhaps by inhibit-
ing hydration, and to have decreased the tumor latency period
for BP and MCA exposure.
Biirki et al. (45) studied the effect of TCPO on the carcino-
genic potential of MCA. In two separate experiments, TCPO (1.5
ymoles), MCA (1.5-3 ymoles), and MCA plus TCPO were applied tqpi-
cally to the backs of 10-week-old mice, twice a week, for 3 weeks
or for 17 weeks. With either exposure period, 87% of the mice
that received only MCA developed tumors, whereas 100% of those
exposed to the combined substances developed tumors. Both the
V-35
-------
total number of tumors and the rate at which they appeared were
significantly higher in mice exposed to MCA plus TCPO than in
those exposed to MCA only. Only 1 tumor was detected in 56 mice
exposed to TCPO. The authors suggested that TCPO increased the
carcinogenic effect of MCA by inhibiting hydration, which increased
the cellular concentration of MCA or its metabolites.
2.5 Carcinogenicity
Topical application of TCPO at doses of 1.5 ymoles for 3
or 17 weeks did not induce tumors in mice, according to a study
by Bxirki et al. (45). However, it did enhance the tumorigenic
effects of MCA. See 1,l,l-Trichloro-2,3-Epoxypropane (TCPO),
Section 2.4.
2.6 Mutagenicity
No information on the mutagenicity of this compound was
found in the sources searched.
2.7 Teratogenicity
Injecting pregnant mice subcutaneously with TCPO on day 11
of gestation was reported to have induced no orofacial anomalies
(46). However, the injected mice had 6.7% resorption of implan-
tations, whereas untreated mice had 1.9%.
2.8 Metabolic Information
No information was found in the sources searched.
2.9 Environmental Release and Ecological Effects
No information was found in the sources searched.
V-36
-------
2.10 Current Testing
The effect of TCPO on the activation of aflatoxin Bl to
metabolites that are mutagenic in Neurospora is being studied
at the National Institute of Environmental Health Sciences,
Research Triangle Park, N.C. T. Ong and J. Guthrie are the
principal investigators (38).
At the University of Tennessee, D. Berry and T. Slaga are
using TCPO to study the role of the aryl hydrocarbon hydroxy-
lase in mouse skin tumorigenesis by benz(a)pyrene and 7,12-
dimethylbenz(a)anthracene (DMBA) (38).
V-37
-------
1-B ROMO-2,3-EPOXYPROPANE (EPIBROMOHYDRIN)
2.1 Bioaccumulation
No information was found in the sources searched.
2.2 Impurities and Environmental Degradation or Conversion
Products
No information was found in the sources searched.
2.3 Acute Toxicity
No information was found in the sources searched.
2.4 Other Toxic Effects
No information was found in the sources searched.
2.5 Carcinogenicity
No tumors were observed when 100 mg of a 10% solution of
epibromohydrin in acetone was painted on the dorsal skin of 30
mice, 3 times a week, for up to 544 days (47).
2.6 Mutagenicity
Epibromohydrin was shown to induce reverse mutations in
the purple adenineless mutant (38701) of Neurospora crassa
W. 40 "distinctus" (32). Epibromohydrin at a 0.08 molar concentration
induced 2.8 reverse mutations per million viable cells and 7.2
per million surviving cells. The overall survival rate was
39.3%.
V-38
-------
Epibromohydrin has also been tested for mutagenicity with
a Klebsiella pneumoniae auxotroph, but the results cannot be determined
from the report of the test (8).
2.7 Teratogenicity
No information was found in the sources searched.
2.8 Metabolic Information
No information was found in the sources searched.
2.9 Environmental Release and Ecological Effects
No information was found in the sources searched.
2.10 Current Testing
No information was found in the sources searched.
V-39
-------
1,4-DICHLORO-2,3-EPOXYBUTANE
No information about the biological properties of 1,4-
dichloro-2,3-epoxybutane was found in the sources searched.
V-40
-------
l,l,l-TRICHLORO-3,4-EPOXYBUTANE (TCBO)
2.1 Bioaccumulation
No information was found in the sources searched.
2.2 Impurities and Environmental Degradation or Conversion
Products
The constituents of technical grade 1,1,l-trichloro-3,4-
epoxybutane (TCBO), as listed by the manufacturer Olin Chemicals
(4), are given in Table V-6.
TABLE V-6
CONSTITUENTS OF TECHNICAL GRADE TCBO
Constituent
Percentage
TCBO
Impurities in production material
Tetrachlorobutyl alcohol, maximum
Dichlorobutylene-3,4-epoxide, maximum
Carbon tetrachloride, maximum
Higher molecular weight derivatives of
the compound (mainly tetrachlorobutyl
alcohol)
Chlorine content
Water
70 ± 3 (GLC)
4
5
5
16
60.5
0.8
The compound's boiling point is 174°C, but it decomposes
at 155°C, with HC1 being liberated (3).
V-41
-------
2.3 Acute Toxicity
The oral LD50 for TCBO in rats is 1.5 g/kg (2). Its der-
mal LD50 in rabbits ranges between 0.2 and 2.0 g/kg. The com-
pound is a severe skin irritant and an eye irritant in rabbits.
It was reported to be nontoxic to rats exposed at 200 mg/liter
for 1 hour (2,3).
2.4 Other Toxic Effects
No information was found in the sources searched.
2.5 Carcinogenicity
No information was found in the sources searched.
2.6 Mutagenicity
Although no experimental details were provided, TCBO was
reported to have given positive results in the Ames microbial
mutagenic test (2,3).
2.7 Teratogenicity
No information was found in the sources searched.
2.8 Metabolic Information
No information was found in the sources searched.
2.9 Environmental Release and Ecological Effects
No information was found in the sources searched.
V-42
-------
2.10 Current Testing
No information was found in the sources searched.
V-43
-------
TETRAFLUOROETHYLENE EPOXIDE (TFEO)
No information about the biological properties of tetra-
fluoroethylene epoxide was found in the sources searched.
V-44
-------
HEXAFLUOROPROPYLENE EPOXIDE (HFPO)
No information about the biological properties of hexa-
fluoropropylene epoxide was found in the sources searched.
V-45
-------
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(NIOSH). Criteria for a Recommended Standard—Occupational
Exposure to Epichlorohydrin (1976)
2. Muir, W.R., Office of Toxic Substances, U.S. Environmental
Protection Agency. Memorandum for TSCA/ITC Members, Alter-
nates and Observers (January 19, 1978). Includes U.S. EPA,
Office of Toxic Substances, Hazard Assessment Group Pre-
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3, 1978)
3. Olin Chemicals. Product data: Trichlorobutylene oxide,
technical grade (1977). Enclosed in EPA Preliminary chem-
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4. Olin Chemicals. Application data: Uses and chemistry of
trichlorobutylene oxide (1977). Enclosed in EPA Prelimin-
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5. Freuder, E., and Leake, C.D. The toxicity of epichlorohy-
drin vapour. Univ. Calif. Berkeley Publ. Pharmacol. 2:
69-77 (1941)
6. Carpenter, C.P., Smyth, H.F., Jr., and Pozzani, U.C. The
assay of acute vapor toxicity, and the grading and inter-
pretation of results on 96 chemical compounds. J. Ind. Hyg.
Toxicol. 31:343-346 (1949)
7. Shumskaya, N.I., Karamzina, N.M., and Savina, M.Y.
[Evaluation of the sensitivity of integral and specific
indexes during acute epichlorohydrin poisoning.] Toksikol.
Nov. Prom. Khim. Veshchestv. 12:33-44 (1971)
8. Voogd, C.E., Mutagenic action of epoxy compounds and
several alcohols. Mutat. Res. 21:52-53 (1973)
9. Rotaru, G., and Pallade, S. [Experimental studies of
histopathological features in acute epichlorohydrin (1-
chloro-2,3-epoxypropane) toxicity=] Morfol. Norm. Patol.
11:155-163 (1966)
10. Pallade, S., Dorobantu, M., Rotaru, G., and Gabrielescu,
E. [Experimental study of epichlorohydrin poisoning.] Arch.
Mai. Prof. Med. Trav. Secur. Soc. 28:505-516 (1967)
11. Pallade, S., Dorobantu, M., and Gabrielescu, E. [Acute
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Mai. Prof. Med. Trav. Secur. Soc. 29:679-688 (1968)
V-46
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12. Lawrence, W.H., Malik, M., Turner, J.E., and Autian, J.
Toxicity profile of epichlorohydrin. J. Pharm. Sci. 61:
1712-1717 (1972)
13. Ippen, H., and Mathies, V. [Protracted chemical burns
with special regard to skin damage caused by epoxide
and propane sultone.] Berufsdermatosen 18:144-165 (1970)
14. Hahn, J.D. Post-testicular antifertility effect of
epichlorohydrin and 2,3-epoxypropanol. Nature 226:87
(1970)
15. Cooper, E.R.A., Jones, A.R., and Jackson, H. Effects of
alpha-chlorohydrin and related compounds on the reproduc-
tive organs and fertility of the male rat. J. Reprod.
Fertil. 38:379-386 (1974)
16. Gage, J.C. The toxicity of epichlorohydrin vapour. Br.
J. Ind. Med. 16:11-14 (1959)
17. Fomin, A.P. Biological effects of epichlorohydrin and its
hygienic significance as an atmospheric pollutant. Gig.
Sanit. 31:7-11 (1966)
18. Kremneva, S.N., and Tolgskaya, M.S. [The toxicology of
epichlorohydrin.] Toksikol. Nov. Prom. Khim. Veshchestv.
2:28-41 (1961)
19. Schultz, C. [Fatty liver and chronic asthma-like bron-
chitis after inhalation of a paint solvent (epichlorohydrin).]
Dtsch. Med. Wochenschr. 89:1342-1344 (1964)
20. Thoburn. Written communication to National Institute for
Occupational Safety and Health (May 1976)
21. Union Carbide Corp. Industrial Medicine and Toxicology
Department. Toxicology Studies—Epichlorohydrin. New
York. Pp 1-5 (1971)
22. Kilian. Written communication to National Institute for
Occupational Safety and Health (June 1976)
23. Kilian. Written communication to National Institute for
Occupational Safety and Health (April 1976)
24. Van Duuren, B.L., Katz, C., Goldschmidt, B.M., Frenkel, K. ,
and Sivak, A. Carcinogenicity of halo-ethers: II. Struc-
ture activity relationships of analogs of bis(chloromethyl)
ether. J. Nat. Cancer Inst. 48:1431-1439 (1972)
25. Van Duuren, B.L., Goldschmidt, B.M., Katz, C., Seidmann,
I.,, and Paul, J.S. Carcinogenic activity of alkylating
agents. J. Nat. Cancer Inst. 53:695-700 (1974)
26. Weil, C.S., Condra, N., Haun, C., and Striegel, J.A.
Experimental carcinogenicity and acute toxicity of repre-
sentative epoxides. Amer. Ind. Hyg...Assoc. J. 24:305-325
(1963)
V-47
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27. Kotin, P-, and Falk, H.L. Organic peroxides, hydrogen
peroxide, epoxides and neoplasia. Rad. Res. Suppl. 3:
193-211 (1963)
28. Sram, R.J., Cerna, M., and Kucerova, M. Genetic risk
of epichlorohydrin as related to occupational exposure.
Biol. Zentralbl. 95:451-462 (1976)
29. Kucerova, M. Cytogenic analysis of human chromosomes
and its value for the estimation of genetic risk. Mutat.
Res. 41:123-130 (1976)
30. Elmore, J.D., Wong, J.L., Leumeach, A.D., and Streips, U.N.
Vinyl chloride mutagenicity via the metabolites chloro-
oxirane and chloroacetaldehyde monomer hydrate. Biochem.
Biophys. Acta 442:405-419 (1976)
31. Strauss, B., and Okubu, S. Protein synthesis and the in-
duction of mutations in Escherichia coli by alkylating
agents. J. Bacteriol. 79:464-473 (1960)
32. Koelmark, G., and Giles, N.H. Comparative studies of
monoepoxides as inducers of reverse mutations in Neurospora
genetics. Genetics 40:890-902 (1955)
33. Epstein, S.S., Arnold, E., Andrea, J., Bass, W., and Bishop,
Y. Detection of chemical mutagens by the dominant lethal
assay in the mouse. Toxicol. Appl. Pharmacol. 23:288-325
(1972)
34. Jones, A.R., Davies, P., Edwards, K., and Jackson, H.
Antifertility effects and metabolism of alpha- and epi-
chlorohydrins in the rat. Nature 224:83 (1969)
35. Dow Chemical, Texas Division (Freeport, Texas). Informa-
tion concerning the development of the criteria document
and recommended health standard for epichlorohydrin. Un-
published report submitted to NIOSH (August 28, 1975)
36. Pet'ko, L.I., Gronsberg, E.S.H., and Chernova, L.N. [New
sanitary-hygiene data on the epichlorohydrin industry=]
Gig. Tr. Prof. Zabol. 10:52-54 (1966)
37. Tox-Tips, Toxicology Information Program, National Library
of Medicine, Bethesda, Md. (.December 1977)
38. CANCERPROJ. National Library of Medicine, Bethesda, Md.
Data Base (1978)
39. Oesch, F. Mammalian epoxide hydrases: Inducible enzymes
catalysing the inactivation of carcinogenic and cytotoxic
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Xenobiotica 3:305-340 (1972)
V-48
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40. Seidegard, J., Depierre, J.W., Moron, M.S., Johannesen,
K.A.M., and Ernster, L. Characterization of rat lung
epoxide(styrene oxide)hydrase with a modified radioactive
assay of improved sensitivity. Cancer Res. 37:1075-1082 (1977)
41. Van Duuren, B.L., and Banerjee, S. Covalent interaction
of metabolites of the carcinogen trichloroethylene in
rat hepatic microsomes. Cancer Res. 36:2419-2422 (1976)
42. Kappus, H., Bolt, H.M., Buchter, A., and Bolt, W. Liver
microsomal uptake of carbon-14-labeled vinyl chloride
and transformation to protein alkylating metabolites in
vitro. Toxicol. Appl. Pharmacol. 37:461-471 (1976)
43. Alexandrov, K., and Thompson, M.H. Influence of inducers
and inhibitors of mixed-function oxidases on benzo(a)pyrene
binding to the DNA of rat liver nuclei. Cancer Res. 37:
1443-1449 (1977)
44. Berry, D.L., Slaga, T.J., Viaje, A., Wilson, N.M., DiGiovanni,
J., Juchau, M.R., and Selkirk, J.M. Effect of trichloro-
propane oxide on the ability of polyaromatic hydrocarbons
and their "K-region" oxides to initiate skin tumors in mice
and to bind to DNA in vitro. J. Natl. Cancer Inst. 58:
1051-1055 (1977)
45. Burki, K., Wheeler, J.F., Akamatsu, Y., Scribner, J.E.,
Candelas, G., and Bresnick, E. Early differential effects
of 3-methylcholanthrene and its "K-region" epoxide on
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(1974)
46. Martz, F., Failinger, C., Ill, and Blake, D.A. Phenytoin
teratogenesis: Correlation between embryopathic effect
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231-239 (1977)
47. Van Duuren, B.L., Langseth, L., Goldschmidt, B.M., and Orris,
L. Carcinogenicity of epoxides, lactones, and peroxy com-
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Cancer Inst. 39:1217-1228 (1967)
48. CHEMLINE. National Library of Medicine, Bethesda, Md.
Data Base (1978)
V-49
-------
POLYCHLORINATED TERPHENYLS
TABLE OF CONTENTS
Page
Overview VI-1
Part I General Information VI-3
Part II Biological Properties
2.1 Bioaccumulation VI-7
2.2 Impurities and Environmental Degradation
or Conversion Products VI-7
2.3 Acute Toxicity VI-9
2.4 Other Toxic Effects VI-9
2.5 Carcinogenicity VI-11
2.6 Mutagenicity VI-11
2.7 Teratogenicity VI-11
2.8 Metabolic Information VI-11
2.9 Environmental Release and Ecological
Effects VI-11
2.10 Current Testing VI-13
References VI-14
Vl-i
-------
POLYCHLORINATED TERPHENYLS
AN OVERVIEW
Polychlorinated terphenyls (PCT's) are complex mixtures
of terphenyls with different numbers and arrangements of
chlorine atoms. When pure, they are white crystalline solids,
but in commercial grades they are light yellow. Commercial
mixtures are numbered according to the percentage of chlorine
in them. In the Aroclor series, for example, the last two
digits in the number denote the percentage of chlorine.
Commercial PCT's contain polychlorinated biphenyls (PCB's)
as impurities.
PCT's are produced by chlorination of commercial terph iyl,
which itself is usually a mixture of ortho-, meta-, and part
terphenyls. In the United States, a reported 8.1 million pc ids
were produced in 1972. However, the manufacturer discontinued
their production in that year, because concern had arisen over
the environmental effects of the chemically similar PCB's and
because all their uses were dispersive. Since then, PCT's have
been imported in small but increasing quantities--from
160,000 pounds in 1973 to 400,000 pounds in 1975.
Before 1973, PCT's were used primarily as plasticizers
and in adhesives, inks, sealants, caulking compounds, and
waxes. They are now used mainly in waxes for investment
casting, an application that leads to their release into the
environment.
No information on the occupational or general population
exposure to PCT's was found in the sources searched.
VI-1
-------
PCT's have been detected in cheeses, fish, oysters, and
human tissues in various locations around the world. No
adequate information on the ecological effects of these
chemicals was found in the sources searched. They are ex-
pected to be very stable; only the lower chlorinated homo-
logs are likely to be degraded at a significant rate by
hydrolytic or similar reactions under normal environmental
conditions.
Erosion of gastric mucosa, alopecia, facial and peri-
cardial edema, and eye discharge were observed in rhesus
monkeys fed PCT's. PCT's are also inducers of hepatic
microsomal enzymes. Information on their potential for
carcinogenicity, mutagenicity, or teratogenicity could not
be located in the sources searched.
VI-2
-------
POLYCHLORINATED TERPHENYLS
PART I
GENERAL INFORMATION
1.1 Identification
CAS No.: 061788338
NIOSH No.: TQ13800
1.2 Synonyms and Trade Names
Polychlorinated triphenyls; polychlorinated diphenyl-
benzenes; PCT's; Aroclor 54xx (Monsanto, production
discontinued); Electrophenyl T-xx(Prodelec); Kanechlor
KC-C-xx(Kanegafuchi)
1.3 Chemical Formula and Molecular Weight
(1)
n 0H1 A C1
18 14-n n
Cl (1-5)
Cl (1-4)
Cl (1-5)
ortho-PCT
Cl (1-4)
Cl (1-5)
Mol. wt. 437 (n=6)
575 (n=10)
Cl (1-5)
Cl (1-5)
Cl (1-4)
Cl (1-5)
meta-PCT
para-PCT
(G17)
1.4 Chemical and Physical Properties
1.4.1 Description;
Polychlorinated terphenyls
are produced by chlorination
of commercial terphenyl (a
mixture of ortho-, meta-, and
para-terphenyls). As commer-
cial products, they are mixtures
of chloroterphenyls, with vary-
ing numbers of chlorine atoms
(homologs) and varying molecular
arrangements (isomers). They
are differentiated by the per-
centage of chlorine in the
mixture.
VI-3
-------
1.4.2 Boiling Point; See Section 1.8, Table VI-1.
1.4.3 Melting Point; See Section 1.8, Table VI-1.
1.5 Production and Use
1.5.1 Production:
1968 (domestic)
1969 (domestic)
1970 (domestic)
.1971 (domestic)
1972 (domestic)
1973 (imports)
1974 'l(imports)
1975 (imports)
.8/9 million Ib
11.6 .million Ib
17.8 million Ib
20.2 million Ib
8.1 million Ib
ca. 160,000 Ib
330,000 Ib
400,000 Ib
Note:
1.5.2 Use:
Imports may increase as polychlorinated ter-
phenyls replace decachlorobiphenyl in invest-
ment casting.
(4)
Now primarily in waxes for investment casting
(lost-wax process). In 1975, four major wax
manufacturing companies supplied 135 invest-
ment casting foundries in the U.S.
(4)
Prior to 1974, used .primarily as plasticizers
(mostly Aroclor 5460) in adhesives, inks,
sealants, caulking compounds, and waxes
(4)
1.6 Exposure Estimates
1.6.1 Release Rate; Current use primarily environmentally
dispersive; although wax is reused,
at least 5-10% deliberately discarded
after each casting
' (4)
1.6.2 NOHS Occupational Exposure;
No information was" found in the sources searched.
1.7 Manufacturers
Monsanto ceased production of polychlor-
inated terphenyls in 1972 because of
their similarities to PCB's and because
they had no closed uses. PCT's as well
as PCB's were marketed under the trade
nameJ "Aroclor" . Most imported PCT's
come from France, where they are manu-
factured by Prodelec. The major im-
porters are Progil, Inc., and Instel,
(2,4)
VI-4
-------
1.8 Data on Specific Polychlorinated Terphenyls
See Table VI-1.
VI-5
-------
TABLE VI-1
CHARACTERISTICS OF COMMERCIAL MIXTURES (2,3,G17)
Name
Description
CAS No.
NIOSH No.
Chlorine
Content
Distillation
Range
Softening
Point
Aroclor 5442* Clear, yellow, 012642238
sticky resin
Aroclor 5460* Clear, yellow
to amber brit-
tle resin
011126424
TQ13850
TQ13900
42%
60%
215-300°C
280-335°C
46-52°C
98-105.5°C
Electrophenyl
T-60**
60%
*Production terminated by Monsanto
**Produced by Prodelec, France (1)
Note: Aroclor numbers starting with 54 refer to PCT's and those starting with 44 or 25 refer to
mixtures of PCT's and PCB's. The last two digits in the number indicate the percentage
of chlorine by weight in the mixture (1).
-------
POLYCHLORINATED TERPHENYLS
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
The similarity of PCT's to PCB's—both are chemically
unreactive and have low water solubility—indicates that PCT's
have a potential for bioaccumulation.
PCT's persisted in cod tissues for at least 70 days
after one-time oral dosage (see Section 2.2) and were detected
in eggs and fatty tissues of herring gulls (Larus artentatus)
from the Bay of Fundy. PCT's were also found, and presumably
were stored, in human tissues (see Section 2.9).
2.2 Impurities and Environmental Degradation or Conversion
Products
Commercial PCT's are mixtures that vary in composition
and degree of chlorination and possibly according to batch (G16)
Aroclor series 25 and 44 contain mixtures of PCB's and PCT's;
series 54 was reported to contain only PCT (5). In addition,
terphenyl compounds can exist in three isomeric forms (ortho,
meta, and para). Separation and identification of the three
isomers is difficult because hundreds of PCT isomers are
theoretically possible and few have been characterized. PCT's
are known to contain PCB's as impurities (4).
VI-7
-------
According to a 1976 WHO monograph (1), PCT's are
stable in the environment. Chemically, the PCT's, like the
PCB's (1), are expected to be very stable and only the least
chlorinated homologs are likely to be degraded at a significant
rate by hydrolytic or similar reactions under environmental
conditions.
Addison et al. (6) noted a reduction of the lower
chlorinated PCT's in the excretions of cod (Gadus morhua)
dosed orally one time with Aroclor 5460. This effect,
also obtained with PCB's, was ascribed to preferential
absorption of the isomers with lower chlorine contents. The
authors reported further that the efficiency of absorption
and excretion of PCT's in the cod seemed poor and that
PCT's were found in all tissues analyzed, with the highest
concentrations in the liver. Appreciable amounts of PCT's
were found in the tissues 70 days after exposure, indicating
their persistence.
Although no specific information on the degradation
products of PCT's was found in the sources searched, they
can be expected, because of their similarity to PCB's,
to be excreted as phenolic metabolites and to appear unchanged
in milk. In birds, PCT's can be expected to be excreted in
eggs (5,1).
VI-8
-------
2.3 Acute Toxicity
The acute toxicity of PCT's, as reported by Fishbein
(7), is given in Table VI-2.
TABLE VI-2
ACUTE TOXICITY OF PCT's
Compound
Aroclor 5442
H
Aroclor 5460
ii
Parameter
LD50
MLD
LD50
MLD
Dosage
10,600 mg/kg*
>1,260<2,000 mg/kg*
>19,200 mg/kg**
>7,940 mg/kg**
Animal
Rat
Rabbit
Rat
Rabbit
Route
Oral
Skin
Oral
Skin
*Administered orally as 50% solution in corn oil
**Administered orally as 33.3% solution in corn oil
2.4 Other Toxic Effects
WHO reported (1) that there had not been any systematic
studies on the toxicity of the PCT's.
Sosa-Lucero and de la Iglesia (8) studied the effects
of Aroclor 5460 on liver microsomal systems and the distrib-
ution of the compound in rats. Residues were found in the
blood, brain, testis, kidney, spleen, heart, fat, and liver
in groups of six male rats who had been fed ad libitum a
diet containing the compound at 10, 100, and 1,000 ppm in
their diet for 7 consecutive days. No residues were found
in the control group. Increases in drug-metabolizing
VI-9
-------
enzyme activities and in the content of microsomal
protein, phospholipids, and cytochrome P-450 were reported.
No adverse effects on health or body weight were noted, but
significant liver enlargement was observed at 1,000 ppm.
Bitman et al. (9) assessed estrogenic activity by
determining the stimulation of the glycogen response of
the immature rat uterus 18 hours after administration of the
test compound. Aroclor 5442 was reported to be active and
Aroclor 5460 inactive.
Allen et al. (10) administered Aroclor 5460 at 5,000
ppm in the diet of six rhesus monkeys for 3 months. Within
1 month the animals had lost considerable hair. At the
end of the experiment, five had an average weight loss of
19%. Acneform lesions of the skin, subcutaneous edema,
ascites, pleural effusion, pericardial edema, liver hyper-
trophy, and gastric mucosal hypertrophy and hyperplasia
were observed. Decreases in hepatic microsomal esterase,
aniline hydroxylase, nitroreductase, and glucose-6-
phosphatase specific activities per gram of microsomal
protein were reported. N-Demethylase activity was increased,
Hematological changes developed gradually over a period of
3 months. A decrease in hemoglobin of approximately 2 g/100
ml and a decrease in hematocrit from 40% to 33% occurred.
No major modifications in the total white cell count were
noted, but there was a gradual decrease in the number of
lymphocytes and a concomitant increase in neutrophils. The
VI-10
-------
total serum protein also decreased and the albumin/globulin
ratio of the serum protein gradually shifted.
2.5 Carcinogenicity
No reports of long-term Carcinogenicity studies with
PCT's were found in the sources searched. Allen and Norback
(11) fed Aroclor 5460 at 5,000 ppm to six rhesus monkeys for
3 months. The effects reported were hypertrophy, hyperplasia,
and dysplasia of the gastric mucosa. The authors suggested
that their findings indicated a potential for Carcinogenicity
and necessitated thorough testing.
2.6 Mutagenicity
No information was found in the sources searched.
2-7 Teratogenicity
No information was found in the sources searched.
2.8 Metabolic Information
No information was found in the sources searched.
2.9 Environmental Release and Ecological Effects
In 96-hour static bioassays with bluegills and channel
catfish exposed to Aroclors 5432, 5442, and 5460, only a few
fish were killed even by exposure at 100 ppm (12).
Zitko et al. (5) found PCT's at 1.4 and 0.1 ppm in the
subcutaneous fat and eggs of Canadian herring gulls (Larus
argentatus), respectively. Thomas and Reynold (13) found
VI-11
-------
PCT's at 0-163 ppm in paperboard samples used in food
packaging. In the Netherlands, Freudenthal and Greve (14)
found PCT's at 0.07 ppb in water from the Rhine River, at
0.12 ppm in oyster tissue, at 0.4 ppm in eel fat, and at 0.5
ppm in human fat.
There are a number of additional reports on the presence
of PCT's in human tissues. According to Doguchi and Fukano
(15), the average concentration of PCT's in the blood of
27 Tokyo residents, none of whom had any known contact with
the chemicals, was 5 ppb. This concentration was greater
than the 3.2 ppb of PCB's in the same blood samples, even
though far more PCB's (58,000 tons) than PCT's (2,000-3,000
tons) had been used in Japanese industry up to 1971.
Doguchi et al. (16) found PCT's at 0.1-2.1 ppm, with
an average of 0.6 ppm, in the fat of 20 Tokyo residents.
In most of the reports, residues were confirmed by perchlor-
ination to give peaks of the perchloroterphenyls or by
gas chromatography/mass spectrometry.
Takizawa and Minagawa (17), as reported by WHO (1),
found the following amounts of PCT's (.in ppm)
in human tissues: liver (0.02), kidney (0.01), brain (0.02),
and pancreas (0.04). Nishimoto et al. (18), according to
Doguchi and Fukano (15), have identified PCT residues in
human fat and milk and in samples of water and sludge.
Minagawa et al. (19) reported residues of PCT at 0.37 and
0.012 ppm on a fat weight basis in human omentum major and
breast milk. Whether these residues present a hazard to
humans or to the environment has not been established.
VI-12
-------
Yap et al. (20) reported that Aroclor 5460 inhibited
2+
the in vitro activity of fish ATPases. PCT inhibited Mg -
ATPase from the muscle of bluegill fish by 31.9% at 0.03 ppm
and by 42.9% at 0.33 ppm. This enzyme and NA+-K -ATPase from
the brain, liver, and kidney were also inhibited by concen-
trations of PCT in the 0.0310 ppm range.
2.10 Current Testing
No information was found in the sources searched.
VI-13
-------
REFERENCES
1. World Health Organization. Polychlorinated Biphenyls
and Terphenyls. Environmental Health Criteria 2.
Geneva (1976)
2. Wood, D. (Monsanto Chemical Co., St. Louis, Mo.).
Personal Communication (April 15, 1978)
3. Panel on Hazardous Trace Substances. Polychlorinated
biphenyls—Environmental Impact. Environ. Res. 5:249-362
(1972)
4. Versar, Inc. (Springfield, Va.). PCBs in the United
States: Industrial Use and Environmental Distribution.
Final Report to the U.S. Environmental Protection
Agency, Contract 68-01-3259 (February 25, 1976)
5. Zitko, V., Hutzinger, O., Jamieson, W.D., and Choi,
P.M.K. Polychlorinated terphenyls in the environment.
Bull. Environ. Contain. Toxicol. 7:200 (1972)
6. Addison, R.V., Fletcher, G.L., Ray, S., and Doane, J.
Analysis of a chlorinated terphenyl (Aroclor 5460)
and its deposition in tissues of the cod (Gadus morhua).
Bull. Environ. Contain. Toxicol. 8:52-60 (1972)
7. Fishbein, L. Toxicity of chlorinated biphenyls. Rev.
Pharmacol. 14:139-156 (1974)
8. Sosa-Lucero, J.C., and de la Iglesia, R.A. Distribu-
tion of a polychlorinated terphenyl (PCT) (Aroclor 5460)
in rat tissues and effect on hepatic microsomal mixed
function oxidases. Bull. Environ. Contam. Toxicol.
10:248-256 (1973)
9. Bitman, J., Cecil, H.C., and Harris, S.J. Biological
effects of polychlorinated biphenyl in rats and quail.
Environ. Health Perspect. 1:145-149 (1972)
10. Allen, J.R., Abrahamson, L.J., and Norback, D.H.
Biological effects of polychlorinated biphenyls and
terphenyls on the subhuman primate. Environ. Res.
6:344-354 (1973)
11. Allen, J.R., and.Norback, D.H. Polychlorinated
biphenyl- and terphenyl-induced gastric mucosal hyper-
plasia in primates. Science 179:498-499 (1973)
VI-14
-------
12. Industrial Bio-Test Laboratories, Inc. Report to
Monsanto Company. Four-day static fish toxicity studies
with Aroclor 1221, Aroclor 5432, Aroclor 5442, Aroclor
5460, and MCR 1016 in bluegills and channel catfish.
IBT No. A9380 (1972)
13. Thomas, G.H., and Reynolds, L.M. Polychlorinated
terphenyls in paperboard samples. Bull. Environ.
Contain. Toxicol. 10:3741 (1973)
14. Freudenthal, J., and Greve, P.A. Polychlorinated ter-
phenyls in the environment. Bull. Environ. Contain.
Toxicol. 10:108-111 (1973)
15. Doguchi, M., and Fukano, S. Residue levels of poly-
chlorinated terphenyls, polychlorinated biphenyls and
DDT in human blood. Bull. Environ. Contam. Toxicol.
13:57-63 (1975)
16. Doguchi, M., Fukano, S., and Ushio, F. Polychlorinated
terphenyls in the human fat. Bull. Environ. Contam.
Toxicol. 11:157-158 (1974)
17. Takizawa, Y., and Minagawa, K. Studies on environmental
accumulation and bioaccumulation of organochloric com-
pounds. In Studies on the Body Effect of Degradation-
Registration Substances. Pp 29-50 (1974)
18. Nishimoto, T., Ueda, M., Tane, S., Chikazawa, H., and
Nishiyama, T. PCT (polychlorotriphenyl) in human
adipose tissue and mothers' milk. Igaku No Ayumi
87:264-265 (1973) (Japanese, Abstract)
19. Minagawa, K., Takigawa, Y., Sakai, H., and Sasagawa, I.
Polychlorinated terphenyls in human fat and mothers'
milk. Nippon Eiseiyaku Zasshi 28:542-547 (1974)
(Japanese, Abstract)
20. Yap, H.H., Desaiah, D., and Cutkomp, L.K. Sensitivity
of fish ATPases to polychlorinated biphenyls. Nature
233:61 (1971)
VI-15
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PYRIDINE
TABLE OF CONTENTS
Page
Overview VII-1
Part I General Information VII-3
Part II Biological Properties VII-5
2.1 Bioaccumulation VII-5
2.2 Impurities and Environmental Degradation
or Conversion Products VII-5
2.3 Acute Toxicity VII-5
2.4 Other Toxic Effects VII-6
2.5 Carcinogenicity VII-9
2.6 Mutagenicity VII-9
2.7 Teratogenicity VII-9
2.8 Metabolic Information VII-10
2.9 Environmental Release and Ecological
Effects VII-11
2.10 Current Testing VII-12
References VII-13
Vll-i
-------
PYRIDINE
AN OVERVIEW
Pyridine is a colorless or slightly yellow liquid with a
disagreeable odor. It is miscible with water, oils, ethanol,
diethyl ether, petroleum ether, and many other organic liquids.
Pyridine is volatile with steam. The technical product
composition of pyridine is usually reported as a distillation
range.
Pyridine can be derived from coal carbonization and can be
recovered from coke-oven gases and from coal tar middle oil. It
can be synthesized from acetaldehyde and ammonia. The production
of pyridine in the United States exceeded 60 million pounds in
1976.
Pyridine has been exported to the United Kingdom (33% of
U.S. output in 1970) for the production of the herbicides
diquat and paraquat. It is also used as a solvent and reagent
in the manufacture of antihistamines, anti-infectives, piperidine,
and waterproofing agents in the textile industry, and in miscel-
laneous compounds such as flavoring agents.
No information on the release rate of pyridine was found.
According to the NOHS, 249,000 persons are estimated to have
occupational exposure to pyridine. SRI estimated the U.S. human
oral exposure to pyridine at 5.04 x 10 g/year, primarily
resulting from its presence in food.
Pyridine is often found in municipal waste water
and has been reported to be present in the working area
VII-1
-------
around coal furnaces and in agricultural crops and fish. The
compound was reported to have inhibited cell multiplication in
the bacterium Pseudomonas putida and the alga Microcystis
aeruginosa. Pyridine also showed the potential for chronic
toxicity in Daphnia magna.
Toxic effects attributed to pyridine in animals and humans
have been reported in the literature. It causes central nervous
system depression and irritation of the skin and respiratory
tract. Large doses produce gastrointestinal disturbances and
liver damage. Data from long-term tests on pyridine are
inadequate for evaluation of its chronic effects, including
carcinogenicity. No reports of relevant tests for mutagenicity
or other short-term tests were found. The only article found
on the teratogenic effects of pyridine reported that it caused
abnormalities in chicken embryos. The metabolic fate of most of
an administered dose of pyridine is unknown, but hydroxylation,
N-methylation, oxidation, and conjugation reactions have been
reported.
VII-2
-------
PYRIDINE
PART I
GENERAL INFORMATION
1.1 Identification CAS No.: 000110861
NIOSH No.: UR84000
1.2 Synonyms and Trade Names
Azabenzene; azine (G16)
1.3 Chemical Formula and Molecular Weight
C5H5N Mol. wt. 79.10
(G22)
1.4 Chemical and Physical Properties
1.4.1 Description: Flammable, slightly yellow or
colorless liquid with nauseat-
ing odor and burning taste
(G21)
1.4.2 Boiling Point; 113-115°C (1)
1.4.3 Melting Point; -42°C (G22)
1.4.4 Absorption Spectrometry:
cyclohexane = 251 256^ 2?9^ 284^ 288 nm
Amax
log e = 3.1, 3.1, 2.0, 1.8, 1.4
(G22)
1.4.5 Vapor Pressure; 10 mm at 13.2°C (G22)
1.4.6 Solubility; Soluble in ligroin and fatty
oils; soluble in all propor-
tions in water, alcohol, ether,
benzene, acetone, and chloro-
form
(G21, G22)
1.4.7 Octanol/Water Partition Coefficient;
Log PQct = 1.04 (G36)
VII-3
-------
1.5 Production and Use
1.5.1 Production; >60 million Ib (1976 capacity) (G15)
1.5.2 Use: In the synthesis of vitamins and drugs; in
waterproofing; as a rubber chemical; as a
denaturant for alcohol and antifreeze mix-
tures; as a dyeing assistant in textiles; in
fungicides; as a solvent for anhydrous mineral
salts, in organic syntheses, and in analytical
chemistry
(G21,G23)
Quantitative Distribution
(1975 U.S. Consumption); Percentage
Exports (primarily to U.K. for the 50
production of the herbicides
diaquat and paraquat)
Solvent and reagent uses 16
Manufacture of antihistamines 13
and anti-infectives
Manufacture of piperidine 7
Manufacture of textile waterproofing 7
agents
Miscellaneous uses, e.g., flavoring 7
agent
100
5.04 x 10 g/year estimated to be in food (1)
1.6 Exposure Estimates
1.6.1 Release Rate;
No information was found in the sources searched.
1.6.2 NOHS Occupational Exposure;
Rank: 602
Estimated no. of persons exposed: 249,000*
*rough estimate (G29)
1.7 Manufacturers
Koppers Co., Inc.
Nepera Chemical Co., Inc. (G24)
VII-4
-------
PYRIDINE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
No information was found on the bioaccumulation of pyridine.
2.2 Impurities and Environmental Degradation or Conversion Products
Refined technical pyridine boils within a 2° range (113-
115°C) (1) . Small amounts of a technical product that is a
mixture of alkylated pyridines are also sold (1). Pyridine is
stable under reducing conditions, but it is readily oxidized.
Because of its high vapor pressure (20 mm/25°C (G15))/ it can
be expected to volatilize to the atmosphere, where it may photo-
oxidize .
2.3 Acute Toxicity
The acute toxicity of pyridine, as reported in the NIOSH
Registry of Toxic Effects of Chemical Substances (G16), is given
in Table VII-1.
TABLE VII-1
ACUTE TOXICITY OF PYRIDINE
Parameter
LD50
-
»
»
Dosage Animal
891 mg/kg Rat
4,000 ppm/4 hr "
1,000 mg/kg »
880 mg/kg D°9
Route
Oral
Inhalation
Subcutaneous
Intravenous
VII-5
-------
TABLE VII-1 (Continued)
Parameter
Dosage
Animal
Route
LD50
LDLo
1,121 mg/kg
4,000 mg/kg
1,200 mg/kg
870 mg/kg
Rabbit
Guinea pig
Mouse
Guinea pig
Dermal
Oral
Intraperitoneal
Pyridine is pharmacologically active by its effect on the
central nervous system (G38). It produces weakness of limbs,
ataxia, unconsciousness and salivation by any route of administra-
tion (Gl). Exposure to pyridine vapors produces moderate mucous
membrane irritation (G38).
In anesthetized dogs, pyridine administered intravenously at a
dose of 880 mg/kg of body weight (equivalent to the LD50)
produced salivation, myosis, lacrimation, nasal secretion,
micturition, cloudy cornea, apnea, and death by cardiac failure (2).
Decreased blood pressure and marked tachycardia also occurred at
this dose level.
Exposure of rats to pyridine vapors at 5-10 mg/liter for
a single 40-minute period decreased the glutamine level in the
kidneys and increased the ammonia excretion in the urine (3). No
changes in ammonia or glutamine levels in the liver were observed.
2.4 Other Toxic Effects
Six rats given diets with 0.1% pyridine gradually lost
weight and died in 2-4 weeks. Lesions of the liver and kidneys
and cirrhosis of the liver were observed (4).
VII-6
-------
Baxter (5,6) hypothesized that pyridine might, by its
methylation in the body, cause hepatic and renal injury by draining
the labile methyl groups from choline and methionine, thus pro-
ducing an "intrinsic" deficiency of these substances. Administra-
tion of pyridine (0.34-1.0%) to rats for up to 4 months in diets
containing low levels of casein and choline appeared to induce
necrosis and fatty changes in the liver. Rats given pyridine with
more nearly optimal diets developed necrosis with vascular
engorgement and hemorrhages in the central areas. Renal damage
often occurred in animals with hepatic injury (5). Increasing
the choline (and casein) content of the diet caused a marked
reduction in fatty changes and fibrosis without any significant
reduction in the severity and extent of the acute necrosis.
Tumor-like nodules were observed in the livers of some rats.
Parenchymal cells at the edges of old necrotic areas in the livers
contained accumulations of oval cytoplasmic bodies that stained
dark brown with hematoxylin and gave the histochemical reactions
of calcium (calcification) (6).
Administration of pyridine intravenously to anesthetized dogs
resulted in the following (2):
a) Increased serum glutamic-oxaloacetic transaminase (SCOT)
and blood urea and decreased serum alkaline phosphatase,
at doses of 88-380 mg/kg body weight. According to the
authors these changes support the concept that pyridine
in high and lethal doses causes liver and kidney damage.
b) Reduced blood pressure only at lethal doses, which
according to the authors suggests that the effect on
blood pressure is secondary to the primary action on the
central nervous system.
VII-7
-------
Kondratyuk (7, from TOXLINE abstract) reported that rats
ingesting pyridine at 0.2 mg/liter in drinking water containing
calcium ions (100 mg/liter) showed a thickening of the mucous
membrane folds of the stomach, abundant mucus in the stomach with
small amounts in the duodenum, as well as catarrhal symptoms
and ulcerations. Kondratyuk also indicated that .calcium in drinking
water increased the toxic effects of pyridine to a greater degree
than magnesium.
Toxic effects of pyridine in humans have been reported. Small
oral doses (2-3 ml) produced mild anorexia, nausea, fatigue,
and mental depression (G26).
Most of the effects observed in humans exposed to pyridine
are transient and occur in the central nervous system and
gastrointestinal tract (G38). The symtoms include headache,
dizziness or giddiness, nervousness, insomnia, mental dullness,
nausea, and anorexia. In some cases, lower abdominal or back
discomfort with frequent urination has been observed. These
transient symptoms, without associated evidence of liver or kidney
damage, have occurred in individuals exposed to pyridine vapors
at an average concentration of 125 ppm, 4 hours a day, for 1-2
weeks.
Serious liver and kidney injury occurred in two individuals
treated for epilepsy with pyridine in daily oral doses of 1.8-2.5
ml for up to 2 months (8). One of the treated individuals died.
No toxic effects except heartburn and occasional nausea were
reported in humans exposed to pyridine in oral doses of 0.31-1.54
ml (8).
Effects on the nervous system, including speech disorders,
VII-8
-------
were observed in a 29-year-old woman who inhaled vapors from
spilled pyridine for 15-20 minutes. No irritation of the upper
respiratory tract was caused by this accident (9, from TOXLINE
abstract).
2.5 Carcinogenicity
Pyridine was administered to rats (Fischer 344) by sub-
cutaneous injection, twice a week, for 1 year at four dose levels (3,
10, 30, 100 mg/kg). The rats were held an additional 6'months for
observation. Neither the total tumor incidence nor the incidence
at particular sites were higher in the exposed animals than in
controls (10).
Large tumor-like nodules in livers of some rats exposed
to pyridine at 0.34-1.0% in the diet for up to 4 months have
been reported (6). No evidence of invasion or metastases was
seen.
Repeated subcutaneous injections of 5% pyridine produced
epithelial proliferation in rabbit ears (11, as reported in G18).
The strain or type of rabbit, the number of survivors, and the
duration of the experiment were not given.
By current standards, none of these studies are considered
adequate to judge the carcinogenicity of pyridine.
2.6 Mutagenicity
No information was found in the sources searched.
2.7 Teratogenicity
Developmental abnormalities were reported in chicken embryos
as follows (12, from TOXLINE abstract):
VII-9
-------
"Pyridine (20 mg/egg) caused typical muscular hypoplasia
of the legs and on rare occasions, abnormality of the facial
skeleton and neck vertebrae. Pronounced synergistic effect was
observed by the joint treatment with ethionine and pyridine."
2.8 Metabolic Information
The fate in the body of most of an administered dose of
pyridine is unknown (13). Hydroxylation, N-methylation, oxidation,
and conjugation reactions, however, have been identified (G38).
In rabbits, oral treatment with pyridine (0.25 g/kg) did not
disturb the ethereal sulphate or glucuronic acid output, although
traces of 3-hydroxypyridine were excreted. N-Methylpyridinium ion
and 3-hydroxypyridine (shown below) are reported metabolites of
pyridine, but they accounted for only a small portion of the
administered dose (13).
3 trace metabolite
Pyridine N-Methylpyridinium ion 3-Hydroxypyridine
Earlier reports (14) suggested that methylation is probably
a detoxification reaction of pyridine. Pyridine is partly
converted by most animals (except the rabbit) to N-methylpyridinium
hydroxide.
When pyridine acetate was administered to dogs (route un-
specified) , methylpyridinium hydroxide equivalent to about 4% of
VII-10
-------
the dose appeared in the urine (13) . Methylation of the pyridine
in the pig, goat, hen, and frog also has been reported. Accord-
ing to early investigations, rabbits did not methylate pyridine
although they excreted some pyridine unchanged. A more recent
article reported that a small amount (113 ing) of the methylated
compound was isolated as the chloroplatinate ((C,H_N,HC1)2PtCl4)
after rabbits were fed 15 g of pyridine. Pyridine is probably
methylated in man; small quantities of the methylated compound
occur in urine (13).
Pyridine also can be metabolized by N-oxidation, which
represents a pathway of metabolic activation (G10). (The
N-oxide is a more potent fungicide than the parent compound.)
2.9 Environmental Release and Ecological Effects
Data on the toxicity of pyridine in aquatic organisms is
given in Table VII-2:
TABLE VII-2
ACUTE TOXICITY OF PYRIDINE IN AQUATIC ORGANISMS
Para-
Species meter
Mosquito fish TLm
(Gambusia affinis)
Water flea TLm
(Daphnia magna)
Carp TLm
(Cyprinus carpio)
Duration Ref-
of Exposure Concentration erence
96 hr 1,300 ppm 15
48 hr 944 mg/liter 17
96 hr 26 ppm 18
VII-11
-------
The toxicity threshold concentration for long-term exposure
in Daphnia magna was reported to be 40 mg/liter (19).
A secondary source (1) reported that Russian investigators
(20,21) detected pyridine in the working area around coke furnaces
and in agricultural crops and fish. A subsequent study (22, from
TOXLINE abstract) indicated that pyridine and phenols were taken
up by crops sprayed with 500 m /hectare of effluent water from
coke manufacturing plants, whereas benzene and naphthalene in the
waste water were not detected in plants. Pyridine has also been
detected in four water supplies (23).
Pyridine at 340 mg/liter and 28 mg/liter was reported to in-
hibit cell multiplication in the bacterium Pseudomonas putida and
the alga Microcystis aeruginosa, respectively (G40).
The nematode Caenorhabditis elegans showed a positive chemo-
tactic response toward pyridine at 0.1-1 mM (16).
2.10 Current Testing
Pyridine has been approved for carcinogenicity bioassay by
NCI (G12) because of large annual production, widespread use,
high potential for human exposure, and the lack of adequate test
data (1).
VII-12
-------
REFERENCES
1. Stanford Research Institute. Summary of Data for Chemical
Selection: Pyridine (June 1977)
2. Venkatakrishna-Bhatt, H., Shah, M.P., and Kashyap, S.S
Toxicological effects of intravenous administration of pyridine
in anaesthetized dogs. Toxicology 4: 165-167 (1975)
3. Bolonova, L.N. Effect of acute pyridine poisoning on ammonia
metabolism in the liver and kidneys. Farmakol. Toksikol.
7:153-156 (1972)
4. Baxter, J.H., and Mason, M.F. Studies of the mechanism of liver
and kidney injury: IV. Comparison of the effects of pyridine
and methyl pyridinium chloride in the rat. J. Pharmacol.
Exp. Ther. 91:350-356 (1947)
5. Baxter, J.H. Pyrddine liver and kidney injury in rats, the
influence of diet, with particular attention to methionine,
cystine and choline. Bull. Johns Hopkins Hosp. 85:138-167
(1949)
6. Baxter, J.H. Hepatic and renal injury with calcium deposits
and cirrhosis produced in rats by pyridine. Amer. J. Pathol.
24:503-525 (1948)
7. Kondratyuk, V.A. Effects of pyridine dissolved in water on
the mucous membrane of the stomach and intestines of
experimental animals. Gig. Sanit. 11:87-88 (1974)(Abstract)
8. Pollock, L.J., Finkelman, I., and Arieff, A.J. Toxicity of
pyridine in man. Arch. Intern. Med. 71:95-106 (1943)
9. Kuselova, M., Kubenova, K., and Kovarik, J. Unusual picture of
acute pyridine poisioning. Prac. Lek. 27:207-209 (1975)(Abstract)
10. Mason, M.M., Gate, C.C., and Baker, J. Toxicology and
carcinogenesis of various chemicals used in the preparation
of vaccines. Clin. Toxicol. 4:185-204 (1971)
11. Stoeber, H., and Wacker, L. A further contribution to the
production of non-typical epithelial growths by protein
putrefactive products. Munch. Med. Wochschr. 57:947-949
(1910) (Abstract)
12. Landauer, W., and Salam, N. Experimental production in
chicken embryos of muscular hypoplasia and associated defects
of beak and cervical vertebrae. Acta Embryol. Exp. 1:51-66
(1974)(Abstract)
VII-13
-------
13. Williams, R.T. Detoxification Mechanisms. 2nd Ed. Wiley,
New York. Pp 561-562, 719 (1959)
14. Williams, R.T. Detoxification Mechanisms: The Metabolism of
Drugs and Allied Organic Compounds. Wiley, New York. P 10 (1949)
15. Waller, I.E., Green, W.C., and Lasater, R. Toxicity to
Gambusia affinis of certain pure chemicals in turbid waters.
Sewage Ind. Waste 29:695-707 (1957)
16. Dusenbery, D.B. Attraction of the nematode Caenorhabditis
elegans to pyridine. Comp. Biochem. Physiol. 53:1-2 (1976)
(Abstract)
17. Dowder, B.F, and Bennett, H.J. Toxicity of selected chemicals
to certain animals. J. Water Pollut. Control Fed. 37:,
1308-1318 (1965)
18. Rao, T.S., Rao, W.S., and Prasad, S.B.S. Median tolerance limits
of some chemicals to the fresh water fish Cyprinus carpio.
Indian J. Environ. Health 17:140-146 (1975)
19. Bringmann, G., and Kuhn, R. The toxic effects of waste water
on aquatic bacteria, algae, and small crustaceans.
Gesundheits-Ing. 80:115 (1959)
20. Naizer, Y., and Mashek, V. Determination of pyridine and its
homologs in the environment of coke plant workers. Gig. Sanit.
39:76-78 (1974) (Abstract)
21. Polishchuk, L.R., and Stempkovskaya, L.A. Determination of
pyridine in farm crops and fish. Gig. Sanit. 39:69-70 (1974)
(Abstract)
22. Polishchuk, L.R. Dynamics of the level of certain organic
toxic substances in plants irrigated with waste water from
by-product coke manufacture plants. Gig. Sanit. 4:117-119
(1975) (Abstract)
23. Shackelford, W.M., and Keith, L.H. Frequency of organic
compounds identified in water, U.S. Environmental Protection
Agency, Athens, Georgia (1976)
VII-14
-------
1,1,1-TRICHLOROETHANE
TABLE OF CONTENTS
Page
Overview VIII-1
Part I General Information VIII-3
Part II Biological Properties
2.1 Bioaccumulation VIII-6
2.2 Impurities and Environmental Degradation
or Conversion Products VIII-6
2.3 Acute Toxicity ' "II-8
2.4 Other Toxic Effects \ :i-15
2.5 Carcinogenicity \ -1-20
2.6 Mutagenicity VIII-21
2.7 Teratogenicity VIII-21
2.8 Metabolic Information VIII-21
2.9 Environmental Release and Ecological
Effects VIII-22
2.10 Current Testing VIII-23
References VIII-24
VHI-i
-------
1,1,1-TRICHLOROETHANE
AN OVERVIEW
1,If1-Trichloroethane, which is also known as methyl chloro-
form and alpha-trichloroethane, is a colorless liquid. It is
insoluble in water but soluble in chloroform, alcohol, and ether.
Commercial products contain small amounts of stabilizing material,
such as para-dioxane and tetraethyl lead.
1,1,1-Trichloroethane can be produced by reaction of 1,1-
dichloroethylene with hydrogen chloride in the presence of
catalysts. U.S. production of this chemical in 1976 was 631 mil-
lion pounds, reflecting a growth rate of about 9.5% per year since
1966, when 250 million pounds were produced. In 1974, U.S. im-
ports are believed to have been negligible; exports are estimated
to be 70 million pounds.
This compound is used as a cleaning solvent for metals and
other materials. It also has miscellaneous uses, for example as
an aerosol component, a coolant in metal cutting oils, and a
carrier for lubricants.
According to NOHS, 2,904,000 workers in the United States are
occupationally exposed to 1,1,1-trichloroethane, whereas a NIOSH
criteria document estimated that 100,000 workers are potentially
exposed to the compound. SRI International estimated that in 1972,
when 440 million pounds of the compound were produced, 6.6 million
pounds were lost to the environment during manufacturing and
278 million pounds were released to the environment in its
commercial use pattern.
VIII-1
-------
The compound's high volatility reduces its potential for
bioaccumulation.
In view of the exponential growth in its production, 1,1,1-
trichloroethane appears to pose a major threat to stratospheric
ozone. (Among man-made chemicals, only Freon 11 and Freon 12 are
considered to present more serious threats.) There is some con-
cern that, because it is not readily attacked by hydroxyl radicals
in the troposphere, 1,1,1-trichloroethane may reach the strato-
sphere, where it could produce oxides of chlorine (C10X).
The heart, lung, liver, kidneys, and central nervous system
are affected by 1,1,1-trichloroethane. The compound is almost
completely eliminated in an unaltered form by the lungs in both
rodents and man.
A recent bioassay by NCI did not reveal any significant
differences between the incidence of tumors in controls and in
exposed animals. An assessment of the carcinogenicity of the
compound could not be made because of the abbreviated life spans
of the test animals. No statistically significant teratogenic
effects were observed in either mice or rats in this study- No
information on the mutagenicity of the compound was found in the
sources searched.
VIII-2
-------
1,1,1-TRICHLOROETHANE
PART I
GENERAL INFORMATION
1.1 Identification CAS No.: 000071556
NIOSH No.: KJ29750
1.2 Synonyms and Trade Names
Aerothene TT; chlorothene (inhibited); chlorothene NU;
Chlorten; methylchloroform; alpha-trichloroethane
(G16)
1.3 Chemical Formula and Molecular Weight
Gl
I
Cl-C-CH. C0H,C1_ Mol. wt. 133.41 (G22)
I J £. J 3
Cl
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless liquid (G21)
1.4.2 Boiling Point; 74.1° C (G22)
1.4.3 Melting Point; -30.41° C (G22)
1.4.4 Absorption Spectrometry;
No information was found in the sources searched.
1.4.5 Vapor Pressure; 100 mm at 20° C (G22)
1.4.6 Solubility; Insoluble in water; soluble
in chloroform; soluble in
all proportions in alcohol,
ether
(G22)
1.4.7 Octanol/Water Partition Coefficient
No information was found in the sources searched.
VIH-3
-------
1.5 Production and Use
1.5.1 Production: 440.7 million Ib (1972)
458.8 million Ib (1975)
631.3 million Ib (1976) (G24)
1.5.2 Use: As a solvent for cleaning precision
instruments; in metal degreasing; as a
pesticide; in cold type metal cleaning;
in cleaning plastic molds (G21,G23)
Quantitative Distribution: Percentage
Solvent including metal degreasing 70
and electrical and electronic
equipment cleaning
Aerosols, solvent for adhesives 15
and polishes, and other uses
Exports 15
100
(G25)
Consumer Product Information;
_ , , . . No. of 1,1,1-trichloro-
No. of products contain- eth£me roducts in cate_
ing 1,1,1-trichloroethane aorv
Total no. of products 'xl°°
Category in category
Cleaning agents 5 0.28%
and compounds
Flame retardant 1 0.17%
chemicals
Household aerosols 82 2.18%
Chemical deodorizers 1 0.31%
Photographic chemicals 6 1.49%
Solvent based cleaning 40 18.35%
and sanitizing agents
Caustics, lyes, and 1 0.44%
drain cleaners
Adhesives and adhesive 10 1.89%
products including
glue
The 146 products surveyed contained an average of 47%
1,1,1-trichloroethane. (G27)
VIII-4
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1. 6 Exposure Estimates
1.6.1 Release Rate; 285 million Ib (G28)
1.6.2 NOHS Occupational Exposure
Rank : 4 2
Estimated no. of persons exposed: 2,904,000
(G29)
In its criteria document, NIOSH estimated
that 100,000 workers in the United States
are potentially exposed to 1,1,1-trichloro-
ethane .
1. 7 Manufacturers
Dow Chemical Co.
Vulcan Materials Co.
Pittsburg Plate Glass Co.
Ethyl Corp. (G24)
VIII-5
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1,1,1-TRICHLOROETHANE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
The high fat solubility and low chemical reactivity of 1,1,1-
trichloroethane will tend to cause it to bioaccumulate, but this
is offset by its high vapor pressure (100 mm at 20°C) and resul-
tant volatility (G22).
2.2 Impurities and Environmental Degradation or Conversion
Products
Impurities found in 1,1,1-trichloroethane include water,
hydrochloric acid, and unidentified nonvolatile residues (G14),
as well as dioxane, butanol, and ethylene dichloride (G38).
Federal specifications provide additional data on the composition
of the technical product. For technical, inhibited 1,1,1-tri-
chloroethane, the specification calls for 94.5% purity by weight
and 90.0% purity by volume. Individual halogenated impurities
must not exceed 0.5%, and total halogenated impurities are limited
to 1.0%. The acidity (as HC1) is restricted to 5 ppm and no free
halogens are allowed (4).
Although 1,1,1-trichloroethane is very stable, small amounts
of stabilizing substances are always added to the commercial
product. Patented additives include glycol diesters, ketones,
ketols, nitriles, dialkyl sulfoxides, imines, dialkyl sulfides,
dialkyl sulfites, tetraethyllead, morpholine, nitroaliphatic
VIII-6
-------
hydrocarbons, 2-methyl-3-butyn-2-ol, tert-butyl alcohol, tetra-
hydrofuran, 1,4-dioxane, sec-butyl alcohol, and monohydric
acetylenic alcohols (G17).
1,1,1-Trichloroethane is very stable in the troposphere (2).
It reacts very slowly with peroxides, ozone, and the hydroxyl
radical with half-lives in excess of 5 years (G14). Possible
products include 1,1-dichloroethylene and dichloroacetaldehyde.
At pH 7, hydrolysis is very slow (t1/_>3,000 hr). ,The
1/2
compound is not photoactive (G14). The National Academy of
Sciences has reported that 1,1,1-trichloroethane, in view of the
exponential growth in its production, ranks third behind Freon 11
and Freon 12 among the major man-made threats to the stratospheric
ozone. There is some concern that, because 1,1,1-trichloroethane
is not readily attacked by hydroxyl radicals in the troposphere,
it may reach the stratosphere, where it could produce oxides of
chlorine (C10X) (2).
2.3 Acute Toxicity
The acute toxicity of 1,1,1-trichloroethane as reported in
the NIOSH Registry of Toxic Effects of Chemical Substances (G16)
is given in Table VIII-1.
VIII-7
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TABLE VIII-1
ACUTE TOXICITY OF 1,1,1-TRICHLOROETHANE
Parameter
Dosage
Animal
Route
LCLo
TCLo
2 7 g Human
for 10 min
1,000 ppm Rat
350 ppm Human
920 ppm "
for 70 min
Inhalation
LD50
ii
ii
n
4,700 mg/kg
750 mg/kg
5,660 mg/kg
9,470 mg/kg
Mouse
Dog
Rabbit
Guinea pig
Intraperitoneal
Oral
n
n
Among the main sites affected by 1,1,1-trichloroethane are
the heart, lungs, liver, kidneys, and central nervous system (5).
Because of the volatility and uses of the compound, most expo-
sures are by inhalation.
Effects of the inhalation of 1,1,1-trichloroethane on the
human heart include decreased blood pressure and bradycardia.
Electrocardiograms of patients anesthesized with 1,1,1-trichloro-
ethane show changes in nodal rhythm and premature ventricular
contractions. Animals show the following effects: cardiovas-
cular depression, decreased stroke volume, cardiac arrhythmias,
VIII-8
-------
tachycardia, and, at very high doses, congestion and fibril-
lation (5). The results of the individual studies are presented
in Table VIII-2.
TABLE VIII-2
ACUTE EFFECTS OF INHALATION OF 1,1,1-TRICHLOROETHANE ON
THE CARDIOVASCULAR SYSTEM (4,5)
Animal
Exposure
Response
Reference Cited
Dog
125,000 ppm
for 1.5-6 min
Abrupt drop in
blood pressure;
ventricular fibril-
lation in one dog on
second exposure;
gross congestion in
all tissues; h,eart
cell necrosis
14
" 8,000 ppm
for 5 min
" 5,000 ppm
for 5 min
" 2,500 ppm
for 5 min
Rhesus 25,000 ppm ,
monkey for 5 min
Rabbit 6,250 ppm
for 10 min
Human Anesthesia
and dog (unspecified)
Sharp decrease in 15
peripheral resistance
followed by decreased
stroke volume, heart
rate, and myocardial
contractility
Cardiac sensitization 16
to epinephrine
No cardiac sensitiza- 16
tion to epinephrine
Cardiac arrhythmias; 17
myocardial depression;
tachycardia
Cardiovascular depres- 18
sion
Little effect on elec- 6*, 13
trocardiograms, but
consistently decreased
blood pressure
primary source
VIII-9
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Histological examination of the lungs of animals acutely
exposed to 1,1,1-trichloroethane revealed congestion and inflam-
matory changes (5). The pulmonary effects of 1,1,1-trichloroethane
are given in Table VIII-3.
TABLE VIII-3
ACUTE EFFECTS OF INHALATION OF 1,1,1-TRICHLOROETHANE ON
THE LUNGS (4,5)
Animal
Exposure
Response
Reference Cited
Human
(female)
Human
Mouse
Several days
intentional
inhalation
4 hr cleaning
metal parts
with 1,1,1-
trichloroethane
100 ppm
for 2 hr/day
9 exposures on
alternate days
Death; autopsy
revealed congestion
of the bronchial
vessels with thick
yellowish-brown
secretions; con-
gestion throughout
the lungs
Death; autopsy
revealed congested
edematous lungs
Lung congestion
19
20
The effects on the liver of acute inhalation exposure to 1,1,1-
trichloroethane, summarized in Table VIII-4, are increases in
weight accompanied by fatty changes and hemorrhagic necrosis (5) .
TABLE VIII-4
ACUTE EFFECTS OF INHALATION OF 1,1,1-TRICHLOROETHANE ON
THE LIVER AND KIDNEYS (4,5)
Animal
Exposure
Response
Reference Cited
Human
2 hr
anesthesia
No effect on SGPT
activity in five
subjects and there-
fore presumably no
hepatotoxicity
VIII-10
13
-------
TABLE VIII-4 (Continued)
Animal Exposure Response Reference Cited
Human 0-2,650 ppm Positive urinary 10
for 15 min urobilinogen
" 500 ppm No evidence of liver 21
7 hr/day or kidney injury
for 5 days
Rat 18,000 ppm Increased kidney 22
for 2 hr weight
" 12,000 ppm Increased liver 22
for 7 hr weight, fatty liver
changes; congestion
and hemorrhagic necrosis;
increased kidney weight
" 8,000 ppm Fatty changes in liver 22
for 7 hr
The effects of 1,1,1-trichloroethane inhalation on the kidneys
have not been studied as extensively as the effects of the chemical
on the liver, but congestion, increase in kidney weight, and
definite disturbances in renal function have been reported in
experimental animals (5). The effects on the kidneys have also
been presented in Table VIII-4.
The most harmful effects of inhaling 1,1,1-trichloroethane
apparently are central nervous system disorders, including
anesthesia, impairment of perceptual speed, delayed reaction
time, decreased manual dexterity, and disturbed equilibrium (5).
These effects are given in Table VIII-5.
VIII-11
-------
TABLE VIII-5
ACUTE EFFECTS OF INHALATION OF 1,1,1-TRICHLOROETHANE ON
THE CENTRAL NERVOUS SYSTEM (5)
Animal
Exposure
Response
Reference Cited
Human
10,000-26,000
ppm
Induction of
anesthesia usually
within 2 min
23
Rat
6,000-22,500
ppm
0-2,650 ppm
for 15 min
1,740-2,180
ppm
1,000 ppm
for 70-75 min
500 ppm
for 450 min
500 ppm
for 3 hr
450 ppm
for 8 hr
350 ppm
for 2 hr
250 ppm
for 2 hr
18,000 ppm
for 5 min
18,000 ppm
for 3 hr
10,000 ppm
for 1-2 min
Maintenance of 23
anesthesia
2 of 7 exposed 10
subjects unable
to stand
Disturbed equilibrium 7
Impaired coordination 7
and equilibrium
Reflexes and equi- 7
librium undisturbed
Balance and coordin- 10
ation not affected
Decreased perceptive 24
capabilities under
stress conditions '
Perceptual speed, 25
reaction times, and
manual dexterity impaired
Perceptual speed, 25
reaction times, and
manual dexterity not
impaired
"Helpless" 22
Unconscious 22
Decreased activity 22
VIII-12
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TABLE VIII-5 (continued)
Animals
Exposure
Response
Reference Cited
Rat
Rat and
cat
Monkey
Rabbit
10,000 ppm
for 10 min
10,000 ppm
for 3 hr
5,000 ppm
for 1 hr
180-900 ppm
for 4 hr
5,000 ppm
for 1 hr
5,000 ppm
for 5 hr
16,850 ppm
for 5 min
16,850 ppm
for more
than 5 min
"Helpless" 22
Semiconscious 22
Mild narcotic effect 22
Threshold for altering 26
conditioned reflex
activity
Slight ataxia 22
Trembling of hands 22
and forearms
Increased EEC activity 18
Decreased EEC activity 18
Six fatal cases of 1,1,1-trichloroethane inhalation in four
separate incidents were reviewed by Stahl et al. (8). All six
deaths resulted from acute inhalation of the compound at high
concentrations. The autopsy reports on the victims can be
summarized as follows:
1. Liver, lungs, spleen, kidneys, and brain congested; lungs
moderately edematous; brain anoxic.
2. Skin moderately cyanotic; brain, liver, kidneys, and
spleen moderately congested; lungs markedly edematous with
signs of aspiration of the stomach contents.
3. Fatty liver with centrilobular fatty change; brain,
spleen, and kidneys congested and lungs congested and edematous,
VIII-13
-------
4. Bullous lesions and focal denudation of buttock skin;
congested and edematous lungs with aggregates of poly-
morphonuclear leukocytes.
In one study, the inhalation LT50 was reported as follows
(1):
Parameter Dosage Animal
LT50 18,000 ppm for 3 hr Rat
14,000 ppm for 7 hr
In addition to the numerous studies on 1,1,1-trichloroethane
by inhalation, a few have been done by other routes.
1,1,1-Trichloroethane applied as a 5% solution in corn oil
to the eyes of rabbits produced chemosis and hyperemia in the
conjunctivae (6, as reported in 5).
A single undiluted application of 1,1,1-trichloroethane to
rabbit eyes was reported by Torkelson et al. (7, as reported in 5)
to cause slight conjunctival irritation but essentially no corneal
damage. In the same study, slight eye irritation was reported in
one of four human subjects exposed to 1,1,1-trichloroethane vapor
at 900-1,000 ppm.
Only a slight reddening and scaliness of the skin were reported
to develop when a pad of cotton saturated with 1,1,1-trichloroethane
was bandaged to the shaved belly of a rabbit 10 times in 12 days.
When applied to abraded skin, 1,1,1-trichloroethane had no sig-
nificant effects on the healing process (7, as reported in 5).
In a human, the ingestion of an unspecified quantity of 1,1,1-
trichloroethane produced kidney damage, as evidenced by elevated
serum bilirubin and the presence of red blood cells and protein in
the urine (10, as reported in 5).
VIII-14
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An intraperitoneal dose of the compound at 3,800 mg/kg had
no effect on liver triglyceride levels in rats, but at higher doses
(nearly lethal) the levels were raised (11, as reported in 4).
Intraperitoneal doses of 1,1,1-trichloroethane at 3,400 mg/kg
produced swelling of the proximal convoluted tubules of the kidneys
in a significant number of mice (12, as reported in 4).
2.4 Other Toxic Effects
Numerous long-term inhalation studies have been performed
using 1,1,1-trichloroethane. In most of the studies no significant
major toxic effects were observed. The results are summarized in
Table VIII-6.
Chronic oral studies were performed using rats and mice dur-
ing the NCI carcinogenicity bioassay (27). 1,1,1-Trichloroethane
was administered by gavage once a day, 5 days/week for 78 weeks.
Rats were given 750 or 1,500 mg/kg/day and mice were given varied
doses averaging 2,807 or 5,615 mg/kg/day. As the study progressed,
increasing numbers of exposed rats exhibited urine staining on the
fur. The exposed rats also developed respiratory problems
characterized by wheezing, rapid or labored breathing, nasal
discharge, and a hunched appearance. A smaller number of controls
exhibited the same symptoms. The exposed rats more often than the
controls developed a bloody discharge or crust around the eyes.
The survival rate of the exposed rats was significantly lower than
that of the controls and was dose dependent. In the first year,
7/20 of the control rats, 56/100 of the low-dose group, and 57/100
of the high-dose group died. The mice exhibited no significant
VIII-15
-------
TABLE VIII-6
EFFECTS OF 1,1,1-TRICHLOROETHANE ON HUMANS AND ANIMALS AFTER PROLONGED OR REPEATED INHALATION
Animal
Number
Monkey
M
H
H
I
I—
(Ti
Dog
Exposure
Response
Reference Cited
Human 11
(males)
500 ppm
6.5-7 hr/day
for 5 days
Headache; eye, nose, and throat
irritation (only in two subjects) ;
body chemistry within normal range
21
3
3
8
250 ppm and 1,000 ppm
for 14 wk (continuous)
3,000 ppm
7 hr/day, 5 days/wk
(53 exposures)
for 74 days
2,700 ppm
8 hr/day, 5 days/wk
for 6 wk
450 ppm
for 90 days (continuous)
165 ppm
90 days (continuous)
250 ppm and 1,000 ppm
for 14 wk (continuous)
No significant changes in body 28
chemistry (HCB, HGB, RBC, WBC, Na,
K, alkaline phosphatase, SCOT,
SGPT, or serum triglycerides);
no lesions attributable to expos-
ure at either dose level found in
pathological examination
No pathological changes in major 29
organs examined
No adverse effects 30
Nonspecific lung inflammation 30
Sporadic lung congestion 30
No significant changes in body 28
chemistry; no lesions attributed
to exposure
-------
TABLE VIII-6 (continued)
Animal
Dog
Number
8
Exposure
2,700 ppm
Response
Slight leukopenia
Reference Cited
30
Rabbit
H
H
H
I
Rat
5-7
5-7
15
15
8 hr day, 5 days/wk
for 6 wk
450 ppm
for 90 days (continuous)
165 ppm
for 90 days (continuous)
5,000 ppm
7 hr/day, 5 days/wk
(31 exposures)
for 44 days
5,000 ppm
7 hr/day, 5 days/wk
(47-48 exposures)
for 66-67 days
2,700 ppm
8 hr/day, 5 days/wk
(30 exposures)
450 ppm
for 90 days (continuous)
165 ppm
for 90 days (continuous)
Nonspecific lung inflammation 30
Sporadic lung congestion 30
Slight depression in growth rate; 31
all other variables normal or
negative
Ataxia, lethargy; retardation of 30
growth rate in females through
week 2, then recovery to control
levels
No adverse effects 30
Normal 30
Nodules on a lower lung lobe in 30
one rat
-------
TABLE VIII-6 (continued)
Animal
Number
Guinea pig 5-12
<
H
I
M
OO
Mouse
180
Exposure
Response
Reference Cited
Rat 15
40
165 ppm
for 90 days (continuous)
250 and 1,000 ppm
Sporadic lung congestion
and pneumonitis
Liver/body weight ratio sig-
30
28
for 14 wk (continuous)
650-1,000 ppm
7 hr/day, 5 days/wk
for 29-93 days
250 ppm and 1,000 ppm
for 14 wk (continuous)
nificantly increased at 1,000
ppm
At 5,000 ppm, remarkable de- 29
crease in growth rate of males
and females and slight centri-
lobular fatty infiltration in
liver but no necrosis; slight
testicular degeneration; at
3,000 ppm slight centrilobular
fatty infiltration, with small
fat-staining globules in cen-
tral hepatocytes
Significant increase in fat 28
droplets in centrilobular
hepatocytes at 1,000 ppm;liver
triglycerides elevated through-
out exposure at 1,000 ppm but
returned to normal after 2 wk
-------
TABLE VII1-6 (continued)
Animal Number Exposure
Mouse 10 250 ppm and 1,000 ppm
Response Reference Cited
At 1,000 ppm, relative and ab- 32
for 14 wk (continuous)
H
H
H
I
M
VO
Rat
19
875 ppm and 1,750 ppm
6 hr/day, 5 days/wk
for 52 wk
solute liver weight signifi-
cantly greater; triglyceride
level elevated; at 1,000 ppm,
centrilobular hepatocyte hyper-
trophy due to small cytoplasmic
vacuoles; occasional cell with
"balloon" degeneration, or exten-
sive enlargement due to cytoplasmic
vacuolization with pycnotic nuclei;
peak fat accumulation; focal necro-
sis at week 10, with acute inflam-
ma tous exudate (mainly neutrophils)
Death rate same as in controls;
neutrophilia in 6% and lymphocyto-
penia in 7% of males at 1,750 ppm;
lymphocytosis in 13% of females
at both levels
27
-------
signs other than a dose-dependent reduction in weight gain and,
in females, a dose-dependent increase in death rate.
A Threshold Limit Value (TLV) of 1,900 mg/m has been set
for 1,1,1-trichloroethane (Gil).
2.5 Carcinogenicity
Results of NCI bioassay studies on technical grade 1,1,1-tri-
chloroethane containing 3% para-dioxane have recently been report-
ed (27). Groups of rats and mice were fed 1,1,1-trichloroethane
at two concentrations 5 days/week for 78 weeks. Rats were fed
750 and 1,500 mg/kg/day, while mice received doses averaging
2,807 and 5,616 mg/kg/day. A variety of neoplasms was reported
in the test animals, but none occurred at frequencies significantly
higher than they did in the controls. A few of the malignant
neoplasms were observed only in the exposed rats—papillary
cystadenocarcinoma in the subcutis of 1/50 of the high-dose
females, transitional-cell carcinoma of the bladder in 1/50 of
the high-dose males, malignant brain glioma in 1/48 of the low-
dose males, and mesenteric metastatic osteosarcoma in 1/50 of the
high-dose females. Only 3% of the exposed rats survived until
the end of the experiment. In the exposed mice, no neoplasms
occurred that had not been previously observed as spontaneous
lesions.
NCI concluded that the neoplasms observed were not attrib-
utable to the test compound because there was no apparent
relationship between the dosage groups, the sex, the species, the
type of neoplasm, or the site of occurrence. Even if such a
VIII-20
-------
relationship could have been established, according to NCI, the
abbreviated life spans of both the rats and the mice made it
inappropriate to assess the carcinogenicity of 1,1,1-trichloro-
ethane on the basis of this bioassay (27) .
2.6 Mutagenicity
No information on the mutagenicity of this compound was found
in the sources searched.
2.7 Teratogenicity
The effects of 1,1,1-trichloroethane on the embryonic and
fetal development of rats and mice were studied.at a vapor concen-
tration of 875 ppm (a concentration two times the maximum allowable
excursion limit for human industrial exposure, as defined by ACGIH
in 1976) . Groups of pregnant Sprague-Dawley rats and Swiss-Webster
mice were exposed to this solvent 7 hours daily on days 6-15 of
gestation. An increase in liver weight was reported to be the
only significant maternal, fetal, or embryonic toxic effect in
rats at 875 ppm. There were no significant findings reported in
mice. Although the authors concluded that the compound had no
statistically significant teratogenic effects in either mice or
rats, certain soft tissue or skeletal abnormalities occurred in
the exposed animals that did not occur in the controls. These
abnormalities included one litter of mice with short tails and
one with cleft palates. In rats, two litters with extra vertebrae
were found (33, as reported in 5).
VIII-21
-------
2.8 Metabolic Information
Because of its volatility and biological stability, 1,1,1-
trichloroethane is almost completely eliminated unaltered through
the lungs in both rodents and man. If metabolized, the compound
is transformed into trichloroacetic acid and trichloroethanol in
a dose-dependent manner (G10).
38
The pulmonary excretion of Cl-labeled 1,1,1-trichloroethane
was measured in humans for 1 hour after the inhalation of a single
breath. In the first hour, 44% of the dose was excreted (9, as
reported in 4).
Hake et al. (1) injected rats intraperitoneally with labeled
1,1,1-trichloroethane at about 700 mg/kg. After 25 hours, 98.7%
of the initial dose was excreted unchanged in the expired air,
14
and 0.5% was converted to C02' Much of the remainder appeared
as the glucuronide of 2,2,2-trichloroethanol in the urine. At
this dose level the metabolism of 1,1,1-trichloroethane apparently
proceeds through an initial oxidation to trichloroethanol, which
is then oxidized to trichloroacetic acid (4). Chloroacetic acid,
S-carboxymethyl cysteine, and two conjugated diacetic acids were
found in the urine of animals after exposure to 1,1,1-trichloro-
ethane under unspecified conditions (G10).
A secondary source reports that 1,1,1-trichloroethane is not
known to be metabolized by aerobic or anaerobic microorganisms
(3, as reported in 4).
VIII-22
-------
2.9 Environmental Release and Ecological Effects
SRI International estimated that in 1972, when 440.7 million
pounds of 1,1,1-trichloroethane were produced in the United States,
6.6 million pounds were lost to the environment during production
and 278 million were released to the environment in its commercial
use pattern (G14). The National Academy of Sciences has reported
that 1,1,1-trichloroethane poses a major threat to the strato-
spheric ozone (2). (See Section 2.2.)
1,1,1-Trichloroethane was found as a contaminant at concen-
trations of 3-10 yg/kg in foods sampled in the United Kingdom
(3, as reported in 4).
The compound has an Aquatic Toxicity Rating (96-hr TLm,
species unspecified) of 100-10 ppm, which is considered slightly
toxic (G16).
2.10 Current Testing
No information was found in the sources searched.
VIII-23
-------
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(1972)
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VIII-24
-------
12. Plaa, G.L., and Larson, R.E. Relative nephrotoxic properties
of chlorinated methane, ethane and ethylene derivatives in
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Rowe, V.K. Experimental human exposure to methylchloroform
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Vapor toxicity of 1,1,1-trichloroethane (methyl chloroform)
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administrations. Anesth. Analg. 39:249-253 (1960)
24. Salvini, M., Binaschi, S., and Riva, M. Evaluation of the
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VIII-25
-------
25. Gamberale,., F. , and Hultengren, M. [Methyl chloroform
exposure: II. Psychophysiological function.] Arbete, Och.
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26. Tsapko, V.G., and Rappoport, M.B. [Effect of methyl chloro-
form vapor on the organism of animals.] Farmakol. Toksikol.
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for Possible Carcinogenicity. CAS No. 71-55-6. NCI Carcino-
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the biological effect of continuous inhalation exposure of
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Vapor toxicity of 1,1,1-trichloroethane determined by ex-
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30. Prendergast, R.A., Jones, R.A., Jenkins, L.J., Jr., and
Siegel, J. Effects on experimental animals of long-term
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trichloroethane, dichlorodifluoromethane, and 1,1-
dichlorethylene. Toxicol. Appl. Pharmacol. 10:270-289
(1967)
31. Adams, E.M., Spencer, H.C., Rowe, V.K., McCollister, D.D.,
and Irish, D.D. Vapor toxicity of trichloroethylene deter-
mined by experiments on laboratory animals. Arch. Ind.
Hyg. Occup. Med. 4:469-481 (1951)
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Hepatic pathology in mice after continuous inhalation ex-
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of maternally inhaled trichloroethylene, perchloroethylene,
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macol. 32:84-96 (1975)
VIII-26
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APPENDIX A
GENERAL REFERENCES
Gl. Browning, E. Toxicity and Metabolism of Industrial Sol-
vents. Elsevier, Amsterdam (1965)
G2. Browning, E. Toxicity of Industrial Metals. 2nd ed.
Appleton-Century-Crofts, New York (1969)
G3. Fairhall, L.T. Industrial Toxicology. 2nd. ed. Williams
& Wilkins Co. (1969)
G4. Sax, N.I. Dangerous Properties of Industrial Materials.
3rd ed. Reinhold Publishing Corp., New York (1975)
G5. Chemical Safety Data Sheets. Manufacturing Chemists As-
sociation, Washington, D.C.
G6. Industrial Safety Data Sheets. National Safety Council,
Chicago, 111.
G7. Shepard, T.H. Catalog of Teratogenic Agents. Johns
Hopkins University Press, Baltimore (1973)
G8. Thienes, C.L., and Haley, T.J. Clinical Toxicology. Lea
& Febiger, Philadelphia (1972)
G9. International Agency for Research on Cancer, World Health
Organization (WHO/IARC). IARC Monographs on: the Evaluation
of Carcinogenic Risk of Chemicals to Man. Lyon, France
G10. Debruin, A. Biochemical Toxicology of Environmental Agents
Elsevier/North-Holland, Inc., New York (1976)
Gil. American Conference of Government Industrial Hygienists.
Threshold Limit Values for Chemical Substances and Physi-
cal Agents in the Workroom Environment with intended
Changes for 1976
G12. National Cancer Institute (NCI). Chemicals Being Tested
for Carcinogenicity by the Bioassay Program, DCCP (1977)
G13. World Health Organization (WHO). Information Bulletin on
the Survey of Chemicals Being Tested For Carc'inogenicity,
No. 6. Lyon, France (1976)
G14. Brown, S.L., Chan, F.Y., Jones, J.L., Liu, D. H. , McCaleb,
K.E., Mill, T., Sapios, K.N., and Schendel, D.E. Research
Program on Hazard Priority Ranking of Manufactured Chemi-
cals. Phase II—Final Report. Prepared for National
Science Foundation. Stanford Research Institute, Menlo
Park, Calif. SRI Project ECU-3386. (1975)
-------
G.M.5. Dorigan, J. , Fuller, B., and Duffy, R. Scoring of Organic
Air Pollutants, Chemistry, Production and Toxicity of
Selected Synthetic Organic Chemicals. MITRE Technical Re-
port. MTR-7248 (1976)
G16. National Institute for Occupational Safety and Health
(NIOSH). Registry of Toxic Effects of Chemical Substances
(1976)
G17. Kirk-Othmer Encyclopedia of Chemical Technology- A. Stan-
den (ed.). Interscience Publishers, New York (1963, 1972)
G18. National Cancer Institute (NCI). Survey of Compounds
Which Have Been Tested for Carcinogenic Activity Through
1972-1973 Volume. DHEW Publication No. NIH73-453
G19. National Institute for Occupational Safety and Health
(NIOSH). Criteria for a Recommended Standard—Occupational
Exposure to...
G20. Suspected Carcinogens—A subfile of the NIOSH Toxic Sub-
stance List (1975)
G21. The Condensed Chemical Dictionary. 9th ed. Van Nostrand
Reinhold Co., New York (1977)
G22. Handbook of Chemistry and Physics. 57th ed. The Chemical
Rubber Company, Cleveland, Ohio (1976)
G23. The Merck Index. 9th ed. Merck & Co., Inc., Rahway, N.J.
(1976)
G24. U.S. International Trade Commission. Synthetic Organic
Chemicals, United States Production and Sales, 1966-76.
U.S. Government Printing Office, Washington, D.C.
G25. Lowenheim, F.A., and Moran, M.K. Faith, Keyes, & Clark's
Industrial Chemicals. 4th ed. John Wiley & Sons, New York
(1975)
G26. Gosselin, R.E., Hodge, H.C., Smith, R.P., and Gleason, M.N.
Clinical Toxicology of Commercial Products. 4th ed. The
Williams & Wilkins Co., Baltimore (1976)
G27. Consumer Product Safety Commission. Chemical Consumer
Hazaird Information System. Washington, D.C. (1977)
G28. U.S. Environmental Protection Agency, Office of Toxic Sub-
stances. A Study of Industrial Data on Candidate Chemicals
for Testing. EPA Contract No. 68-01-4109 (November 1976)
G29. National Occupational Hazard Survey (NOHS). National
Inst.itute for Occupational Safety and Health, Cincinnati
Ohio (1976)
G30. The Aldrich Catalog/Handbook of Organic and Biochemicals.
Aid-rich Chemical Co., Inc. (1977-1978)
-------
G31. McCutcheon1s Functional Materials 1977 Annual. McCutcrheon
Division, MC Publishing Co. (1977)
G32. The Encyclopedia of Chemistry. 3rd ed. C.A. Hampel and
G.G. Hawley (eds.) Van Nostrand Reinhold Co., New York
(1973)
G33. Casarett, L.J., and Doull, J. Toxicology, the Basic
Science of Poisons. Macmillan Publishing Co., Inc., New
York (1975)
G34. Radian Chemical Data Base Report Generator. Prepared for
U.S. Encironmental Protection Agency, Office of Res.earch
and Development. Radian Corporation (1977)
G35. Rochester Computer Service, Data Base for Gosselin et al.,
Clinical Toxicology of Commercial Products (G26)
G36. Leo, A., Hansch, C., and Elkins, D. Partition coefficients
and their uses. Chem. Rev. 71:525-616 (1971)
G37. 1977-78 OPD Chemical Buyers Directory. Chemical Market-
ing Reporter. Schnell Publishing Co., New York (1977)
G38. Patty, F.A. Industrial Hygiene and Toxicology. Vol. 2,
2nd ed. Wiley Interscience, New York (1963)
G39. Stanford Research Institute. Directory of Chemical Pro-
ducers. Menlo Park, California (1977)
G40. Verschueren, K. Handbook of Environmental Data on Organic
Chemicals. Van Nostrand Reinhold Co., New York (1977)
G41. U.S. Environmental Protection Agency, Office of Toxic Sub-
stances. A Study of Industrial Data on Candidate Chemi-
cals for Testing. EPA-560/5-77-006 (August 1977)
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APPENDIX B
KEY TO ABBREVIATIONS
TCLo Lowest Published Toxic Concentration
The concentration of a substance in air that has
been reported to produce any toxic effect in ani-
mals or humans over a given exposure time
TDLo Lowest Published Toxic Dose
The lowest dose of a substance introduced by any
route other than inhalation over a given period
of time that has been reported to produce any toxic
effect in animals or humans
LCLo Lowest Published Lethal Concentration
The lowest concentration of a substance in air,
other than an LC50, that has been reported to have
killed humans or animals over a given exposure time
LDLo Lowest Published Lethal Dose
The lowest dose of a substance, other than an LD50,
introduced by any route other than inhalation over
a given period of time that has been reported to
have killed humans or animals
LC50 Median Lethal Concentration
The concentration of a test material that kills
50% of an experimental animal population within a
given period of time
LD50 Median Lethal Dose
The dose of a test material, introduced by any route
other than inhalation, that kills 50% of an experi-
mental animal population within a given period of
time
LT50 Median Lethal Response Time
Statistical estimate of the time from exposure to
the death of 50% of the organisms in a population
subjected to a toxicant under specified conditions
MLD Median Lethal Dose
The dose of a test material, introduced by any route
other than inhalation, that kills 50% of an experi-
mental animal population within a given period of
time
-------
TLm Median Tolerance Limit
The concentration of a test material at which 50%
of an experimental animal population survive for a
specified time period
TLV Threshold Limit Value
The airborne concentration of a substance to which
nearly all workers may be repeatedly exposed day
after day without adverse effect
TWA Time-Weighted Average
The average concentration of a substance for an
8-hour workday or 40-hour workweek
NOHS Occupational Exposure:
Rank: A number representing the chemical's place in
a list ranking approximately 7,000 occupational
hazards according to the number of workers ex-
posed; the lower the number, the more common
the hazard
Estimated no. of persons exposed: This figure includes
full- and part-time workers. For hazards ranked
1-200, the figure given is a projection to
national statistics by NIOSH in its National1
Occupational Hazard Survey (NOHS). For the re-
maining hazards, the number given in the NOHS
was multiplied by a fixed muber to give a rough
estimate of national exposure. The fixed number
(30) is derived from the statistical sampling
technique used in the NOHS.
*U.S. GOVERNMENT PRINTING OFFICE : 1978 0-720-3^5/6124
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