EPA 560-10-78/001
INITIAL REPORT OF THE TSCA
IKTERAGENCY TESTING COMMITTEE
TO THE ADMINISTRATOR,
ENVIRONMENTAL PROTECTION AGENCY
JANUARY 1978
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INITIAL REPORT OF THE TSCA INTERAGENCY TESTING COMMITTEE
TO THE
ADMINISTRATOR, ENVIRONMENTAL PROTECTION AGENCY
October 1, 1977
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CONTENTS
Committee Membership i(
Acknowledgments ii
SUMMARY ill
CHAPTER 1. INTRODUCTION
1.1 Background 1
1.2 Committee Establishment and Responsibilities 2
CHAPTER 2. DEVELOPMENT OF THE COMMITTEE'S INITIAL RECOMMENDATIONS
2.1 Selection of the Committee's Basic Approach 4
2.2 Establishment of the Initial Listing 7
2.3 Reduction to the Master File 7
2.4 Selection of the Preliminary List 8
2.5 Public Comment on the Preliminary Mst 10
2.6 Selection of Substances for Detailed Review 11
2.7 Consideration for Listing and Designation 14
2.8 Consideration of Availability of Testing Facilities
and Personnel 15
CHAPTER 3. RECOMMENDATIONS OF THE COMMITTEE
3.1 Substances and Categories of Substances Recommended
for Testing 17
3.2 Reasons for Recommending Testing of the Substances
and Categories 19
3.2.A Alkyl Epoxides 19
3.2.B Alkyl Phthalates 20
3.2.C Chlorinated Benzenes, Mono- and Di- 21
3.2.D Chlorinated Paraffins, 35-64% Chlorine 22
3.2.E Chloromethane 23
3.2.F Cresols 24
3.2.G Hexachloro-l,3-Butadiene 25
3.2.H Nitrobenzene 26
3.2.1 Toluene 27
3.2.J Xylenes 28
APPENDICES
APPENDIX A DATA SOURCES USED FOR PREPARATION OF THE
INITIAL LIST 29
APPENDIX B PRODUCTION, RELEASE AND EXPOSURE SCORES 32
APPENDIX C ORDERING OF THE CHEMICALS BASED ON
PRODUCTION, RELEASE, AND EXPOSURE 38
APPENDIX D BIOLOGICAL AND ENVIRONMENTAL SCORES 39
INFORMATION DOSSIERS' I-X
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EXECUTIVE OFFICE OF THE PRESIDENT
COUNCIL ON ENVIRONMENTAL QUALITY
722 JACKSON PLACE, N. W.
WASHINGTON, D. C. 20006
October 4, 1977
Honorable Douglas M. Costle
Administrator
Environmental Protection Agency
Washington, B.C. 20460
Dear Mr. Costle:
The enclosed document is the first official report
submitted to you by the Interagency Testing Committee
pursuant to Section 4(e) of the Toxic Substances Control
Act (TSCA). It reflects the consensus of representatives
from all eight member agencies: that the ten listed
substances and categories of substances be recommended
as high priority for testing under TSCA and designated
for consideration by EPA within twelve months.
The report describes the process employed by the Committee
in making its recommendations and the rationale for each
designation. A supporting dossier for each designation
will be forwarded to the Office of Toxic Substances in
the next few weeks.
Only a portion of the compounds identified in the July
preliminary report has been considered to date. The
first revision of our recommendations will be based largely
upon further review of those chemicals previously identi-
fied. Because this is a continuing process, we will, of
course, identify additional chemicals for such review as
information becomes available to us.
The Committee has been hampered in its deliberations by
the lack of a readily available and consolidated source
of data on the many chemicals to which man and the
environment are exposed. Other activities under TSCA,
e.g., development of coordinated data systems, inventory
reporting, and other information collection under Section 8,
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should be of considerable value in future Committee efforts.
Therefore, we expect that a number of additional substances
will be listed and integrated in our future reports.
We hope our analysis and recommendations will be helpful
to EPA in its implementation of the Toxic Substances
Control Act.
Sincerely,
Warren R. Muir, Ph.D.
Chairman
TSCA Interagency Testing
Committee
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TSCA INTERAGENCY TESTING COMMITTEE
Statutory Member Agencies
Council on Environmental Quality National Institute of Environmental
Warren R. Muir, Member and
Committee Chairman
Department of Commerce
Sidney R. Caller, Member
Bernard Greifer, Alternate
Environmental Protection Agency
William M. Upholt, Member
James R. Beall, Alternate
National Science Foundation
Marvin E. Stephenson, Member
and Committee Vice Chairman
Carter Schuth, Alternate
Health Sciences
Hans L. Falk, Member
Warren T. Piver, Alternate
National Institute for Occupational
Safety and Health"
Norbert P. Page, Member
Jean G. French, Alternate
National Cancer Institute
James M. Sontag, Member
Occupational Safety and Health
Administration
Grover C. Wrenn, Member
James M. Vail, Alternate
Liaison Agencies (non-Voting)
Department of Defense
Seymour L. Friess
Food and Drug Administration
Allen H. Helm
Department of Interior
Charles R. Walker
U.S. Consumer Product Safety
Commission
Robert M. Hehir
Joseph McLaughlin
Committee Staff
Secretary: Phyllis D. Tucker
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ACKNOWLEDGMENTS
The Committee wishes to acknowledge the important contributions
of the many individuals and groups who have significantly aided
us in our work. These include:
— Clement Associates, Inc., technical support contractor;
— the National Science Foundation, for funding and managing
the technical support contract and the National Cancer
Institute and National Institute of Environmental Health
Sciences for assisting in that funding;
— government experts who assisted in the scoring of biological
activity and test needs, including Laurence Fishbein of the
National Center for Toxicological Research, Elizabeth Weisburger
of the National Cancer Institute, and a number of experts from
the Department of Interior;
— EPA staff members who assisted the Committee in a variety
of activities, and particularly:
Donald Barnes, Office of Toxic Substances
Joyce Dain, Interim Secretary to the Committee
John Lyon, Office of General Counsel
Joseph Herenda, staff support to EPA member
Lamar Miller, interim staff support to EPA member
Ralph Northrop, Jr., Office of Toxic Substances
— the numerous experts who prepared presentations and materials
for the Committee; and
— the many individuals and organizations who submitted comments
on the Committee's Preliminary List.
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SUMMARY
The Toxic Substances Control Act (TSCA) established the TSCA
Interagency Testing Committee, giving it the continuing responsibility
to identify and recommend to the Administrator of the Environmental
Protection Agency chemical substances and mixtures which should be
tested to determine their hazards to human health and the environment.
The Committee's initial recommendations are to be published in the
Federal Register and transmitted to the EPA Administrator within nine
months of the effective date of TSCA. The Committee is to consider
additions to its recommendations at least every six months.
In meeting its charge, the Committee has, with the assistance of a
technical support contractor, carried out a multi-step screening
procedure to identify for its detailed review a limited number of
substances and categories of substances likely to have priority for
testing to determine their effects on human health and the
environment. A number of substances and categories identified by this
process have been reviewed by the Committee, which has given careful
consideration to each of the eight factors specified in Section
4(e)(l)(A) of TSCA. The Committee has also considered such factors as
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designated by the Committee for consideration by EPA within the next
12 months. They are (arranged alphabetically):
Substance or Category Testing Recommended
Alkyl Epoxides Carcinogenicity, mutagenicity, teratogenicity,
other chronic effects, environmental effects,
and epidemiological study
Alkyl Phthalates Environmental effects
Chlorinated Benzenes, Carcinogenicity, mutagenicity, teratogenicity,
Mono- and Di- other chronic effects, environmental effects,
and epidemiological study
Chlorinated Paraffins Carcinogenicity, mutagenicity, teratogenicity,
other chronic effects, and environmental
effects
Chloromethane Carcinogenicity, mutagenicity, teratogenicity,
and other chronic effects
Cresols Carcinogenicity, mutagenicity, teratogenicity,
other chronic effects, and environmental
effects
Hexachloro-1,3- Environmental effects
butadiene
Nitrobenzene Carcinogenicity, mutagenicity, and
environmental effects
Toluene Carcinogenicity, teratogenicity, other
chronic effects, and epidemiological study
Xylenes Mutagenicity, teratogenicity, and
epidemiological study
The Committee's reasons for each recommendation and a more detailed
definition of each of the categories are presented in Section 3.2.
The Committee expects that the precise definition of each category
will be considered further by EPA in the course of developing testing
rules. The Committee also recognizes that certain members of a
category may already have been adequately tested for one or more of
the effects for which testing of the category has been recommended.
In that case, no further testing for that combination of substance and
effect would be needed.
A dossier summarizing the Information considered by the Committee in
selecting each substance or category will be forwarded to EPA in the
next few weeks. The Committee will continue its review of the
remaining substances and categories already selected for detailed
review, and may identify and review others, in anticipation of its
next report.
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INITIAL REPORT OF THE TSCA INTERAGENCY TESTING COMMITTEE
TO THE
ADMINISTRATOR, ENVIRONMENTAL PROTECTION AGENCY
October 1, 1977
CHAPTER 1. INTRODUCTION
1.1 BACKGROUND
Section 4(e) of the Toxic Substances Control Act (P.L. 94-469,
hereafter referred to as TSCA) established the TSCA Interagency
Testing Committee. That Committee has the continuing responsibility
to identify and recommend to the Administrator of the Environmental
Protection Agency chemical substances or mixtures which should be
tested to determine their hazard to human health or the environment.
The statute provides that the Committee shall make its initial
recommendations to EPA by October 1, 1977.
To carry out this responsibility, the Committee has developed and
executed a multi-step screening procedure to identify for its detailed
review a number of chemical substances and categories of chemical
substances expected to have a high priority for testing based on the
criteria set forth in Section 4(e)(l)(A) of TSCA. The Committee
received extensive technical support in this screening, and in the
gathering of data on substances and categories selected for detailed
review, from Clement Associates, Inc. under a contract with the
National Science Foundation. After reviewing the information
available to it on each candidate, including public comments submitted
in response to the Committee's July, 1977, publication of a
preliminary list of substances under consideration, the Committee has
selected the ten substances and categories being recommended to the
EPA Administrator in this report. As required by the statute, the
Committee will continue its review process, reporting to the EPA
Administrator within six months from the date of this report such
additional recommendations as the Committee finds desirable during
that period.
This report documents the procedures used by the Committee in
selecting those substances and categories now being recommended for
testing, and, as required by the statute, provides the Committee's
reasons for making each such recommendation. In addition to the
material contained in this report, the Committee is now finalizing a
series of dossiers developed by its technical support contractor which
will summarize all of the non-confidential information considered by
the Committee in deciding to recommend each substance or category for
testing. These dossiers will be transmitted to the EPA in a few weeks.
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1.2 COMMITTEE ESTABLISHMENT AND RESPONSIBILITIES
The Committee, as established by Section 4(e) of TSCA, has eight
members, appointed by the eight Federal agencies identified for
membership in Section 4(e)(2)(A) of the Act. In addition, a number of
alternates have been designated as permitted by Section 4(e)(2)(B)(i).
The Committee has adopted the name "TSCA Interagency Testing
Committee", which is frequently shortened in this report to
"Committee". As provided by Section 4(e)(2)(B)(iii), it has selected
a chairman from among its members. The Committee has also invited
several other Federal agencies with programs related to the control of
toxic substances, but which were not included in the statutory
membership of f.he Committee, to designate liaison representatives to
attend Committee meetings. Current Committee members, alternates, and
liaison representatives are identified in the frontispiece.
The Committee's testing priority recommendations are required by
Section 4(e) to be published in the Federal Register and transmitted
to the EPA Administrator within nine months of the January 1, 1977,
effective date of TSCA. At least every six months thereafter, the
Committee is required to review its recommendations and make such
revisions as are necessary.
The Committee's recommendations are to be in the form of a list of
chemical substances or mixtures set forth, either individually or in
groups, in the order in which the Committee determines the EPA
Administrator should consider taking action under Section 4(a) in
developing and promulgating testing regulations. The Committee is
authorized to designate up to 50 of these substances or groups for
which the EPA Administrator must within 12 months either initiate
rulemaking requiring their testing or publish reasons for not taking
such action.
In developing its recommendations, the Committee is directed by
Section 4(e)(l)(A) of TSCA to consider, along with all other relevant
factors: the production volume, environmental release, occupational
exposure, and non-occupational human exposure to the substance or
mixture; the similarity of the substance or mixture in question to
others known to present unreasonable risk of injury to health or the
environment; the extent of data on the effects of the substance or
mixture In question on health or the environment and the extent to
which additional testing of the substance or mixture may produce data
from which effects can reasonably be determined or predicted; and the
reasonably foreseeable availability of facilities and personnel for
performing the testing being recommended. The Committee is also
directed by Section 4(e) to give priority attention in establishing
its list of recommendations to substances or mixtures which are known
or suspected to cause or contribute to cancer, gene mutations, or
birth defects.
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The Committee's specific reasons for including each substance or
mixture in its recommendations are required to be published in the
Federal Register and transmitted to the EPA Administrator along with
the priority list.
While Section 4(e) refers to the Committee's recommendations as a list
of "chemical substances and mixtures", Section 26(c)(l) authorizes the
EPA Administrator to take actions (including the promulgation of
Section 4(a) testing regulations) with respect to categories of
chemical substances or mixtures as well. A category is defined in
TSCA as a group whose members are similar in molecular structure; in
physical, chemical, or biological properties; in use; in mode of
entrance into the human body or into the environment; or in any other
way, so long as the grouping is not based solely on its members being
"new chemical substances" as defined in the Act. Since the EPA
Administrator is authorized to promulgate testing regulations for
categories of chemical substances or mixtures, the Committee has
concluded that its recommendations to the EPA Administrator may also
include categories (or groups) of chemical substances or mixtures, as
well as individual substances and mixtures. This conclusion is
consistent with Section 4(e) which states that the Committee's
recommendations for testing "shall be in the form of a list of
chemical substances and mixtures which shall be set forth, either by
individual substance or mixture or by groups of substances or
mixtures... ."
In order to maintain consistency in this report and in keeping with
its meaning in TSCA, the term "category" will be used to reflect
groupings of substances. "Substance" will be used to refer to both
individual chemicals as well as mixtures.
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CHAPTER 2. DEVELOPMENT OF THE COMMITTEE'S INITIAL RECOMMENDATIONS
2.1 SELECTION OF THE COMMITTEE'S BASIC APPROACH
Estimates of the number of chemical substances and mixtures subject to
TSCA range from tens of thousands to over 100)000; the number and
Identities of these substances and mixtures will not be established
until after the completion of the chemical inventory under Section
8(b) of TSCA. Nevertheless, all of these substances and mixtures,
together with others which may be manufactured in the future, are
subject to the promulgation of testing rules under Section 4(a) and are
thus within the purview of the Interagency Testing Committee.
At the same time, Section 4(e) of TSCA specifies a number of factors
which the Committee is to consider in determining whether to recommend
a substance for testing. Careful consideration of these factors
requires the collection and review of a sub jtantial amount of data
concerning the production, use, chemical and biological activity, and
previous testing of each substance or category of substances under
consideration.
As a result, because of the lack of a comprehensive and readily
accessible data base on current chemicals, the large number of
potential candidates for the Committee's consideration, and the
statutory deadline for the Committee's initial recommendations to EPA,
the Committee has had to select for its detailed consideration only a
small subset of the possible candidates.
In considering alternative approaches to selecting a limited number of
substances for detailed review, the Committee met with a number of
experts on chemical data systems and chemical characterization.
Several possible approaches were identified. One was a nomination
approach in which Committee members or other experts would nominate
specific chemicals for consideration. Another was to use
structure-activity relationships to identify for review substances
chemically similar to others of known hazard. Yet another approach
was to focus the Committee's attention on those substances known to
have high levels of production volume, environmental release, or human
exposure.
After considering these alternatives, the Committee decided to adopt a
combined strategy employing features of each. This resulted in a
multi-step screening process wherein a relatively large number of
substances were considered initially and at each subsequent step a
smpTler subset was selected for collection of more data and more
intensive review.
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The basic steps in the process adopted by the Committee, which are
illustrated in Figure 1 and are described in more detail in
subsequent sections, were as follows:
a. Establishment of an INITIAL LISTING of about 3,650
substances and categories of substances previously
identified as potential hazards to human health or
the environment,
b. Compilation of a smaller MASTER FILE (about 1,700
substances and categories) through elimination from
the INITIAL LISTING of substances not in commercial
production or used predominantly as pesticides, food
additives, or drugs,
c. Selection of a PRELIMINARY LIST of about 330 substances
and categories for further consideration based on
evaluation of the production volume, environmental
release, occupational exposure, and general human
exposure levels of the substances in the MASTER FILE,
d. Selection of about 80 substances and categories for
detailed review based on evaluation of the potential
biological activity and need for health and ecological
effects testing of substances appearing on the
PRELIMINARY LIST,
e. Selection of substances and categories recommended
for testing after review of preliminary dossiers
prepared by the Committee's contractor, public
comments on the PRELIMINARY LIST, and other pertinent
information available to the Committee from
various agencies,
f. Documentation of the Committee's reasons for including
each substance or category in its list of
recommendations and completion of a final dossier
summarizing the information considered by the Committee
in reaching its decision.
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STEPS IN SELECTION PROCESS
MERGING OF SOURCE LISTS
!SE£ APPENDIX A)
ETC.
-80140.. ol 10/1/77)
10 Jlol 10/1/77
INITIAL
LISTING
MA
* F
EXCLUSION OF:
• DRUGS
• FOOD ADDITIVES
• PESTICIDES
*
NON-COMMERCIAL
CHEMICALS
iTER
LE *'
PRELIMINARY
LIST
/ PUBLIC I/ 1
fc /COMMENTS ON/ /PRELIMINARY/ COMt
/ PRELIMINARY/ / DOSSIERS / SELE
/ "-.ST / / /
SCREENING FOR: SCREENING FOR: DETAILED
REVIEW
• POTENTIAL FOR • HEALTH EFFECTS
ENVM,ARONAMENTAL - ENVIRONMENTAL EFFECTS
EXPOSURE • TESTING NEEDS
rflTTEE
CTIONS
• SUBMIT TO EPA
ADMINISTRATOR
• PUBLISH IN FEDERAL
REGISTER
ELIMINATION OF
CHEMICALS:
• REGULATED
• WELL CHARACTERIZED
» CONSIDERED INERT
• POORLY CHARACTERIZED
NATURAL PRODUCTS
• INSUFFICIENT INFORMATION
FIGURE 1. SELECTION SCHEME USED BY THE TSCA INTERAGENCY COMMITTEE IN SELECTING ITS INITIAL RECOMMENDATIONS
TO THE EPA ADMINISTRATOR (OCTOBER 1977)
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Carrying out this multi-step process required the collection, review,
coding, and analysis of data on a large number of chemical substances,
as well as the application of scientific judgment in many areas where
adequate data were unavailable. The Committee was supported
extensively in these efforts by Clement Associates, Inc. under a
contract with the National Science Foundation (Contract No. NSF ENV77-
15417 with partial funding by the NIEHS and NCI. The contractor employed
expert consultants from a variety of disciplines in carrying out its tasks
under the contract. In addition, many U.S. Government agencies made
data and expertise of their employees available to the Committee for
these efforts.
Several of the steps of the Committee's procedure employed
quantitative scoring of the substances under consideration. Members
of the Committee used their professional expertise and judgment in
applying these scores to the decisions at each step.
2.2 ESTABLISHMENT OF THE INITIAL LISTING
In order to focus its initial attention on substances likely to
require health and/or ecological effects testing, and for which
sufficient preliminary data were likely to be available to permit more
detailed reviews at later steps, the Committee chose to limit its
initial consideration to substances or categories of substances which
had already been identified in previous reviews as being of concern
because of potential adverse effects on human health or the
environment or as having large production volumes and a potential for
substantial human exposure or environmental release. Nineteen
separate source lists of this type were identified by the Committee
and pooled to produce the INITIAL LISTING of about 3,650 substances,
mixtures, and categories. The individual source lists are identified
and described briefly in Appendix A.
2.3 REDUCTION TO THE MASTER FILE
The INITIAL LISTING included a number of substances having pesticide,
food additive, or drug uses, all of which are regulated under other
Federal statutes and are exempted from regulation by TSCA. To
identify them, the INITIAL LISTING was compared with lists of
pesticides prepared by the EPA and lists of food additives and drugs
prepared by the Food and Drug Administration, using Chemical Abstracts
Service (CAS) Registry Numbers. This initial purge of substances
subject to other statutes was incomplete, since some entries on source
lists did not include CAS numbers. To compensate for this, a further
manual purging was required. Consideration was also given to the fact
that a substance used as a pesticide, food additive or drug may also
have other uses that are subject to the authority of TSCA. Since
pesticides, food additives, and drugs are generally produced in
limited volumes, substances identified as such but having annual
production over 10 million pounds were considered likely to have other
uses as well and were retained on the truncated list for further
review of their uses. Substances identified as pesticides, food
additives, or drugs but known to the Committee or its contractor to
have other uses within the jurisdiction of TSCA were also retained.
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The resulting file was reduced further by the elimination of chemicals
which were judged not likely to be in commercial production. This was
accomplished by comparing the file against EPA's Candidate List of
Chemical Substances, prepared by the Office of Toxic Substances (dated
April 1977). Again, the basis of comparison for this purge was an
assigned CAS number. Consequently, this purge did not affect those
chemicals on source lists for which no CAS number was given. In an
attempt to eliminate substances which are not in commercial
production, the following rule was adopted: any substance not
identified by a CAS number which appeared on the NIOSH Registry
(Source List 13 of Appendix A) and on none of the other source lists
was judged not likely to be in commercial production. This decision
was based on the fact that the NIOSH Registry lists any substance for
which toxic effects have been reported, including research chemicals.
A scan of the substances eliminated by the application of this rule
demonstrated its usefulness: few of the purged substances were
recognized to be in commercial production,
As a result of the purges described above, a MASTER FILE of
approximately 1700 substances emerged.
2.4 SELECTION OF THE PRELIMINARY LIST
Having developed a MASTER FILE of substances to be considered for
possible recommendation to EPA for testing, the Committee began to
apply the eight factors explicitly identified for its consideration in
Section 4(e)(l)(A). While recognizing that there would be advantages
to applying all of the first seven factors* simultaneously in
evaluating the relative priorities for detailed review of the
substances under consideration, the Committee concluded that
assembling and evaluating the necessary data for all substances on the
MASTER FILE would not be feasible within the time schedule established
by statute, considering the limitations of current chemical
information systems and the number of professional judgments which
would have to be made. Evaluation of the fifth, sixth, and seventh
factors (relating to chemical similarity to substances of known
hazard, existing health and environmental effects data, and need for
testing) was anticipated to require more independent review and
judgment and to be the more time-consuming portion of the task.
Hence, the Committee decided to further reduce the number of
substances under consideration before explicitly evaluating those
factors which had, to some extent, already been reflected in the
choice of source lists.
The eighth factor, the reasonably forseeable availability
of facilities and personnel for performing the needed
testing, was considered principally by the Committee in
terms of the aggregate facilities and personnel needs for
carrying out all of the Committee's recommendations. See
Section 2.8 for further discussion of this factor.
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This reduction, which resulted in the selection of the PRELIMINARY
LIST, was based principally on evaluation of the first four factors
identified for the Committee's consideration in Section 4(e)(l)(A) of
TSCA. These are:
(i) quantity of the substance produced annually
(ii) amount of the substance released into the
environment
(ill) number of individuals occupationally
exposed and duration of their exposure
(iv) extent to which the general population
will be exposed.
Using a combination of published data and judgment, the Committee's
contractor made an attempt to score each substance in the MASTER FILE
for these four factors. Appendix B describes in more detail how
scores were assigned to substances. Information on the use or uses of
a substance was critical to the assignment of scores for environmental
release and general population exposure, and scores for those factors
could not be assigned if use information could not be found by the
contractor. For about 1,000 of the 1,700 substances in the MASTER
FILE this was the case; as a result, for only about 700 of the
substances was it possible to assign scores. By combining the scores
for the four factors, as described in Appendix C, a rank-ordered list
of the scored substances was prepared for the Committee's
cons ideration.
In selecting the approximately 330 substances and categories included
on the PRELIMINARY LIST, the Committee considered all of the scored
substances and eliminated from current consideration a number of them
which in the Committee's professional judgment were found to be:
a. Currently under stringent regulation or of lower
priority for the Committee's purposes
because their hazard is reasonably well
characterized (e.g., vinyl chloride and
mercury);
b. Essentially inert materials (e.g. certain
polymers) or substances reasonably well
characterized as having low toxicity (e.g.,
methane);
c. Covered by testing requirements under food,
drug and cosmetic or pesticide legislation
(e.g., citric acid); or
d. Certain natural products (e.g., asphalt)
whose consideration should be deferred pending
better characterization for testing purposes.
Others of the scored substances were specifically selected by the
Committee for inclusion on the PRELIMINARY LIST based on judgment of
members that further review was needed. The remainder of the scored
substances were considered for inclusion on the PRELIMINARY LIST based
on their relative ranking in the scoring process.
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In addition to the scored substances, the Committee also considered in
selecting the PRELIMINARY LIST the unscored substances from the MASTER
FILE and a limited number of additional substances recommended by
Committee members or the Committee's contractor. A number of
substances from these sources were included on the PRELIMINARY LIST
based on the Committee's knowledge of the substance and its uses or
the Committee's professional judgment that the substance should be
further evaluated.
In reviewing substances for possible inclusion on the PRELIMINARY
LIST* the Committee also considered the desirability of grouping
substances into categories. In several cases the Committee grouped
chemically-related substances from the MASTER FILE while in other
cases the Committee retained groups which had already appeared in one
of the source lists. About 15% of the entries on the PRELIMINARY LIST
were categories.
2.5 PUBLIC COMMENT ON THE PRELIMINARY LIST
The PRELIMINARY LIST, together with a background document describing
its development, was published by the Committee in July, 1977. Notice
was published by the Committee in the Federal Register (42 FR 30531
and 42 FR 40756) announcing the availability of the list and
background document and requesting public comment. Comments were
specifically requested on:
a. The methodology used by the Committee in
developing the PRELIMINARY LIST;
b. Substances not appearing on the PRELIMINARY
LIST which commentors might recommend for
consideration by the Committee and the
commentor's reasons for the recommendation;
c. Substances appearing on the PRELIMINARY LIST
which commentors might recommend that the
Committee not consider further and the reasons
for that recommendation; and
d. Comments on the needs for and relative priority
of testing of the substances being considered by
the Committee.
As an additional aid to commentors and others interested in the
Committee's activities, copies of the list of substances comprising
the MASTER FILE and a tabulation of the scores for production volume,
environmental release, and occupational and general population
exposure considered by the Committee in selecting the PRELIMINARY LIST
we^ made available for public inspection at the headquarters and
regional offices of the Environmental Protection Agency.
Comments on the PRELIMINARY LIST were received from about 65
industrial firms, trade associations, environmental organizations,
government agencies, and individuals. About two-thirds of the
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commentors reconnnended deletion from the Committee's further
consideration of one or more substances or categories appearing on
the PRELIMINARY LIST, while four commentors recommended additional
substances for the Committee's consideration. About one-fifth of the
commentors included comments on the methodology employed by the
Committee in developing the PRELIMINARY LIST and about one-third
included comments on other issues related to the Committee's
activities. Such issues were the use of categories in the Committee's
recommendations to EPA, documentation of the Committee's reasons for
its decisions with respect to specific substances, and provision of
opportunity for public comment on the Committee's actions.
Public comments on the PRELIMINARY LIST have been reviewed by the
Committee and considered in the development of the Committee's initial
recommendations. Four of the seven additional substances recommended
by commentors were added to the PRELIMINARY LIST for consideration in
selecting substances and categories for detailed review. Because of
the large number of comments recommending deletions of substances from
the Committee's consideration and the limited time available under the
statutory deadline, pertinent comments were considered on a
substance-by-substance or category-by-category basis during the
Committee's review of preliminary dossiers and consideration of
reasons for and against recommending testing. Comments on the
Committee's methodology have been reviewed and will be considered in
subsequent activities of the Committee. In the Committee's judgment,
the recommended changes in methodology would not, if implemented,
alter its initial recommendations. Comments dealing with use of
categories, documentation of the Committee's reasons for actions, and
other more general issues were also reviewed and considered in the
development of the Committee's recommendations.
2.6 SELECTION OF SUBSTANCES FOR DETAILED REVIEW
This step of the Committee's procedure extended the scoring of the
substances under consideration to factors (v) through (vii) of Section
4(e)(l)(A). These factors are:
(v) the extent to which the substance or
mixture is closely related to a chemical
substance or mixture which is known to
present an unreasonable risk of injury to
health or the environment;
(vi) the existence of data concerning the effects
of the substance or mixture on health or the
environment; and
(vli) the extent to which testing of the substance
or mixture may result in the development of
data upon which the effects of the substance
or mixture on health or the environment can
reasonably be determined or predicted.
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To accomplish this, each substance on the PRELIMINARY LIST was scored
for each of seven biological activity factors by a number of experts
available through the Committee's contract. The factors were:
carcinogenicity, mutagenicity, teratogenicity, acute toxicity, other
toxic effects such as reproductive effects or organ-specific toxicity,
bioaccumulation,1 and ecological effects. After reviewing a summary of
information on the biological activity of the substance developed by
the contractor based on the open literature, each of the contractor's
scorers assigned a score to the substance for the effect(s) for which
that scorer was responsible.
A total of nine scorers was used by the contractor, with two or three
scorers separately evaluating each effect in most cases. Each scorer
considered both the summary information provided by the contractor and
his personal knowledge of the substance and chemically-related
substances in assigning scores. Any substantial discrepancies among
individual scorers were identified, discussed among the scorers, and a
consensus reached; in the case of minor discrepancies in the scores
for any factor, the scores of the several scorers were averaged.
In addition, three of the effects (carcinogenicity, mutagenicity, and
ecological effects) were separately scored by government experts from
the National Cancer Institute, National Center for Toxicological
Research, and Department of Interior, respectively. These scores were
averaged with those of the contractor's scorers.
Scores assigned for the various effects took the form of either a
numerical score (generally 0, 1, 2, or 3) or a letter score (generally
x, xx, or xxx). Assignment of a numerical score indicated a judgment
that further testing of the substance is not needed for the effect
under consideration, while the magnitude of the score indicated the
degree to which the effect had been confirmed or the dose level at
which it had been found. Assignment of a letter score, on the other
hand, indicated a judgment that further testing should be carried out,
with the number of "x's" assigned reflecting a judgment as to the
level of numerical score that might be anticipated after testing. For
example, in scoring a substance for carcinogenicity a score of 3 meant
that the substance is well established as a carcinogen in humans or
experimental animals, while a score of xxx meant that the substance is
strongly suspected of carcinogenic activity but has not been
adequately tested. In averaging the scores assigned to a substance by
the several scorers for a given factor, no mixing of numerical and
letter scores was permitted. Any discrepancies between scorers in
chosing the numerical or letter scale were discussed among the scorers
and resolved. The criteria applied by the scorers in assigning scores
for the various factors are described in more detail in Appendix D.
Categories of substances appearing on the PRELIMINARY LIST were not
generally scored as entities, but rather, scores were assigned
separately for each of the example substances listed under the
category heading in the list.
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Using these scores, the contractor provided the Committee a. series of
lists of the substances appearing on the PRELIMINARY LIST ranked
according to various criteria. These included separate lists for each
factor ranked by the average score a substance received for that
factor (identifying those substances judged most in need for testing
for a single effect) and a list ranked by the sum of the letter scores
received by a substance for all factors (identifying substances
requiring testing for a number of effects). Also tabulated on each
list was an exposure index for each substance which was derived from
the earlier scoring of production volume, environmental release, and
occupational and general population exposure. For the human health
effects factors and total letter score lists the exposure index used
was the sum of the production volume, occupational exposure, and
general population exposure scores, while for the bioaccumulation and
ecological effects factors, the exposure index was the sum of the
production volume and environmental release scores. The Committee
also received from its contractor a list of those substances evaluated
by the scorers which werg known or might be anticipated to have
additional adverse health or environmental effects as a result of
contaminants appearing in the commercial product or degradation
products of the substance under consideration.
The Committee's selection of substances and categories from the
PRELIMINARY LIST to be carried forward for detailed review used the
various lists provided by its contractor as guides, but reflected the
independent judgments of the members of the Committee. First, the
scores themselves were reviewed, with any major discrepancies between
the contractor's scores and those of the government scorers or the
judgments of individual Committee members being considered. Then, the
Committee turned to the various ranked lists, reviewing in turn the
substances ranked most in need of testing on the sum-of-letter-scores
list or the lists for the individual factors. Each
substance appearing in the top 75 to 100 positions on one or more of
these lists was considered by the Committee and a decision made
whether to select it for detailed review.
Particular attention was paid by the Committee to substances known or
suspected to be carcinogens, mutagens, or teratogens, in keeping with
the statutory guidance provided the Committee in Section A(e)(l)(A) of
TSCA. This emphasis was reflected not only in the Committee's
consideration of individual substances and categories, but also in its
structuring of the review process, since these effects were scored
individually and, in effect, received greater attention than did other
effects scored in groups (e.g., other toxic effects or ecological effects)
Categories of substances appearing on the PRELIMINARY LIST were also
reviewed in terms of the scoring of their example members and the
Committee's Judgment as to retaining them. A number of decisions to
modify previous categories or define new categories were made by the
Committee during this review process.
In reviewing these lists, more than two-thirds of the individual
substances scored by the contractor were explicitly considered by the
Committee. Approximately eighty substances and categories were
selected by the Committee for the drafting of preliminary dossiers and
further detailed review. Of these, about half were individual
substances and half categories.
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2.7 CONSIDERATION FOR LISTING AND DESIGNATION
For each of the approximately eighty substances and categories
selected for detailed review, preliminary dossiers have been (or are
being) prepared by the Committee's contractor. Within the time period
allowed by the statute for development of the Committee's initial
recommendations, preliminary dossiers were drafted for about
one-half of the substances and categories for detailed review.
Consideration of these and other information resulted in the
initial recommendations transmitted by this report. Consideration of
the remaining substances and categories already selected for detailed
review, and others which may subsequently be selected, will continue
and will be reflected in subsequent recommendations to EPA by the
Committee.
The preliminary dossiers summarized information obtained from the open
literature relating to the identification, relevant chemical and
physical properties, production volume, uses, environmental release,
and exposure to the substance under consideration as well as
information on the nature and findings of previous studies of its
human health and environmental effects, information on the biological
activity of other chemically similar substances was also included
where available. Preliminary dossiers for categories of substances
included these types of information for specific members of the
category, generally the example members identified in the PRELIMINARY
LIST.
Using the information summarized in the preliminary dossier, together
with information submitted in public comments on the PRELIMINARY LIST,
information available to the Committee from various Federal agencies,
and the members' individual knowledge, the Committee reviewed each
substance or category. Each of the factors specified in Section
4(e)(l)(A), as well as any other relevant factors identified by the
Committee on a case-by-case basis, was considered. In particular, in
considering factor (vi) of Section 4(e)(l)(A), the existence of data
concerning the effects of the substance on helath or the environment,
the Committee considered test programs currently in progress, as well
as data already generated. Another factor considered in certain
instances was the status of current regulatory action relative to the
substance. In each case where a category of substances was under
consideration the appropriate definition of the category and the need
for data on all members of the category were considered. Where relevant
to the particular type of testing under consideration for a substance or
category, factor (viii) of Section A(e)(l)(A), the availability of
test facilities- and personnel, was discussed on a case-by-case basis.
In general, however, this factor was considered in the aggregate after
the Committee's tentative recommendations for all substances and
categories had been identified. The Committee's consideration of this
lector is discussed further in section 2.8 of this report.
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After reviewing end thoroughly discussing the information available to
the Committee on the substance or category under consideration, a
decision was made regarding whether to recommend the development of
test rules by EPA and, if so, for which effects. Subsequently, one or
more Committee members participated in the drafting of the supporting
reasons for each recommendation and these reasons were again reviewed
by the Committee. A final decision to recommend the substance or
category for testing represents a consensus by the Committee members
that such testing is needed to evaluate the effects of the substance
(or of each individual substance falling within the definition of a
category) on human health and the environment, and that priority
attention should be given by EPA to requiring the conduct of such
testing. The Committee recognized, of course, that some members of
recommended categories may have already been adequately tested for the
effects of concern and would not require further testing.
Several substances and categories reviewed by the,Committee were
deferred for further consideration because of insufficient information
to adequately define the categories or to determine the needs for
testing.
Assignment of priority order to the substances and categories
recommended for testing was also considered. The Committee concluded
that all of the substances and categories being recommended at this
time should be given equal priority in EPA's development of test
rules. Factors contributing to this decision were the limited number
of recommendations being made, the Committee's decision to designate
all recommended substances and categories for consideration by EPA
within 12 months, and the Committee's understanding of EPA's plans to
develop its test rules for various effects, e.g., carcinogenicity,
rather than for individual substances or categories. The Committee
recommends that these substances and categories be included in the
first applicable "effects rule".
2.8 CONSIDERATION OF AVAILABILITY OF TESTING FACILITIES AND PERSONNEL
One of the criteria listed in Section 4(e)(l)(A), that the Committee
was required to consider, is the reasonably foreseeable availability of
facilities and personnel for performing the testing it recommends.
The Committee reviewed the results of recent surveys of toxicology
testing capabilities conducted by the Society of Toxicology (SOT) and
the DHEW Committee to Coordinate Toxicology and Related Programs
(CCTRP). While the SOT surveyed general toxicology testing
capabilities, the CCTRP specifically assessed inhalation test
capabilities. The Committee also reviewed the capabilities and
plans of the National Center for Toxicological Research (NCTR), the
possible impact of the FDA's Good Laboratory Practices, and the
logistics and practical considerations for carcinogenicity,
mutagenicity, and reproductive effects testing. It also was briefed
on ecological test capabilities and needs in that area.
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Based upon these reviews, the Committee has concluded that there are
sufficient toxicology testing capabilities in the U.S. to carry out
the health effects testing recommended by the Committee in this
report.
A more difficult area to assess was that of environmental or ecological
testing. Capabilities for acute studies are probably adequate, but
the National capability for conducting long-term tests of chemical
pollution on the environment will be less certain until the test
standards and protocols are defined through the rulemaking process.
The Committee feels, however, that the testing burden likely to
result from recommendations in this report is reasonable.
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CHAPTER 3. RECOMMENDATIONS OF THE COMMITTEE
3.1 SUBSTANCES AND CATEGORIES OF SUBSTANCES RECOMMENDED FOR TESTING
As described in Chapter 2 of this report, the Committee has, with the
assistance of a technical support contractor, carried out a multi-step
screening procedure to identify for its detailed review a limited
number of substances and categories of substances likely to have
priority for testing to determine their effects on human health and
the environment. A number of substances and categories identified by
this process have been reviewed by the Committee, which has given
careful consideration to each of the eight factors specified in
Section 4(e)(l)(A) of TSCA. The Committee has also considered such
other factors as it judged relevant on a case-by-case basis. Such
additional factors have included test programs currently in progress,
the current status of regulatory action with respect to a substance,
and the need for test data on all members of certain categories rather
than on one or more individual members of the category.
The eighth factor specified in Section 4(e)(l)(A) for the Committee's
consideration, the reasonably foreseeable availability of facilities
and personnel for performing the recommended testing, has (as
described in Section 2.8 of this report) been considered by the
Committee with respect to the aggregate requirements of all of the
testing recommendations made here, as well as for each individual
testing recommendation. In the Committee's judgment there are, or can
be made available within the next few years, adequate facilities and
personnel for conducting the testing now being recommended by the
Committee. Furthermore, any specific limitations of facilities or
personnel which cannot now be identified by the Committee would be
expected to be short-term in nature and can be taken into account by
EPA in establishing the time periods for submission of the test data
under Section 4(b)(l).
In selecting substances and categories for inclusion in its initial
recommendations, the Committee has also given priority attention to
substances known or suspected to cause cancer, gene mutations, or
birth defects.
Based on its consideration of the factors identified in Section
4(e)(l)(A) and all other relevant factors identified by the Committee,
and using all of the information available to it, including the
knowledge and professional judgment of its members, it is the
consensus of the TSCA Interagency Testing Committee that the ten
substances and categories of substances listed in the accompanying
table should be given priority consideration by the Administrator of
the Environmental Protection Agency for the promulgation of
regulations under Section 4 (a) requiring the conduct of the types of
testing specified. Each of these substances and categories is
designated by the Committee for consideration by EPA within the next
12 months.
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SUMMARY OF TESTING RECOMMENDATIONS
BY THE
TSCA INTERAGENCY TESTING COMMITTEE
Substance Carcinogenic! ty Mutagenicity
or Category
Alkyl Epoxides X X
Alkyl Phthalates
Chlorinated Benzenes, X X
(Mono- and Di-)
Chlorinated Paraffins X X
Chlorome thane X X
Cresols X X
Hexachloro-
1,3-butadiene
Nitrobenzene X X
Toluene X
Xylenes X
j.ypes or lesting Kecommenaea
Teratogenicity Other Chronic
Effects
X X
X X
X X
X X
X X
X X
X
Environmental
Effects
X
X
X
X
X
X
X
Epidemiological
Study
X
X
X
X
00
Table 1
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In listing and designating these ten substances and categories, the
Committee has decided that all should be given equal priority by EPA
in the development of test rules under Section 4 (a) of TSCA. All are
of high priority and should be included in the first applicable
"effects rule" (e.g., carcinogenicity) developed by EPA.
In selecting categories of substances for inclusion in its
recommendations, the Committee recognizes that some members of a
category may have already been adequately tested for one or more of
the effects listed; in such cases no additional testing would be
required. The Committee also recognizes that the precise definition
of each category will have to be considered and decided by EPA in
developing its test rules.
The Committee's reasons for including each substance or category of
substances on its list of recommendations, which are required by
Section 4(e)(l)(B) to be submitted with the Committee's
recommendations, are presented in the following section. In addition,
the Committee will forward to EPA in the next few weeks a dossier on
each substance or category included on the Committee's list of
recommendations. These dossiers will summarize the information
pertaining to each substance or category which was considered by the
Committee in making its decision to recommend testing.
3.2 REASONS FOR RECOMMENDING TESTING OF THE SUBSTANCES AND
CATEGORIES
The ten substances and categories which the Committee has designated
for consideration by the EPA Administrator for development of test
rules within twelve months are listed below with the Committeie's
reasons for recommending them.
3.2.A ALKYL EPOXIDES
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
Epidemiology
CATEGORY IDENTIFICATION: This category includes all noncyclic
aliphatic hydrocarbons with one or more epoxy functional .groups.
REASONS FOR RECOMMENDATIONS:
Production, Release and Exposure: Although these compounds are
generally used as industrial intermediates, several alkyl epoxides are
produced in very large quantities (e.g., ethylene oxide at over 4
billion pounds per year). The vast amounts produced thus raise
concerns primarily with respect to workplace exposure. The reactivity
of these compounds is such that environmental persistence is not
anticipated; however, their reaction products may be of significance.
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EFFECTS OF CONCERN: The epoxy structure Is a relatively reactive
functional group which is believed to be the source of the
carcinogenic and mutagenic activity which is well characterized for
several members reviewed (particularly the diepoxides). Thus, while
some members of the group appear to be relatively well characterized
as potential mutagens and/or carcinogens, these results and the
presence of the epoxy functional group raise the need for testing
other compounds in this group for these and other effects.
Carcinogenicity: Diepoxides are demonstrated carcinogens in animal
studies. Ethylene oxide proved inactive while propylene oxide showed
carcinogenic activity in mice. Other alkyl epoxides are less well
tested. Because of the alkylating properties of these compounds it is
recommended that alkyl epoxides be tested for carcinogenic potential.
Mutagenicity of most members of this group tested provides further
concern for carcinogenic potential.
Mutagenicity; Because most members of this group which have been
tested proved to be mutagenic; other members of this group should be
tested for this effect.
Teratogenicity: In general, these compounds have not been adequately
tested for teratogenicity but should be, considering the reactivity of
the epoxy group toward biological materials.
Other Chronic Effects: Because of the reactivity of epoxides with
biological materials, they should be tested for specific chronic organ
effects and behavioral changes.
Environment Effects; While the persistence of these compounds as
epoxides is not great, concern is expressed for reaction products. In
view of this possibility, the fate of epoxides in the environment
should be determined through testing.
Epidemiology: Because of the large scale production of several
of these compounds, and because of the strong toxicological
evidence of possible carcinogenic and mutagenic effects,
the Committee recommends that retrospective epidemiologic studies be
required for two or three of the highest exposure compounds when
suitable cohorts can be identified.
3.2.B ALKYL PHTHALATES
TESTING RECOMMENDATIONS:
Environmental Effects
CATEGORY IDENTIFICATION: This category consists of all high
production (e.g., 10 million Ibs/yr or greater) alkyl esters of
1,2-benzene dicarboxylic acid (orthophthalic acid).
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REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure; Many of these compounds are
produced in large volume, some of them over one hundred million pounds
per year. Their use as plasticizers in a wide variety of products
results in large volumes of alkyl phthalates reaching the aquatic
environment either as wastes from formulating plants or from use and
disposal of end products.
Effects of Concern:
Environmental Effects; Many of the alkyl phthalates are quite stable,
breaking down only slowly to monophthalates or phthalic acid.
There has been a great deal of information published on their
environmental fate and toxicity to aquatic organisms. Some are known
to have considerable toxicity to fresh water fish. In view of the
large volume in which they can be expected to reach the aquatic
environment and persist and accumulate in aquatic organisms, it is
important to have data on the toxicity to aquatic organisms of all
high production alkyl phthalates. Each such compound should be tested
for chronic toxicity to typical aquatic organisms, especially fish.
Effects on reproduction (or population) should be included in this
testing.
3.2.C CHLORINATED BENZENES. MONO- AND DI-
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
Epidemiology
CATEGORY IDENTIFICATION: This category consists of four
closely-related chemical substances: monochlorobenzene (CAS No.
108-90-7), and ortho-, meta-, and paradichlorobenzene (CAS Nos.
95-50-1, 541-73-1, and 106-46-7).
REASONS FOR RECOMMENDATIONS:
Production, Release and Exposure; The chlorobenzenes are produced in
large quantities, monochlorobenzene over 300 million pounds/year and
ortho- and para-dichlorobenzene approximately 50 million pounds each.
These chemicals are widely used in industrial processes, as solvents,
and in many consumer products. Therefore, the exposure and potential
for hazard is great, particularly in light of their high release rate
and anticipated persistence in the environment.
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Effects of Concern:
Careinogenicity; One very limited animal study suggested the
induction of sarcomas following subcutaneous injections of
para-dichlorobenzene. A possible association of several cases of
leukemia with human exposure to mixtures of ortho- and
para-dichlorobenzenes has also been reported. These studies, as well
as other animal toxicity experiments, do not provide sufficient data
on which to assess the carcinogenic potential of members of this
class.
Mutagenicity: While a study has demonstrated back mutations in yeast
exposed to ortho-dichlorobenzene, the data are inadequate to assess
the potential mutagenic hazard. Additional testing is needed in view
of the widespread release and exposure. The other chemicals in this
class should also be tested for mutagenicity.
Teratogenicity; While teratogenic effects are suspected for certain
higher chlorobenzenes, the mono- and dichlorobenzenes have not been
adquately tested.
Other Chronic Effects; Liver, kidney, respiratory and neurological
effects have been observed with high level exposures. Effects at
lower levels cannot be characterized from existing data. Chronic
studies should be undertaken.
Environmental Effects; The environmental fate of these compounds
should be determined. Evidence exists for environmental pollution and
bioaccumulation in aquatic life. The effects are unknown. Studies
should be initiated to assess the impact of these chemicals on
terrestrial and aquatic systems.
Epidemiology; A possible link has been made between exposure to
ortho- and para-dichlorobenzene and leukemia. Further efforts to
evaluate chronic effects should be made by the identification and
evaluation of specific populations who are or have been exposed to
either ortho- or paradichlorobenzene.
3.2.D CHLORINATED PARAFFINS, 35-64% CHLORINE
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
CATEGORy IDENTIFICATION: This category is comprised of a series of
mixtures of chlorination products of materials known commercially as
paraffin oils or paraffin waxes; those having a chlorine content of
35% through 64% by weight are included.
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REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure; The 1972 annual production of
chlorinated paraffins was about 80 million pounds. The use of these
materials in a wide variety of household and paint products, as well
as adhesives and flame retardants, results in an estimated release
rate of about 50 million pounds per year.
Effects of Concern:
Human Health Effects; A chronic study in mice showed evidence
of degenerative changes in the liver and spleen; no data are available
on the carcinogenicity, mutagenicity, teratogenicity, or other chronic
effects of these mixtures. The Committee recommends that commercial
products in this category be tested for such effects.
Environmental Effects; The occurrence of residues of chlorinated
paraffins in fish indicates the need for critical assessment of the
biological significance of this contamination of the aquatic
environment. The persistence, environmental fate, and chronic effects
on aquatic organisms of the chlorinated paraffins should be determined
by appropriate testing.
3.2.E CHLOROMETHANE
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
SUBSTANCE IDENTIFICATION: CAS No. 74-87-3
REASONS FOR RECOMMENDATIONS:
Production. Release, and Exposure; The 1974 U.S. production of
chloromethane was over 350 million pounds, most of this being used as
a synthetic intermediate. However, it is estimated that about 5% of
the annual production (over 15 million pounds per year) is released
into the environment. NIOSH estimates that the number of workers
exposed to chloromethane numbers about 31,000.
Effects of Concern:
Carcinogenicity; To date, chloromethane has not been the subject of a
carcinogenicity study, although it is structurally related to
chloroform, carbon tetrachloride, and iodomethane, all of which have
been reported as being carcinogenic. Moreover, chloromethane has
recently been reported as exhibiting mutagenic properties in the
Salmonella mutagenic test with microsomal activation.
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Mutagenicity; The initial positive results in the Salmonella
mutagenic test with microsomal activation should be supplemented
with test data regarding chromosomal abberrations.
Teratogenicity; The absence of data in this area, coupled with known
toxic effects, calls for the initiation of studies to determine the
extent of the potential hazard to the reproductive system and the
fetus.
Other Chronic Effects: Exposure to chloromethane has been implicated
in damage to the central nervous sytem, liver, kidneys, bone marrow
and cardiovascular systems. Effects on these systems should be
examined in chronic toxicity tests.
3.2.F CRESOLS
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Teratogenicity
Other Chronic Effects
Environmental Effects
CATEGORY IDENTIFICATION: This category consists of the three isomers
cf methyl phenol: ortho-cresol (CAS No. 95-48-7), meta-cresol (CAS No.
108-39-4), and para-cresol (CAS No. 106-44-5).
REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure; Cresols are produced in large
quantities, having a combined U.S. production in 1975 of about 90
million pounds. An annual release rate of about 45 million pounds has
been estimated. Their wide use as industrial solvents leads to
substantial occupational exposure. NIOSH estimates that roughly two
million workers are exposed to cresols. In addition, cresols are used
in many consumer products, resulting in a large general exposure.
Effects of Concern:
Carcinogenicity; Cresols have not been evaluated for carcinogenicity.
Because of widespread exposure and suggestive evidence of
mutagenic effects in certain plants, cresols should be tested for
car inogenicity.
Mutagenicity; There is some suggestion of the mutagenic potential of
cresols in certain plants, but its potential as a human mutagen has
not been assessed. It is, therefore, recommended that further
mutagenic studies be conducted.
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Teratogenicity: The teratogenicity of the cresols has not been
assessed, but such testing is needed in view of the evidence of
biological activity of cresols (see Other Chronic Effects, below) and
their widespread exposure.
Other Chronic Effects; Although toxic effects involving the central
nervous system, lungs, kidneys, liver, pancreas, and spleen have been
observed following acute exposure to cresol-containing products,
adequate testing of cresols for chronic effects following
prolonged exposure has not been reported and should be conducted.
Environmental Effects! There is evidence that creosote oils
containing cresols are acutely toxic to fish and taint fish flesh at
low concentrations. Because of their substantial release into the
aquatic environment, cresols should be tested for chronic effects on
fish and other aquatic organisms.
3.2.G HEXACHLORO-1.3-BUTADIENE
TESTING RECOMMENDATIONS:
Environmental Effects
SUBSTANCE IDENTIFICATION: CAS No. 87-68-3
REASONS FOR RECOMMENDATIONS:
Production, Release, and Exposure; Although the most recent (1974)
data available indicate that this compound is no longer commercially
manufactured in the U.S., it continues to be produced as a waste
byproduct of various chlorination processes and is also imported into
the U.S. for industrial solvent use. The release of
hexachlorobutadiene into the environment has not been quantified, but
there is good evidence of widespread distribution in the aquatic
environment.
Effects of Concern:
Environmental Effects; Hexachlorobutadiene's human health
effects are being studied in depth. It is a stable substance
which is widely distributed in the aquatic environment and has
been reported to bioaccumulate in fish and other aquatic
organisms. These factors indicate that hexachlorobutadiene
should be tested to determine its fate in aquatic systems and
its effects on invertebrates, fish, higher vertebrates, and
plant life in aquatic systems. Its appearance in some
European agricultural products suggests that its uptake by
plants and/or foraging species should also be studied.
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3.2.H NITROBENZENE
TESTING RECOMMENDATIONS:
Carcinogenicity
Mutagenicity
Environmental Effects
SUBSTANCE IDENTIFICATION: CAS No. 98-95-3
REASONS FOR RECOMMENDATIONS:
Production. Release, and Exposure; U.S. production of nitrobenzene in
1975 was about 400 million pounds. Its release to the environment has
been estimated to be about 20 million pounds annually. Although its
predominant use (97 percent of production) is in closed systems in
aniline manufacture, nitrobenzene is also an industrial solvent and dye
intermediate. General population exposure can arise from environmental
release, and from dispersive uses such as perfume in soap; cleaner for
woodwork, wood flooring and paneling; ingredient of metal polishes and
shoe blacking. Nitrobenzene liquid and vapor penetrate intact skin
readily, and the efficiency of vapor absorption by inhalation is high.
Effects of Concern:
Carcinog enic i ty; No information is available on the carcinogenicity
of nitrobenzene. Since it is biologically active, producing cellular
changes,
nitrobenzene should be tested for
carcinogenicity.
Mutagenicity; Although there is evidence of its biological activity,
no mutagenicity testing has been reported for nitrobenzene.
Mutagenicity testing should be performed.
Environmental Effects; Nitrobenzene is a relatively persistent
substance in the environment. Its low volatility, stability to light,
and low water solubility indicate that bioaccumulation is possible.
Acute effects have been demonstrated in fish. Nitrobenzene inhibits
oxygen utilization and hydrogen sulfide production in sewage
microorganisms, inhibits growth in yeast, and is toxic to various soil
bacteria and microorganisms. Additional data are needed to adequately
characterize the persistence and fate of nitrobenzene and its
matabolites in the aquatic environment. Testing is needed for such
characteristics as well as to determine the effects of chronic exposure
to nitrobenzene on fish, aquatic invertebrates, aquatic plant life, and
w&_erfowl.
26
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3.2.1 TOLUENE
TESTING RECOMMENDATIONS
Carcinogenicity
Teratogenicity
Other Chronic Effects
Epidemiology
SUBSTANCE IDENTIFICATION: CAS No. 108-88-3
REASONS FOR RECOMMENDATIONS:
Production, Release and Exposure; Toluene is produced in large
quantities with an annual production rate in excess of 5 billion
pounds. Because of its widespread use as a solvent, as well as a
multiplicity of other uses, toluene has an unusually high occupational
exposure (over 1 million workers). Its presence in many
consumer products leads to a large general exposure. Toluene is currently
being substituted for many benzene-uses and has an annual release rate
exceeding 1 billion pounds.
Effects of Concern:
Carcinogenicitv; Previous studies based solely on skin application
techniques in animals have demonstrated a carcinogenic potential for
toluene. Some of these studies were limited in design and prevented
an appropriate appraisal of the carcinogenic hazard of toluene. It
is, therefore, recommended that testing be conducted in long-term
animal experiments taking into consideration the appropriate route of
exposure.
Teratogenicity; Information is lacking on the teratogenic hazard of
this chemical, thus necessitating the initiation of studies to
determine if toluene is teratogenic.
Other Chronic Effects; Liver, central nervous system 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.
Epidemiology: Occupational studies have been conducted predominantly
on the acute toxic effects of toluene. There is little information on
chronic effects in humans from exposure to low levels of toluene over
an extended period of time. Because of its long-term use,
high human exposure, and demonstrated effects in animals,
epidemiological studies may be particularly important in assessing
the human health effects of toluene.
27
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3.2.J XYLENES
TESTING RECOMMENDATIONS:
Mutagenicity
Teratogenicity
Epidemiology
CATEGORY IDENTIFICATION: This category consists of the three isomers
of dimethyl benzene: ortho-xylene (CAS No. 95-47-6), meta-xylene (CAS
No. 108-38-3), and para-xylene (CAS No. 106-42-3)
REASONS FOR RECOMMENDATIONS:
Production, Release^ and Exposure; In the aggregate, approximately
8 billion pounds of xylenes are produced each year. Approximately 900
million pounds are released to the environment each year. Mixed
xylenes were ranked by NIOSH 13th out of approximately 7000 agents in
terms of the number of workers exposed. Xylenes are also used in a
wide variety of consumer products, resulting in general population
exposures.
Effects of Concern:
Mutagenicity; Mutagenesis tests have not been reported for any of the
xylenes, but should be conducted in view of widespread exposure and
evidence of toxic effects to several organ systems.
Teratogenicity; Xylenes cross the placental barrier and, according to
two Russian studies, are embryotoxic. Therefore, they should be
tested for teratogenicity.
Epidemiology; Because of their long-term use, high human exposure,
and demonstrated effects in animals, epidemiological studies may
be particularly important in assessing the human health effects
of xylenes and should be conducted.
28
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APPENDIX A
DATA SOURCES USED FOR PREPARATION OF THE INITIAL LIST
01 Toxic Pollutants in Point Source Water Effluent Discharge
This list of 120 chemicals and categories consists of Appendices A
and C of the settlement agreement dated 7 June 1976 between the
Environmental Defense Fund and EPA. It is a priority list of
toxic pollutants subject to regulations through point source
effluent limitations CSectlon 307Ca)) under the Federal Water
Pollution Control Act.
02 Scoring of Organic Air Compounds, June 1976, MITRE, MTR-6248
This list of 337 chemicals and categories was compiled and
documented by MITRE (September 1976) under contract to EPA. The
relevant factors in selecting chemicals for the list were: (1)
quantity produced, (2) potential for atmospheric release, and (3)
toxicological effects.
03 Final Report of NSF Workshop Panel to Select Organic Compounds
Hazardous to the Environment, April 1975
This list of 80 chemicals and categories was compiled and
documented by Stanford Research Institute under contract to the
National Science Foundation. The list consists of those chemicals
having the greatest potential for environmental release, selected
from the universe of manufactured organic chemicals with the
highest calculated release rates.
04 Potential Industrial Carcinogens and Mutagens
This list of 88 chemicals has been compiled by the National Center
for Toxicological Research. The list is made up of industrial
compounds which are potential carcinogens and/or mutagens, and
which have been selected based upon available data concerning
activity, use, production, and population at risk.
05 Occupational Carcinogens for Potential Regulatory Action
This list of 116 chemicals and categories was compiled by OSHA
from suspected carcinogens. Selection was based primarily upon
data available through the NIOSH Registry (Source List 13).
07 Chemicals Tested or Scheduled for Testing at the Fish-Pesticide
Research Laboratory, Department of Interior
This list consists of 174 toxic chemicals which are suspected of
being hazardous to fish and wildlife.
08 Substances with Chronic Effects other than Mutagenicity,
Carcinogenic!ty, or Teratogenicity; A Subfile of the NIOSH
Registry
A subfile of the NIOSH Registry (Source List 13)
29
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09 Criteria Documents Prepared or Planned by NIOSH, February 24, 1977
This list of 127 chemicals and categories consists of substances
for which criteria documents have been or will be prepared and
delivered to the Department of Labor. In selecting these
chemicals NIOSH considered: a) the number of workers exposed, b)
known or suspected toxic effects, and c) physical and chemical
properties.
10 Suspected Carcinogens; A Subfile of the NIOSH Registry
This is a list of 1,900 chemicals and categories which have been
reported to have produced cancer in test animals. The list is
included in Source List 13.
11 Suspected Mutagens; A subfile of the NIOSH Registry
This is a list of approximately 100 chemicals and categories which
have been reported to have produced mutagenic effects in test
systems. This list Is included in Source List 13.
*
13 NIOSH Registry of Toxic Effects of Chemical Substances, 1976
This list of 21,543 chemicals and categories was compiled and
documented in the NIOSH Registry. Only those substances which
were on Source Lists 8, 10, 11, or 12 were Included in the INITIAL
LISTING.
17 The Ecological Impact of Synthetic Organic Compounds on Estuarine
Ecosystems, September, 1976, EPA-1600/3-76-075
This list of 9 chemicals was compiled as part of a study of the
impact of synthetic organic compounds on estuarine ecosystems.
The effects of the 9 chemicals and a number of pesticides were
analyzed and documented in the study.
18 Threshold Limit Values for Chemical Substances and Physical
Agents in the Workroom Environment with Intended Changes for 1976,
American Conference of Government Industrial Hygienists
This list of approximately 570 chemicals and categories was
compiled by the ACGTH to give Threshold Limit Values for chemical
substances and physical agents in the workroom environment.
19 National Occupational Hazard Survey (1972-1974)
This list of over 7,000 chemicals and other hazards has been
compiled by NIOSH. These hazards are ranked according to the
estimated number of workers exposed. Only the chemicals ranked
among the top 500 hazards were included in the INITIAL LISTING.
20 Chemicals Being Tested for Carcinogenicity by the Bioassay
Program, DCCP, National Cancer Institute, 1977
This list of 372 chemicals Includes those which have been selected
for bioassay by the National Cancer Institute.
* 12 See Page 3la 30
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21 EPA/Office of Toxic Substances List of Priority Toxic
Chemicals, 1977
This list of 162 chemicals was compiled by EPA/OTS from the NIOSH
list of carcinogens CSource List 10).
22 A Study of Industrial Data on Candidate Chemicals for
Testing, EPA Contract # 68-01-4109, November, 1976
This list of 650 chemicals and categories was compiled by Stanford
Research Institute as part of the contracted effort to produce
Source List 03. Production and calculated release data are
Included.
Ik General List of Problem Substances, Environmental Contaminants
Committee, Ottawa, Ontario, Canada, 1977
This list of 160 chemicals and categories of environmental concern
was compiled by the Canadian government.
OTHER LISTS USED FOR REFERENCE BUT NOT USED AS SOURCE LISTS
FOR THE INITIAL LISTING:
06 Survey of Compounds which have been Tested for Carcinogenic
Activity (Index, 1970-1971), NIH/HEW
This list of 3,634 chemicals and categories is a cumulative index
by CAS number of PHS 149 volumes through 1970-1971.
14 Research Project to Gather and Analyze Data and Information on
Chemicals that Impact Man and the Environment
This list of 3,200 chemicals and categories was compiled and
documented by Stanford Research Institute under contract to the
National Cancer Institute. The documentation includes total
production and calculated release data for each of the chemicals
in nine hazard categories: (1) over-the-counter drugs, (2)
prescription drugs, (3) cosmetics, (4) trade-sales paints, (5)
water pollutants, (6) air pollutants, (7) soaps and detergents,
(8) pesticide residues in food, and (9) intentional food
additives.
16 Other Potential Modifiers of the Stratosphere, 1975
This list of 41 chemicals was compiled by the National Institute
of Environmental Health Sciences from the universe of 275
manufactured chemicals ranked for release rate used by Stanford
Research Institute in preparing Source List 03. This list
identifies potential modifiers of the stratosphere and provides
related information.
23 EPA/Office of Research and Development, Chemical Production
A set of production data compiled by EPA/ORD on approximately 140
chemicals.
31
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12 Suspected Teratogens; A subfile of the NIOSH Registry
This is a list of approximately 200 chemicals and
categories which have been reported to have produced
teratogenic effects in test animals. This list is
included in Source List 13.
31a
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APPENDIX B
PRODUCTION, RELEASE, AND EXPOSURE SCORES
A. The production, environmental release, occupational
exposure, and general population exposure factors described
in the text were scored in the following manner:
in the following manner:
Factor 1: Production
Annual production data were collected from a number
of sources:
a. Scoring of Organic Air Compounds (Source List
02 of Appendix A)
b. A Study of Industrial Data on Candidate
Chemicals for Testing (Source List 22 of
Appendix A)
c. EPA/OR&D Chemical Production (Source List 23
of Appendix A)
d. Synthetic Organic Chemicals, United States
Production and Sale, 1975, United States
International Trade Commission
e. Chemical Economics Handbook, 1975 Stanford
Research Institute
f. Chemical and Engineering News: Vol. 52,
No. 51, dated 12/23/74; Vol. 55, No. 18,
dated 5/2/77; Vol. 55, No. 24, dated 6/13/77
The Factor 1 score assigned to a chemical was
the common logarithm of the highest annual production
value (in millions Ibs/yr) found in any of the
above sources. If an annual production value was
not available for a chemical in any of these sources,
a Factor 1 score of -0.5229 (corresponding to an
assumed annual production of 300,000 pounds) was
assigned.
32
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Factor 2: Quantity Released Into the Environment
The quantity of chemical released Into the environment
was scored on a scale from 0 to 3 as follows:
Score Release Rate Estimate Based on Uses
3 ^30 percent Mostly dispersive uses
2 3 to 30 percent Some dispersive uses
1 .3 to 3 percent Few dispersive uses;
or primarily industrial
chemical with propensity
for leaks
0 \.3 percent Well contained industrial
chemical
Estimates of release rates for a number of chemicals
are given in Source List 22 of Appendix A. For those
chemicals for which no release rates were given, an
estimate was made on the basis of the dispersive
nature of the chemical's uses as indicated in the
above table.
An estimate was also made of the chemical's persistence
according to the following table:
Score Lifetime Example
3 Infinite (years Compounds of metals, freons,
or greater) CC14, N20, SF6, many poly-
mers
2 Order of 1 year Tetrachloroethylene, flame
retardants, phthalate esters,
silicones
1 Order of a few S02
days
0 Hours or less Reactive compounds
The sum of the scores of the two subfactors, release
quantity and persistence, was taken as an indication
of the environmental burden posed by the chemical.
Factor 3: Occupational Exposure
The source of data on occupational exposure to
chemicals was the National Occupational Hazard
Survey (NOHS) conducted by the National Institute for
33
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Occupational Safety and Health. In this survey,
the approximately 7000 most common hazards occurring
in the working place were rank ordered. To achieve
an occupational exposure score with a range and di-
rection similar to those of the other factors, the
Factor 3 score assigned to a chemical was 3.8451
minus the common logarithm of its rank on the NOHS
list. (3.8451 is the logarithm of 7000.) Chemicals
which did not appear on the NOHS list were given a
score of zero, equivalent to having been ranked
number 7000 on the survey.
Factor 4: Extent to Which the General Population
is Exposed
Four individual subfactors were scored and then summed
to measure the general population exposure. The four
subfactors were scored as follows:
SUBFACTOR 1 Number of people exposed to the chemical
(exclusive of a workplace environment)
Score No. of People Example
3 V20 X 10 Widely used household
products (e.g., wearing
apparel, shoe polish,
certain surface coat-
ings, common paints and
their solvents, common
plastics and their addi-
tives, detergents,
furnishings and carpets,
wood cleaning products,
refrigerants, natural
gas, nonfood packaging
materials, flame
proofers)
General air, food and
water contaminants
Automotive products
(e.g., gasoline and
additives, rubber,
surface coatings,
plasticizers, flame
proofers)
Products used widely
in commercial buildings
(mostly same as house-
hold, including
commercial cleaners,
disinfectants)
34
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Score No. of People Example
4
2 2-20 X 10 Less widely used house-
hold products (e.g.,
uncommon paints,
specialty apparel such
as baby wear, hobby
uses, arts and crafts,
tools)
Regional air and water
pollutants, farm
chemicals (exclusive
of pesticides)
4
1 0.2-2 X 10 Specialty hobbies
(e.g., photography),
specialty products
Neighborhood air and
water pollutants from
local industries
0 ^ 2 X 10 Chemical intermediates
rarely found outside
the workplace
SUBFACTOR 2 Frequency of exposure (to the typical person
in ranking number of people exposed under Sub-
factor 1)
Score Frequency Exampless
3 Daily or more often General air, food and
water contaminants,
household products in
regular use, material
used inside auto-
mobiles, clothing
2 Weekly Hobby crafts, house-
hold products used
intermittently (e.g.,
certain cleaners),
bleaches, gardening
products
1 Monthly Dry cleaning, certain
solvents, house mainten-
ance (e.g., polishes,
certain cleaning agents),
automobile maintenance
0 Yearly or less Application of house-
frequently hold paints, specialty
products
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SUBFACT0R 3 Exposure Intensity. This Is Intended to
reflect the total amount of material that
comes Into contact with the average or typical
person whose exposure has been scored under
subfactors 1 and 2. Scoring of this factor
considered the number of grams of the
material that makes contact with the average
person In the course of one exposure (dally,
weekly, monthly or yearly as scored In sub-
factor 2). Thus, for example, a trace pollutant
may lead to exposure of a typical person of the
order of micrograms per day every day; use of a
specialty solvent might lead to exposure of a
typical person of the order of grams per day
once a year: these would be scored 3,0 and 0,3
respectively on subfactors 2 and 3.
Score Intensity Examples
3 High (10*1 or more Plastics, fabrics,
grams per exposure) surface coatings,
volatile solvents In
closed spaces, liquids
contacting skin, high
concentration gases
2 Medium (10"' to Fabric additives,
10"*- g per exposure) solvents in open spaces
or outdoors, dusts,
solutes, transitory
exposures to vapors or
aerosols
1 Low (10"-*to 10 Low level indoor exposure,
g per exposure) volatile substances from
home furnishings and
building materials (e.g.,
plasticizers, flame
proofers), low volatility
solvents, pigments
0 Very low (less "H\Ar\ Environmental contaminants
10"* g per exposure (low level air, food, and
water contaminants),
monomers in polymers
SUBFACTOR 4 Penetrability. This is a measure of the material
that comes into contact with a person (whether by
dermal, inhalation, or ingestion exposure) and that
is expected to be absorbed into the body (even
transitorily) with potential for interaction with
cells.
36
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Score
3
Penetrability
High (10 to 100%
absorption)
Medium (1 to 10%
absorption)
Low (0.01 to 1%
absorption)
Negligible
(less than 0.01%
absorption)
Examples
Organic solvents in liquid,
mist, or aerosol form,
vapors and gases If likely
to be soluble in body fluids,
respirable-sized particles,
surface active agents,
materials known to have
high dermal systemic
toxicity
Solvents with low volatility
and/or larger molecules,
organic materials in
water solution, waxes and
polishes, coarse dusts
Certain solids, dermal
exposure to most inorganic
materials in water solution
Polymers, metals
B. In making the judgments called for in scoring
Factors 2 and 4 above, knowledge of the
chemical's uses was necessary. Use Information
was collected from the following sources:
1. The Condensed Chemical Dictionary,
Ninth Edition, Hawley, Van Nostrand
Reinhold Company, New York, 1977.
2. The Merck Index, Ninth Edition, Merck
and Company, Inc., Rahway, N.J., 1976.
3. Faith, Keyes, and Clark's Industrial
Chemicals, Lowenheim and Moran, Fourth
Edition, J. Wiley and Sons, Inc., New
York, 1975.
4. Chemical Marketing Reporter, Schnell
Publishing Company, Inc., New York.
5. Encyclopedia of Chemical Technology,
Klrk-Othmer, Inter-Science Publishing
Company, New York, 1972.
37
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APPENDIX C
ORDERING THE CHEMICALS BASED ON
PRODUCTION, RELEASE, AND EXPOSURE
A linear weighting scheme was used to rank order the
chemicals. The rank of the jth chemical, r^, was computed
by the formula:
4 fij
rj " -2T wi >
J i-1 ,±
where w^ is the weight assigned to the i"1 factor,
f.. is the 1th factor score of the jth chemical,
and s. is a scaling factor chosen to normalize the assig-
ned scores.
The four scaling factors employed were:
si - log 20,850 - 4.3191; 20,850 million Ib/yr
being the maximum of all Factor 1 chemical production
quantities.
82 "6; 6 being the maximum of all Factor 2
environmental release scores.
s3 - 3.8451 - log 3 - 3.3680; third being the
highest NOHS rank among the scored chemicals.
(Ranked first and second on the NOHS list were
continuous noise and mineral oil, the former not
being a chemical hazard and the latter not being among
the scored chemicals.)
84 "12; 12 being the maximum of all Factor 4 general
population exposure scores.
This choice of s^, s2, s , s , guaranteed that
for all i and j, and furthermore, that for each i,
for at least one chemical j.
- 1
•i^
38
si
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APPENDIX D
BIOLOGICAL AND ENVIRONMENTAL SCORES
A. The five human health effect factors and two environmental effect
factors mentioned in the text were scored in the following
manner:
Factor 1: Carcinogenicity
a. Numerical Scores Assigned:
3 Established carcinogen in humans or in 2 animal
species, or in one animal species in well-replicated
experiments
2 Established carcinogen in 1 animal species
1 Insufficient or inadequate experimental data for
definite conclusions, but either (a) no experimental
or structural reason for suspicion, or (b) good
negative mutagenicity tests, or (c) low biological
activity. (Note: some inert compounds — examples,
argon, nitrogen — were given a score of zero on
this factor despite not having been tested.
0 Adequately tested in animals with negative results
in each of two species
b. Letter Scores Assigned*:
xxx Needs testing, strongly suspect (close structural
relationship to known carcinogen, positive result in
validated in vitro test, inconclusive but suspicious
positive animal test, etc.)
xx Needs testing, suspect (structural resemblance to
known carcinogen, etc.)
x Needs testing, some reason for suspicion (potent
organ-specific toxin, enzyme inducer, suspect co-
carcinogen, etc.)
*Chemicals presently undergoing testing for Carcinogenicity in
the framework of the NCI bioassay program were scored as
suspect carcinogens. Their special status was documented for
the members of the Committee.
c. Criteria for Accepting Positive Test Results (scores 2 or 3)
Validated positive findings in animal studies consisted of
any test results which clearly Indicated treatment-related
Carcinogenicity or tumorlgenlc effects. This was based on the
criteria set out in the report of the National Cancer Advisory
Board, Subcommittee on Environmental Carcinogenicity, "General
Criteria for Assessing the Evidence for Carcinogenicity of
Chemical Substances (1976)".
39
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d. Criteria for Accepting Negative Test Results (including
zero scores)
In general, the protocol of the test conformed to, or was
reasonably consistent with the current NCI Guidelines (J.M.
Sontag et al., Guidelines for Carcinogen Bioassay in Small Ro-
dents, DHEW 76-801). It was recognized that many older tests
do not conform to these guidelines. Therefore, good scientific
judgment was applied to the evaluation of these tests in order
to determine whether differences in protocols significantly
weakened confidence in the reported negative results. In
assigning a zero score, the guiding principle was the judg-
ment that further testing was unnecessary.
Factor 2; Mutagenlcity
a. Numerical Scores Assigned:
2 Mutagen in two or more test systems*
1 Mutagen in one test system
0 Tested in more than one system with negative results
and no reason for suspicion (similar to inactive com-
pounds, etc.)
*These and other scores were normalized to the 0-3 scale or
x-xxx scale respectively for all factors involved.
b. Letter Scores Assigned:
xxx Needs testing, strong reason for suspicion (structur-
al similarity to known mutagen, reported carcinogeni-
city, teratogenicity, or other cellular toxicity)
xx Needs testing, some reason for suspicion (structural
similarity to known mutagens and/or carcinogens)
x Needs testing, no reason to assign high priority
c. Examples of Short-Term Test Systems Considered for Scoring
Were:
The Salmonella/microsome test, (Ames), E. coll WP2 uvr
A, etc. test (Bridges, Witkin), B. subtllis MAS Rec~, etc.
test (Kada), E. coll pol A+/pol Al- test (Rosenkranz), Yeast
test (Zimmerman), Neurospora test (de Serres) and Drosophila
test (Vogel).. Mammalian cells in culture and in vitro trans-
formations were also considered.
40
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Factor 3: Teratogenicity
a. Numerical Scores Assigned:
3 Confirmed teratogen in humans or in two appropriate
animal species
2 Confirmed teratogen in 1 animal species
1 Insufficient or inadequate experimental data for
definite conclusions, but either (a) no experimental
or structural reason for suspicion, or (b) low biolo-
gical activity
0 Adequately tested in two suitable animal species with
negative findings for teratogenic activity
b. Letter Scores Assigned:
xxx Needs testing, strongly suspect (close structural
relationship to known teratogen, Inconclusive but
suspicious positive animal tests, etc.)
xx Needs testing, suspect (equivocal result in animal
test, etc.)
x Needs testing, some reason for suspicion
c. Criteria for Acceptance of Teratogenicity Tests
Accepted teratogenicity tests conformed reasonably to the
recommendations and principles outlined in "Principles for
Evaluating Chemicals in the Environment," National Academy
of Sciences, pp. 173-182, 1975; and "The Testing of Chemi-
cals for Carcinogenicity, Mutagenicity, Teratogenicity,"
Department of Health and Welfare, Canada, pp. 137-176,
March 1973.
Factor 4: Acute Toxicity
a. Numerical Scores Assigned:
3 extremely toxic: < 50 mg/kg
2 very toxic: 50-500 mg/kg
1 moderately toxic: 0.5-5 g/kg
0 very slightly toxic: > 5 g/kg
41
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b. Letter Scores Assigned:*
zz not tested, but suspected to be in range 2-3
x not tested, but suspected to be in range 0-1
*See factor 2 for normalized scored.
c. Criteria for Quantitation of Acute Toxicity
Standard systems of toxicity rating based on probably lethal
dose in humans were used when available . Lowest lethal
doses and LD50 values in various animal systems were also
widely used.
Factor 5: Other Toxic Effects
a. Numerical Scores Assigned:
3 Effects at low doses (Guidelines: < 1 mg/kg/day)
2 Effects at moderate doses (Guidelines: 1-10 mg/kg/day)
1 Effects at high doses (Guidelines: >10 mg/kg/day)
0 Very low or negligible biological activity (e.g.,
nitrogen, argon, etc.)
b. Letter Scores Assigned:
xxx Needs testing (structural similarity to another
chemical which rates 2 or 3; questionable reports
of effects which need confirmation, etc.)
xx Needs testing, some reasons for suspicion
x Needs testing, inadequate information available
to give high pirority
c. Criteria for Scoring
This factor includes both reversible and irreversible
effects, delayed or cumulative toxicity, organ-specific
effects, effects on reproduction, behavior, etc. The score
entered reflects the toxic effects noted in animals (or in
humans if data were available) at the lowest dose-range. If
the chemical was reported or suspected to have more than
one toxic effect, xxx or xx for one type of toxic effect
superseded any numerical score for another. Also, x for one
type of toxic effect superseded 2 or 1 for another. In many
cases, reports of one type of effect at low doses engen-
dered suspicion of the likelihood of others; in such
cases the chemical was scored with the appropriate number of
x's, unless thoroughly tested.
42
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Factor 6: Bioaccumulation
a. Numerical Scores Assigned:
3 High
2 Appreciable
1 Low (
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Factor 7: Ecological Effects
a. Numerical Scores Assigned:
3 Effects at low concentrations (10-9 or less in air or
water)*
2 Effects at moderate concentrations (10-7 - 10-9 in air
or water)
1 Effects at high concentrations (10~° or greater in air
or water)
0 No reported effects that could justify priority for
testing
*In air for gases or vapors: 1 part of chemical per billion parts
air by volume (ppb). In water for liquids and solids: 10"^ gram
per cubic meter (ng/m^)
b. Letter Scores Assigned:*
xx Testing needed, possibility of major or widespread ef-
fects
x Testing needed, possibility of minor or local effects
*See factor 2 for normalized scores.
c. Criteria for Scoring:
Ecological effects considered included beside toxic effects
on non-human animals and plants, ecosystem effects, effects
on atmosphere and climate, ozone depletion, etc. Generally,
numerical scores (established hazard) were assigned only to
a limited number of thoroughly tested chemicals (e.g., pes-
ticides, some metal containing compounds, or some specific
chemicals). In other cases, the potential for ecological
effects was judged according to availability of data on
toxicity in particular, published information on specific
tests, structural similarity to compounds of better known
eco-toxicity, published data on depletion potential for
stratospheric ozone. Zero scores were assigned only to com-
pounds with low biological activity (LD50 > 1 g/kg or AQTR >
100 ppm).
B. An extra factor was scored if the presence of a contaminant in
a commercial product was the major reason for concern, or if a
trace degradation product was the major reason for concern (ex-
amples: dioxin, methyl mercury).
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Factor 8: Contaminants and Environmental Degradation or Conversion
Products
a. Numerical or Letter Scores Assigned:
1 Contaminants, etc., known to be Important
0 Contaminants, etc., not suspected, or known to be of
no importance.
x Contaminants, etc., suspect, needs testing
b. Criteria for Scoring:
The scores for this factor were not averaged. A letter
score took priority over a numerical score at any time; if
no letter score was assigned to a chemical, the numerical
score 1 was overriding. A zero score was assigned only if
it was scored unanimously by all scorers. The score for this
factor was not added: (1) if the principal breakdown product
was the major problem and it was the basis for scores
on other criteria such as persistence and toxicity (examples:
DDE, PAN); (2) for in vivo metabolism of carcinogens to
active forms (e.g., arene oxides, activated nitrosamines, etc.
etc.).
C. It is of relevance for the scoring method to add that in order
to facilitate the inclusion of a zero score in a letter score
average, the zero score was changed into 0.1X. Also, in some
instances fractional numerical or letter scores were assigned
by scorers.
D. The following literature sources were extensively used by the
scorers:
References of general interest
1. NIOSH Registry of Toxic Effects of Chemical Substances (1976)
2. Kirk-Othmer Encyclopedia of Chemical Technology. Edited by
A. Standen, Interscience Publishers, New York (1963, 1972).
3. The Condensed Chemical Dictionary, 9th ed. Van Nostrand
Reinhold Co., New York (1977).
4. The Merck Index, 9th ed. Merck & Co., Inc., Rahway, N.J.
(1976).
5. Chemical Consumer Hazard Information System. Consumer
Product Safety Commission, Washington, D.C. (1977).
6. A Study of Industrial Data on Candidate Chemicals for Test-
ing. Stanford Research Institute, Palo Alto, California,
(1976).
45
-------
7. The Encyclopedia of Chemistry. Hanpel & Hawley, 3rd ed.
Van Nostrand Reinhold Co., New York (1973).
8. Brown, S.L., et al. Research Program on Hazard Priority
Ranking of Manufactured Chemicals, Phase II- Final Report
to National Science Foundation. Stanford Research Institute
Menlo Park, California (1975).
9. Dorigan, J., et al. Scoring of Organic Air Pollutants,
Chemistry, Production and Toxicity of Selected Synthetic
Organic Chemicals, MITRE, MTR-6248 (1976).
1. References on Carcinogenicity
Cl. Survey of Compounds Which Have Been Tested for Carcinogen-
ic Activity Through 1972-1973 DHEW Publication No. NIH
73-453, National Cancer Institute, Bethesda, Maryland
C2. Suspected Carcinogens - A subfile of the NIOSH Toxic Substan-
ces List.
C3. IARC Monographs on the Evaluation of Carcinogenic Risk of
Chemicals to Man. Lyon, France. WHO, International Agency
for Research on Cancer.
C4. Chemicals Being Tested for Carcinogenicity by the Bioassay
Program, DCCP. National Cancer Institute (1977).
C5. Information Bulletin on the Survey of Chemicals Being Tes-
ted for Carcinogenicity, No. 6. WHO, Lyon, France (1976).
2,3. References on Mutagenicity and Teratogenicity
MT1. Shepard, T.H. Catalog of Teratogenic Agents. Johns Hopkins
University Press, Baltimore (1973).
MT2 EMIC/Environmental Mutagenicity Information Center File,
National Laboratories, Oak Ridge, Tennessee.
4,5. References on Acute Toxicity and Other Toxic Effects
A01. Thienes. C.L. & Haley, T.J. Clinical Toxicology. Lea
& Febiger, Philadelphia (1972).
A02. Gosselin, Hodge, Smith & Gleason. Clinical Toxicology
of Commercial Products, 4th ed. The Williams and Wilkins
Company, Baltimore (1976).
A03. Casarett, L.J. & Doull, J. Toxicology, the Basic Science
of Poisons. McMillan Publishing Co., Inc., New York.
A04. Debruin, A. Biochemical Toxicology of Environmental Agents.
Elsevier/North Holland, Inc., New York (1976).
46
-------
A05. Threshold Limit Values for Chemical Substances and Physical
Agents in the Workroom Environment with Intended Changes
for 1976. American Conference of Government Industrial
Hygienists.
A06. Criteria for a Recommended Standard - Occupational Exposure
to...., prepared by NIOSH..
A07. Browning, E. Toxicity and Metabolism of Industrial Solvents.
Elsevier, Amsterdam (1969).
A08. Browning, E. Toxicity of Industrial Metals, 2nd ed.
Appleton-Century-Crofts, New York (1969).
A09. Fairhall, L.T. Industrial Toxicology, 2nd. ed. Williams
& Wilkins Co., Baltimore, Maryland (1969).
AGIO. Sax, N.I. Dangerous Properties of Industrial Materials,
3rd ed. Reinhold Publishing Corp., New York (1975).
A011. Chemical Safety Data Sheets. Manufacturing Chemists
Association, Washington, D.C.
A012. Industrial Safety Data Sheets. National Safety Council,
Chicago, Illinois.
6,7. References on Bioaccumulation and Ecological Effects
BE1. Applegate, V.C., J.H. Howell, A.E. Hall, Jr. & M.A. Smith,
1957 Toxicity of 4.346 Chemicals to Larval Lampreys and
Fishes. U.S. Dept. Interior, Fish & Wildlife Service.
Special Scientific Report-Fisheries No. 207. Wash., D.C.
BE2. Battelle Columbus Laboratories 1971, Effects of Chemicals
on Aquatic Life: Selected Data from the Literature through
1968. Vol. 3 of Water Quality Criteria Data Book. U.S.
Environmental Protection Agency, Washington, D.C.
BE3. Hahn, W., and P. Jensen, Water Quality Characteristics of
Hazardous Materials; Texas A & M University, (1974) (Taken
from the NIOSH Registry of Toxic Effects of Chemical Substan-
ces (1976).
BE4. Kemp, H.T., R.L. Little, V.L. Ho Ionian, and R.L. Darby.
1973, Effects of Chemicals on Aquatic Life (Compilation
Dated 1968-1972). Water Quality Data Book - Vol. 5 U.S.
Environmental Protection Agency, Duluth, Minn.
BE5. Leo, A., C. Hansch, & D. Elkins, Partition Coefficients
and Their Uses. Chem. Rev. 71:525-616 (1971).
BE6. Lincer, J.L., M.E. Haynes, and M.L. Klein, 1976. The
Ecological Impact of Synthetic Organic Compds. on Estuarine
Ecosystems. U.S. Environmental-Protection Agency,
Gulf Breeze, Florida, EPA-600/3-76-075.
47
-------
BE7. Metcalf, R.L., P.Y. Lu, and I.P. Kapoor, 1973. Environmental
Distribution and Metabolic Fate of Key Industrial Pollutants
and Pesticides in a Model Ecosystem. Illinois University,
Water Resources Center, Research Report 69 , Urbana, Illinois.
BE8. Pimentel, D. 1971. Ecological Effects of Pesticides on
Non-target Species. Executive Office of the President,
Office of Science and Technology, Washington, D.C.
BE9. Sauter, S., K.S. Buxton, K.J. Malek, and S.R. Petrocelli,
1976. Effects of Exposure to Heave Metals on Selected Fresh-
water Fish. Toxicity of Copper, Cadmium, •Chromium, and Lead
to Eggs of Seven Fish Species. Environmental Protection
Agency, Duluth, Minnesota. EPA-600/3-76-105.
BE10. National Academy of Sciences. 1973. Water Quality Criteria,
1972. U.S. Environmental Protection Agency, Ecological
Resaerch Series No. EPA-R3-73-033.
BE11. McKee, J.E., and H.W. Wolf (eds.) 1963. Water Quality
Criteria, 2nd Edition. State Water Quality Control Board,
Sacramento, California.
BE12. U.S. Environmental Protection Agency. 1976. Criteria Document
PCBs. Washington, D.C.
BE13 National Institute of Environmental Health Sciences, 1973.
Symposium on Phthalate Ester Plasticizers. Environmental
Health Perspectives, Experimental Line 3.
BE14 National Academy of Sciences 1975a. Principles for Evaluat-
ing Chemicals in the Environment. Washington D.C.
BE15 National Academy of Sciences 1975b. Assessing Potential
Ocean Pollutants. Washington D.C.
BE16 U.S. Environmental Protection Agency 1975. Quality Criteria
for Water (preliminary draft). Washington D.C.
BE17 National Academy'of Sciences 1976. Halocarbons: Effects on
Stratospheric Ozone, Washington D.C.
48
-------
INFORMATION DOSSIERS ON SUBSTANCES
DESIGNATED BY
TSCA INTERAGENCY TESTING COMMITTEE
(October 1977)
Prepared by
Clement Associates, Inc.
1055 Thomas Jefferson Street, NW
Washington, DC 20007
December 1977
Contract No. NSF-C-ENV77-15417
Prepared for
TSCA Interagency Testing Committee
Washington, DC
-------
Clement Associates, Inc.
Technical Support Team
Ian C.T. Nisbet, Ph.D., Project Director
Jay Turim, Ph.D., Project Manager
Morton Beroza, Ph.D.
Nan S. Gray
John F. Guy
Robert Katz, Ph.D.
Alfred E. Pinkney
Mukund J. Shah, Ph. D.
Barbara Turnham
The team acknowledges the assistance of a number of Clement's
Associate Scientists and consultants during preparation of
dossiers.
-------
TABLE OF CONTENTS
Foreword
Alkyl Epoxides
Alkyl Phthalates
Chlorinated Benzenes, Mono- and Di-
Chlorinated Paraffins, 35-64% Chlorine
Chloromethane
Cresols
Hexachloro-1,3-Butadiene
Nitrobenzene
Toluene
Xylenes
I
II
III
IV
V
VI
VII
VIII
IX
X
Appendices
General References
Key to Abbreviations
Appendix A XI-l
Appendix B XI-U
-------
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 the responsibility for making recommendations to the Adminis-
trator of the Environmental Protection Agency (EPA) regarding
chemical substances which should be given priority by EPA for test-
ing 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 in-
stances added additional information. Conclusions presented in the
dossiers about specific studies were made by Clement scientists and
were reviewed by the Committee. The information in the dossiers thus
reflects the collective knowledge and judgment of the Committee and
its technical contractor. It has been used as the primary basis for
the designation of the chemicals involved for priority testing in the
Committee's Initial Report to the Administrator, Environmental Protec-
tion Agency (Federal Register 42, 55026, October 12, 1977).
The dossiers were designed to provide the Committee with informa-
tion on the chemicals' physical and chemical properties, exposure
characteristics, and biological properties in sufficient detail to
support an informed judgment on whether the substances could be given
priority for testing. The dossiers are not comprehensive critical re-
views. Such reviews could not be performed with the constraints im-
posed upon the Committee (and, therefore, the contractor) by the
statutory deadlines of TSCA.
Faced with the task of preparing dossiers which could be quickly
assembled and yet contain sufficient information for the Committee.'s
purposes, Clement proceeded along the following lines.
Literature searches were conducted using the National Library of
Medicine's TOXLINE and the Environmental Mutagen Information Center
(EMIC) automated data banks. Each reference on a list of sources of
general information (see General References - Appendix A) was reviewed.
Further references and information were obtained from monographs, cri-
teria documents, reviews, and reports available from government agency
files and trade' association libraries. Information received in re-
sponse to the Committee's July 1977 Federal Register notice requesting
information on certain substances was reviewed. Clement scientists
relied ,upon their own knowledge of the literature to augment the data
sources.
In general, secondary sources were consulted first in preparing
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 specifically noted otherwise,
the information cited in these dossiers was derived from the pri-
mary sources.
-------
-------
ALKYL EPOXIDES
TABLE OF CONTENTS
Page
Overview I-l
Part I - General Information
Butane, l,2:3,4-diepoxy stereoisomers J~3
Ethane, 1,2-epoxy- 1-5
Butane, 1,2-epoxy- I~8
Propane, 1,2-epoxy- 1-10
Summary of Characteristics 1-12
Specific References 1-13
Part II - Biological Properties
Butane, l,2:3,4-diepoxy steroisomers
2.1 Bioaccumulation 1-14
2.2 Contaminants and Environmental 1-14
Degradation or Conversion
Products
2.3 Acute Toxicity 1-14
2.4 Other Toxic Effects 1-16
2.5 Carcinogenicity 1-17
2.6 Mutagenicity 1-21
2.7 Teratogenicity 1-22
2.8 Metabolic Information 1-22
2.9 Ecological Effects 1-22
References .1-23
I-i
-------
Page
Part II - Biological Properties (Continued)
Ethane, 1,2-epoxy-
2.1 Bioaccumulation 1-25
2.2 Contaminants and Environmental 1-25
Degradation or Conversion
Products
2.3 Acute Toxicity 1-26
2.4 Other Toxic Effects 1-28
2.5 Carcinogenicity 1-29
2.6 Mutagenicity 1-31
2.7 Teratogenicity 1-33
2.8 Metabolic Information 1-34
2.9 Ecological Effects 1-34
2.10 Current Testing 1-34
References 1-36
Propane, 1,2-epoxy-
2.1 Bioaccumulation 1-39
2.2 Contaminants and Environmental 1-39
Degradation or Conversion
Products
2.3 Acute Toxicity 1-39
2.4 Other Toxic EFfects 1-42
2.5 Carcinogenicity 1-43
2.6 Mutagenicity 1-43
2.7 Teratogenicity 1-45
2.8 Metabolic Information 1-45
2.9 Ecological Effects 1-45
2.10 Current Testing 1-45
References 1-46
I-ii
-------
Page
Part III - Status of Carcinogenic!ty Studies on 1-47
Epoxides at the National Cancer In-
stitute
Part IV - Information on Structural Analogs 1-49
References 1-52
I-iii
-------
-------
ALKYL EPOXIDES
AN OVERVIEW
This category includes all noncyclic aliphatic hydrocarbons
with one or more epoxy functional groups. Specific epoxides discussed
'in this dossier are diepoxybutane, ethylene oxide, butylene oxide and
propylene oxide. Diepoxy butane, butylene oxide and propylene oxide
are colorless liquids and ethylene oxide is a colorless gas. All are
soluble in water and common organic solvents.
Several alkyl epoxides are produced in very large quantities (e.g.,
annual production of ethylene oxide exceeded 4 billion pounds and pro-
pylene oxide exceeded 1.8 billion pounds in 1976). These compounds are
used as intermediates in the manufacture of industrial chemicals such
as ethylene glycol, and propylene glycol. Ethylene oxide may be present
in several consumer products, including paint strippers and detergents
and is used in medical facilities for sterilization of heat-sensi-
tive materials.
It is estimated that 100 million pounds of ethylene oxide and over
40 million pounds of propylene oxide are annually released into the
environment. Occupationally, about 165,000 workers are estimated to be
exposed to the former compound and 264,000 workers to the latter. An-
other 105,000 workers are estimated to be exposed to butylene oxide.
These compounds do not accumulate in animal tissue, nor do they per-
sist appreciably in the environment. However, one of their reaction pro-
ducts, ethylene chlorohydrin, may be of potential concern. Little infor-
mation was found on the ecological effects of the alkyl epoxides.
Diepoxides are reported to be carcinogenic in animal studies. No
carcinogenic effect has been observed for ethylene oxide while propy-
lene oxide is reported to be carcinogenic in rats. Epoxides are reported
1-1
-------
to be mutagenic in several test systems. Teratogenicity data on
epoxides are not available in the literature.
1-2
-------
HKXL EPQJODES
PART I
GENERAL INFORMATION
I. Butane, l,2:3,4-diepoxy stereoisoners (including (+-)-l,2:3,4-diepoxy
butane and roeso-l,2:3,4-diepoxy butane)
1*1 Identification
NUO6K f
A. Butane, l,2:3,4-diepoxy- 001464535 EJ82250
B. Butane, (+-)-l,2:3,4-diepoxy- 000298180 EJ84000
C. Butane, nBSO-l,2:3,4-diepoxy- 000564001 EJ87500
1.2 Synonyms and Trade Names
A. l,l'-Bi(ethylene) oxide; bioxiran; bioxirane; butadiene diepoxide;
butadiene dioxide; l,2:3,4-diepoxybutane; threitol, l,2:3,4-dianhydxo-;
2,2'^dioxirane; erythritol anhydride; 2,4-diepoxybutane; dioxybutadiene
(G9,G16,G23)
B. dl-Butadiene dioxide; dl-l,2:3,4^diepoxy butane; bioxirane; (R*, R*) -(-»-) -
2, 2 '-bioxirane; l,2:3,4-diantydro-dl-threitol
(G9,(
C. meso-diepOKybutane; raes6-l,2:3/4-diepoxybutane; erythritol anhydride;
1,2:3, 4-dianhydro-erythritol; (R*,S*) -2, 2' -bioxirane
1*3 ChftPvLc^l Pooffiffl and
0 0
/\ /\
H2C - CH— HC - C&2 C4H6°2 MBl. wt. 86.09
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless liquid (G9,G
1.4.2 Boiling Point; 138-144° C (G22)
1.4.3 Malting Point: A. No information found in sources searched
B 4° C (G22)
C. -16° C (G22)
1-3
-------
1.4.4 Absorption Spectrometry; IR epoxide band at 1250 on
(G9)
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility; Soluble in alcohol and water
(G23,G22)
1.4.7 Octanol/Vfater Partition Coefficient;
No information found in sources searched
1.5 Production and Use
1.5.1 Production;
No information found in sovrces searched
1.5.2 Use; In curing polymers; for crosslinking textile
fibers; to prevent microbial spoilage
1.6 Exposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
No information found in sources searched
1.7 Manufacturers
No information found in sources searched
1-4
-------
ALKYL EPQXIEES
II. Ethane/ 1,2-epoxy —
1.1 Identification CAS No.: 000075218
NIOSH No. : KX24500
1.2 Synonyms and Trade Names
Ethylene oxide; Anprolene; dihydrooxirene; djjnethylene oxide; E.O.;
E.T.O.; oxacyclopropane; oxane; oxidoethane; alpha, beta, oxido ethane;
oxiran; oodrahe; di-hydro oxirene
(G16)
1.3 Chemical Formula and Molecular Weight
HjC - CH2
1.4 Chemical and Physical Properties
Mol. Wt. 44.05
1.4.1 Description;
Colorless, flarrroable gas at ordinary room
temperature and pressure; colorless mobile
flammable liquid below 12 °C; reduces AgN03;
reacts with active hydrogen compounds and
with inorganic chloride in foods to form
ethylene chlorohydrin
1.4.2 Boiling Point:
1.4.3 Melting Point;
10.7° C
-111° C
(G9,(
(G22)
1.4.4 Absorption Spectrometry;
1.4.5 Vapor Pressure;
1.4.6 Solubility;
169, 171 nm
log € - 3.58, 3.57
400 mm at -4.9° C
Soluble in water, alcohol, ether, acetone
and benzene
1.4.7 Octanol/Water Partition Coefficient;
poct = °'30
(5)
1-5
-------
1.5 Production and Use
1.5.1 Production; 3,961.800 Million Ibs (1972)
4,466.854 Million Ibs (1975)
4,184.258 Million IDS (1976} (G24)
1.5.2 Use; As a fumigant for foodstuffs and textiles; to
sterilize surgical instruments and medical mater-
ials; as an agricultural fungicide; in organic
syntheses, esp. in the production of ethylene
glyool; as starting material for the manufacture
of ncnionic surfactants
(G23)
Quantitative Distribution of Uses;
Percent
Ethylene glycol 'for antifreeze)
Ethylene glycol (for polyester)
Ethylene glycol (miscellaneous)
Surface-active agents
Ethanolamines
Miscellan«
(G25)
Consumer Product Information;
Ethylene oxide is present in:
cuiiuerical gas sterilizing agents;
aluminum brighteners;
paint stripper;
detergent;
polymer in denture adhesive
(G35)
1.6 Exposure Estimates
1.6.1 Release Rate: 98.8 Million Ibs
1.6.2 NOHS Occupational Exposure;
Rank: 773
Estimated no. of persons exposed: 165,000*
*rough estimate (G29)
1-6
-------
1.7 Manufacturers
BASF Wyandotte Corp.
Calcasieu Chemical Corp.
Celanese Chemical Co.
Dow Chemical Co.
Houston Chemical Co.
Jefferson Chemical Co.
Koch Chemical Co.
Northern Petroleum Co.
Olin Corp.
Shell Chemical Co.
Sun Olin Chemical Co.
Texas Eastman Co.
Union Carbide Corp.
1-7
-------
ALKYL EPQXTngg
III. Butane, 1,2-epoxy-
1.1 Identification CAS No.: 000106887
NIOSH NO.: EK36750
1.2 Synonyms and Trade Names
Butylene oxide; butane, 1,2-epoxy; 1-butene oxide; 1,2-butene oxide;
ethylene oxide, ethyl; 1,2-butylene oxide
(G16)
1.3 Chemical Formula and Molecular Weight
A
CH2 CH - 0*2 - CH3 C^gO Mol. wt. 72.12
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless liquid, highly flammable
(G21)
1.4.2 Boiling Point; 63.3° C (G22)
1.4.3 Melting Point; -150° C (G21)
1.4.4 Absorption Spectronetry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility; Decomposes in hot water;
Soluble in water;
Very soluble in alcohol, acetone, and
organic solvents;
Soluble in all proportions in ether
(G21,G22)
1.4.7 Octanol/Water Partition Coefficient;
No information found in sources searched
1-8
-------
1.5 Production and Use
1.5.1 Production;
9 million Ibs (estimate) (1974) (61
1.5.2 Use; As an intermediate for polymers; used in combination with
amines to stabilize trichloro- and tetrachloroethylene;
used as a fuel additive to prevent carburetor icing and
improve antiknock properties
(021,1,2,3)
1.6 Exposure
1.6.1 Release Rate;
~ 7 Million IDS (7)
1.6.2 NOHS Occupational Exposure;
Rank: 1106
Estimated no. of persons exposed: 105,000*
*rough estimate (G29)
1.7 Manufacturers
Dow Chemical Company
Story Chemical Corp., Farchan Division
(G24,4)
1-9
-------
IV. Propane, l,2-epoxy-(dl)
1.1 Identification CAS NO.: 000075569
NIOSH No.: TZ29750
1.2 Synonyms and Trade Names
Epoxypropane; 1,2-epoxypropane; ethylene oxide, methyl; methyl oxirane;
propane oxide; 1,2-propylene oxide; methyl oxiran
(G16,G22)
1.3 Chanical Formula and Molecular Weight
Q
H,C - CH - CH^ CJU3 Mol. wt. 58.08
* 3 T6 (G16,G22)
1.4 Chanical and Physical Properties
1.4.1 Description; Colorless liquid/ ethereal odor/ extremely
flammable
(G23)
1.4.2 Boiling Point; 34.3° C (G22)
1.4.3 Melting Point; -112.13° C (G23)
1.4.4 Absorption Spectrometry;
No information found in sources searched
1.4.5 Vapor Pressure; 400 mm at 17.8° C (G22)
1.4.6 Solubility; Soluble in all proportions in water, alcohol
and ether
(G22)
1.4.7 OctanoiyWater Partition Coefficient;
Poet • 0-13 (5)
1-10
-------
1.5 Production and Use
1.5.1 Production; 1,640.00 Million Ibs (1972)
1,523.613 Million Ibs (1975)
1,823.222 Million Ibs (1976) (G24)
1.5.2 Use; As a chemical intermediate in preparation of polyethers
to form polyurethanes; used in preparation of propylene
and dipropylene glycols; used in preparation of lubricants,
surfactants, oil emulsifiers; as a solvent, fumigant,
soil sterilant
(G23)
Quantitative Distribution of Uses;
Percent
Polypropylene glycol and polyester 56
glycols for urethanes
Propylene glycol 29
Dipropylene glycol 5
Surfactants 5
Glycol ethers and miscellaneous 5
"153
(G25)
1.6 Exposure Estimates
1.6.1 Release Rate: 40.8 Million Ibs (G28)
1.6.2 NOBS Occupational Exposure;
Bank: 582
Estimated no. of persons exposed: 264,000*
*rough estimate (G29)
1.7 Manufacturers
BASF Wyandotte Corp.
Dow Chemical USA
Jefferson Chemical Co., Inc.
Olin Corp.
Oxirane Chemical Co.
Celanese Corp.
Calcasieu Chemical Corp.
Texas Eastman Co.
Northern Petrochemicals Co.
Premier Petrochemical Co.
Shell Oil Co.
Sunolin Chemical Co.
Union Carbide Corp.
1-11
-------
OF CHARACTERISTICS
AIKXL EPCOCCDES
Hane
Solubility
poct
Estimated
Environmental
Release
(Million Ibs)
Butane, 1,2:3,4- s in H_O and ale
iliemw Kt-»r»w>—
diepoxy stereo-
isoraers
ethane, 1,2-epoxy- s in H2O, ale, eth, -0.30
ace, bz
Butane, 1,2-epoxy- s in HO; vs in
ale, aoe, os.
oo in eth
98.8
Propane, 1,2-egaxy- <*> in HO, ale
(dl) and eth''
0.13
40.8
Production
(Million Ibs)
Estimated no.
of persons
exposed
(Occupational)
3,961.800 (1972)
4,466.854 (1975)
4,184.258 (1976)
~165,000
9. (1974) ~105,000
1,640.00 (1972) -264,000
1,523.613 (1975)
1,823.222 (1976)
Use
In curing polymers; for
crosslinking textile fi-
bers; to prevent roicro-
bial spoilage
In mfg. of ethylene gly-
col (in anti freeze, in
plctstics and fibers), sur-
factants, ethanolatnines
Stabilizer for chlorinated
solvents (trichloro- and
tetrachloro- ethylene)
fuel additive
Mfg. of polvethers to
footo polyurethanes; mfg.
of propylene glycols
* Jto information found in sources searched.
1-12
-------
SPECIFIC REFERENCES FOR PART I
1. Dial, W.R., Stabilization of liquid halogenated aliphatic hydrocarbons-
Pittsburgh Plate Glass Co. U.S. Patent 3,250,331 March 13, 1962.
2. Copelin, H.B. Stabilization of chlorinated Hydrocarbons - E.I Dupont
de Nemours and Co. Patent 2,797,250 June 25, 1957.
3. Thomas, C.L. Motor Fuel anti-icing additives U.S. Patent 2,857,254
October 21, 1958.
4. Chemical Week Buyers Guide, 1977.
5. EPA, Office of Toxic Substances. Review of the enivcoonental
fate of selected chemicals. Task 3, Final report, Contract No.
68-01-2681, May, 1977.
6. Chemical Selection of Subgroup Clearinghouse on Environmental
carcinogens. National Cancer Institute (November 1977).
7. Personal Connunication with Warren Piver (Novenber, 1977).
1-13
-------
AIJQCL
Butane, l,2:3,4-Diepoxy
Butane, (+ -)-l,2:3,4-Diepoxy
Butane, l,2:3,4-Diepoxy, Meso
PART U
2.1 Bioaccunulation
These ocu%xxmJa are soluble in water ard react with water/ where they
are hydrolyzed to more water-soluble ccnpounds. Thus/ they are
to l
2.2 Contaminants and Envirormental Degradation or Conversion Products
Oiepoxybutane preparation involves reaction of l,4-dichloro-2,3-
butanediol or a 2,3-dihalogeno-l,4-tutanediol oorpound with sodium hydroxide.
The DL-form has been prepared from l,4-dibrono-2-buteneand the meao-fonn
from l/4-dihydroxy-2-butene or 3/4-epoxy-l-butene (G9) . Diepoxybutane is
slowly hydrolyzed in water to erythritol or threitol (G9) . The starting
material? outlined above may be contaminants in the final product; however
no published data on technical products and impurities were available in
the literature.
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chanical Substances (G16) reports
ie acute toxicity of dLepoxy butane as follows:
1-14
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Butane, l,2:3,4-Diepoxy
Parameter Dosage Animal Route
ID50 78 ing/kg rat oral
LC50 90 ppm/4hr rat inhalation
ID50 72 mg/kg mouse oral
LD50 89 mg/kg rabbit skin
Butane, (+ -)-l,2:3-4-Diepoxy
ID50 210 mg/kg rat oral
LCSO 56 ppm/4hr rat Inhalation
IDLo 400 mg/kg mouse skin
ID50 800 mgAg rabbit skin
Butane, l,2:3,4-Diepoxy-, Meso-
LDLo 400 mg/kg mouse skin
UD50 25 mg/kg mouse intraperitoneal
Smyth et al. (1) reported the following data on mixed stereoisomers
of diepoxybutane.
U350 78 mg/kg rat oral
UD50 89 ml/kg rabbit skin
0.01 ml. of undiluted diepoxybutane caused primary skin irritation
(necrosis) on the clipped skin of rabbits within 24 hours of application (1).
Inhalation of concentrated vapors in air killed all of 6 rats within
15 minutes (1).
The LCSO for a 4-hour exposure to rats is 90 ppm. Lachrymation, cloud-
ing of the cornea, Labored breathing, and congestion of the lung occurs.
Survivors have atrophy of the thymus, involution of the spleen, and decreased
weight gain during the recovery period (G38).
1-15
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Diepoxybutane has been reported to cause chemical eye injury. Smyth
reported (1) severe burn, cornea! necrosis eye injury in rabbits from
0.5 ml of a 10% solution in water or propylene glycol.
Five minute exposure to 10 ppm caused pronounced nasal and eye irri-
tation, whereas 5 ppm was tolerated (G38).
2.4 Other Toxic Effects
Skin applications repeated 3 times weekly for 1 year caused consistent
sebaceous gland suppression, intense hyperkeratosis and marked hyperplasia.
Following six intramuscular administrations of 25 mg/kg to rats, leukopenia
and relative lymphopenia occur (G38).
IXiring carcinogenicity testing by lifetime skin application on mice,
Van Duuren et al. (2) reported the following skin irritation effects of two
isomers of l,2:3,4-diepoxybutane.
Compound Concentration Skin Irritation
(% in acetone)
D,L- 10 and 3 Severe hair loss, crusting
and/or scarring persisting
throughout experiment.
Meso 10 and 3 Hair loss and crusting per-
sisting for 3 months or more,
recurring 2 or more times
during the experiment.
Diepoxybutane was locally narcotizing to tissues and caused extreme
irritation of the pulmonary tract. It has pronounced radiomimetic effects
\growth inhibitory, mutagenic and cytotoxic activity) (G38).
1-16
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In man, minor accidental exposures to mixed stereoisomers have caused
swelling of the eyelids and eye, and upper respiratory tract irritation with-
in 6 hours (G38).
2.5 Carcinogenicity
Diepoxides are more frequently carcinogenic than monofunctional epcxides
(3). Carcinogenicity data on diepoxybutane has been reported in two second-
ary sources, PHS-149 (G18) and an IAPC monograph (G9, Vol. 11). Van
Duuren et al. have published a series of articles (2-5) on the carcino-
genicity of diepoxybutane. IARC (G9) evaluated the anijnal data on diepoxy-
butane as follows:
"D-L- and meso-l,2:3,4-diepoxybutane are carcinogenic
in mice by skin application: both compounds produced squamous-
cell skin carcinomas. The D,L-racemate also produced local
sarcomas in mice and rats by subcutaneous injection. L-l,2:3,4-
Diepoxybutane is carcinogenic in mice by intraperitoneal injection."
Results of earlier experiments (6) on the carcinogenicity of the
diepoxybutanes were inconclusive because of the low survival rate of the
mice. One malignant tumor was observed in the group receiving the D,L-isomer.
Only 4 animals survived for longer than 8 months and after 12 months there
were no survivors. In the group receiving the meso-isomer, 10 animals
survived more than 8 months and 4 malignant tumors were observed (4).
The later, studies (2, see Table 1) lead to the conclusions that both
sterioisomers are clearly carcinogenic and that the D,L-isomer is a more
active carcinogen and also more toxic than the meso-isomer. D,L- and
1-17
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ineso-diepo^Ybutane gave both benign and malignant tumors.
Table 1
Effects of Skin Painting of Diepoxyfautanes on Mice (2)*
Gcinpound
D,L.
Me so
Concentration
(% in acetone)
10
3
10
3
Median
Survival
Tiioe (days)
165
475
357
491
Cumulative Ito.
of mice with
Papilloma Carcinona
1
10
5
1
0
6
4
0
*30 mice per group. Papillomas include animals
which developed only one or more benign tumors.
Animals that have one or more squamous epidermial
carcinomas are counted under the column titled
"carcinoma",
D,L-diepoxybutane is carcinogenic to mouse skin but does not induce
gastric cancers in rats. This finding is related to the rapid acid-
catalyzed hydrolysis of epoxides in the rat stomach. It induced tumors
mainly at the site of application and did not give any significant in-
cidence of tumors at sites distant from the site of application. Connective
tissue of rats is not usually sensitive to tumor induction by these com-
pounds (3).
In a carcinogenicity study of 1,2:3,4-diepoxybutane by skin painting
20 mice (strain 57B1) were given a total dose of 1 mMole of the compound
(duration of experiment not specified). The first tumor appeared at 5
months, with all 20 animals having survived to this period. Seven developed
skin tumors and two developed malignant lymphonas (G18,7).
1-18
-------
Experimental protocols and tumorigenic data from carcinogenicity
studies of diepoxybutane by skin application and subcutaneous injection are
shown in Tables 2 to 4.
Table 2
Carcinogenicity Study of Diepoxyfautane by Skin Application
Oc
ound
meso-1,2:3,4-
Diepoxybutane
D/L-l/2:3/4-
Oiepoxybutane
Control (Sol-
vent)
Animal
30 mice
30 mice
90 mice
(Beference: G9/ G18/ 4)
Route of Exposure
Median
Survival
Time
skin applications on the 154 days
clipped cloT^l skin
10 rag/animal in 0»1 ml
acetone 3 times weekly
same as above
same as above
Tufflorigenic
Effects
6/30 sguamous
papill<
78 days 2/30 squanous
papillcnas
1/30
cell
votv>ii» iin
235 days 8/90 squamous
Table 3
Carcinogenicity Study of Diepoxybutane by Skin Application
D,L-l/2:3,4-
Diepoxybutane
Animal
30 mice
Route of Exposure
Median
Survival
Time
3 and 10 rag in 0.1 ml 165 days
acetone skin application for high
on the clipped dorsal dosage
skin/ 3 times weekly for (10 mg)
lifespan
Tumorigenic
Effects
V30 - skin papil-
lona (at 10 mg
dose)
10/30 skin papillo-
roa
6/30 squamous-cell
carcinoma (at
3 mg dose)
1-19
-------
Table 3 (continued)
meso-l,2:3,4- 30 mice
Diepoxybutane
Control
(acetone)
60 mice
same as above
same as above
357 days 5/30 skin papillona
for high 4/30 squamous-cell
dosage carcinoma (at 10
(10 mg) mg dose)
1/30 skin papillona
0/30 carcinoma (at
3 mg dose)
447 days No skin tumor
(Reference: G9, G18, 2)
Table 4
Subcutaneous Injection of D,L-l,2;3,4-diepoxybutane
Dose, ing in
0.05 ml Number of
Animal Tricaprylin Animals
Median Survival Duration of
Time (days) Test (days)
Tumors at
Injection Site
mice
mice
rat
0.1
1.1
1
50
30
50
456
328
471
489
401
550
2 Adenocarcinona!
5 FibrosarccBnas
5 Fibrosarcomas
1 Adenocarcinona
9 Fibrosarconas
Solvent-treated control mice developed
no tumors at injection site. Distant
tumors were not numerically significant.
once weekly over the specified time
all adenocarcinonas were of breast origin
(P^erence: G9, G18, 3)
1-20
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2.6 Mutagenicity
The irutagenicity of the individual stereoisomers of diepoxybutane has
been tested only in plants.
Mixed stereoiscners have been reported in an IAPC monograph (G9, Vol. 11)
to be nutagenic in a number of microbial, insect/ and human studies, as
follows.
a) Prophage induction in Bacillus megaterium and Psevvflqtonas pyocyanea
(8) and in Escherichia coli k-12 (9).
b) Reverse nutation induced in strain TA 1535 of Salmonella typhimurium
(10), in ScMzosaocharomyces porobe (11) and in B and B/r strains
of Escherichia coli (12), after treatment for 1 hour at 37°C with
0.01 M and 0.02 M aqueous solutions, respectively.
c) Reverse nutations induced in the purple, adenine-requiring mutant
38701 of Neurospora crassa after treatment with a 0.2 M solution (13).
d) Mitotic gene conversions were produced in strain 04 of Saocharomyces
cerevisiae (14-15), after 5 hours of treatment with a 0.005 M
solution.
e) Sex-linked recessive lethal mutations, visible nutations, semi-lethal
nutations, and translocations were produced in Drosophilia melanogaster
(16-19).
f) Chromosome aberrations were found in cells taken from a patient
suffering from Franconi's anaemia after treating the cells in vitro
with diepoxybutane (20).
1-21
-------
Bianchi and Cotin (21) have reported that diepoxybutane is a chemical
rrutagen in maize pollen but the capacity to affect the hereditary material
differs depending on the specific isoner employed. The L-form is the most
effective followed by D and meso forms. Also, the racemic solution shows
more or less pronounced synergism.
2.7 Teratogenicity
No information was found in searched literature.
2.8 Metabolic Infor/nation
Epoxides have been found to undergo rapid acid-catalyzed hydrolysis in
the rat stomach (3). Diepoxybutanes are hydrolyzed to erythritol, a naturally
occurring sugar, when mixed with water (G23).
2.9 Ecological Effects
No information was found in sources searched.
1-22
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REFERENCES
1. Smyth, H.F. , Jr., Carpenter, C.P. , Weil, C.S. and Pozzani, U.C.
Range-finding toxicity data. Arch. Industr. Hyg. 10:61-68 (1954).
2. Van Duuren, B.L. , Orris, L. and Nelson, N. Carcinogenicity of epoxides,
lactones and peroxy compounds. II. J. Nat. Cancer Inst. 35:707-717
(1965) .
3. Van Duuren, B.L. , Langseth, L. , Orris, L. , Teetor, G. , Nelson, N. and
Kuschner, M. Carcinogenicity of epoxides, lactones and peroxy com-
pounds. IV. Tumor response in epithelial and connective tissue in
mice and rats. J. Nat. Cancer Inst. 37:825-838 (1966).
4. Van Duuren, B.L. , Nelson, N. , Orris, L. , Palmes, E.D. and Schmitt, F.L.
Carcinogenicity of epoxides, lactones and peroxy compounds. J. Nat.
Cancer Inst. 31:41-55 (1963).
5. Van Duuren, B.L. Carcinogenic epoxides lactones and haloetners and
their node of action. Ann. N.Y. Acad. Sci. 163:633-651 (1969).
6. Walpole, A.L. Carcinogenic action of alkylating agents. Ann. N.Y.
Acad. Sci. 68:650-761 (1958).
7. Kbtin, P. and Falk, H.L. Organic peroxides, hydrogen peroxide, epoxides
and neoplasin. Radiat. Res. Supp. 3:193-211 (1963).
8. Lwoff, A. Lysogeny. Bact. Rev. 17:269-337 (1953).
9. Heinenann, B. and Howard, A.J. Induction of lambdabacteriophage in
Escherichia coli as a screening test for potential antitumor agents.
Appl. MicrdbloTr 12:234-239 (1964).
10. McCann, J. , Choi, E. , Yamasaki, E. and Ames, B.N. Detection of
carcinogens as nutagens in the Salnmella/microsome test: assay
of 300 chemicals. Proc. Nat. Acad. Sci. "(Wash.) 72:5135-5139 (1975).
11. Clarke, C.H. and Loprieno, N. The influence of genetic background on
the induction of methionine reversions by diepoxybutane in Schizosaccharo-
myces pombe. Microb. Genet. Bull. 22:11-12 (1965).
n *-w™«.(™™i—
12. Glover, S.W. A comparative study of induced reversions in Escherichia
coli. In: Genetic Studies with Bacteria, Carnegie Institute of
Publication 612, Washington, DC , p. 121-136 (1956) .
13. Kjzflmark, G. and Westergaard, M. Further studies on chemically induced
reversions at tlie adenine locus of Neurospora. Hereditas 39:209-224 (1953)
-------
14. Zimmerman, F.K. Induction of mitotic gene conversion by mutagens.
Mutation Res. 11:327-337 (1971).
15. Zimnerman, F.K. and Vig, B.K. Mutagen specificity in the induction
of mitotic crossing over in Saccharomyces cerevisiae. Mol. Gen. Genet.
139:255-268 (1975).
16. Bird, M.J. and Fahmy, O.G. Cytogenetic analysis of the action of
carcinogens and tumour inhibitors in Drosophila melanogaster.
I.l:2,3:4-Diepoxybutane. Proc. Poy. Soc., Ser. B. 1403:556-578 (1953).
17. Watson, W.A.F. Further evidence of an essential difference between
the genetical effects of mono- and bifunctional alkylating agents.
Mutation Pes. 3:455-457 (1966).
18. Watson, W.A.F. Studies on a recombination-deficient mutation of
Drosophila. II. Respon
Res. 14:299-307 (1972).
Drosophila. II. Response to x-rays and alkylating agents. Mutation
. 14::
19. Fahmy, O.G. and Fahmy, M.J. Gene elimination in carcinogenesis:
reinterpretation of the somatic mutation theory. Cancer Res.
30:195-205 (1970).
20. Wolman, S.R. and Auerbach, A.D. Induction of chromosome damage in
fibroblasts from genetic instability syndromes. Proc. Amer. Ass.
Cancer Res. 16:69 (1975).
21. Bianchi, A. and Contin, M. Mutagenic activity of isomeric forms of
diepoxybutane in maize. J. Heredity 53:277-281 (1962).
1-24
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ETHYLENE OXIDE
(Ethane, 1,2-epoxy)
2.1 Bioaccumulation
Ethylene oxide is readily soluble in water and has a log
value of -0.30. Therefore this compound is not believed to accumulate in
animal tissues (1). Since ethylene oxide has such a high vapor pressure,
one would not expect to find it in the aquatic environment.
2.2 Contaminants and Environmental Degradation or Conversion Products
An IAFC monograph (G9, Vol. 11) has reported the following information
on technical products and impurities of ethylene oxide from the EPA
Compendium of Registered Pesticides (2). Ethylene oxide is available in
technical and pure (99.7%) grades. A typical technical grade product con-
tains water (0.03%), acetaldehyde (0.01%), acetic acid (0.002%), non-
volatile residue (O.lg/1). Ethylene oxide is also available as a 10-80%
pressurized or liquified gas formulated with carbon dioxide, trichloro-
fluoromethane or dichlorodifluoromethane to reduce fire hazards. In one
study (3), 2.3% air and 0.7% acetylene by weight have been reported as the
only impurities in 97.0%-98.6% commercial grade ethylene oxide. Ethylene
oxide production involves direct catalytic oxidation of ethylene with
air or oxygen (G9, Vol. 11). The starting materials may possibly add
contaminants.
Ethylene oxide is a volatile polar compound which is moderately
reactive toward a variety of nucleophilic species, including water, via
1-25
-------
acid, base and neutral reactions (1). It is rapidly hydrolyzed (t,/-"^.S
days in neutral solutions) (G14,G15). If dispersed into the atmosphere,
ethylene oxide will be oxidized by hydroxy radical with a half life of one
to six days. However, it is extremely unreactive towards peroxides and
ozone (G14,G15). The biochemical oxygen demand (BOD) is reported to be
31% of theoretical after 10 days at 70° F at 100 ing/foil. Total theoretical
oxygen demand is 1.82 gm/gm (G15).
After sterilization and fumigation of various organic materials and
synthetic objects with ethylene oxide, residues of ethylene oxide, ethylene
chlorohydrin and ethylene glycol are found (35).
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances (G16) reports
the acute toxicity of ethylene oxide as follows:
Parameter Dosage Animal Route
LD50 330 mgAg rat oral
LC50 1462 ppm/4hr rat inhalation
LC50 836 ppm/4hr mouse inhalation
LC50 960 ppm/4hr dog inhalation
ID50 270 mgAg guinea pig oral
I£Lo 7000 ppm/150 min guinea pig inhalation
Hollingsworth et al. (3) have reviewed the toxicity of ethylene oxide.
Major toxic effects and sources cited in this article are as follows:
Exposure to 50,000 to 100,000 ppm causes death in guinea pigs after a
few minutes. Exposure to 3000 to 6000 ppm for 30 to 60 minutes is dangerous
1-26
-------
to the life of guinea pigs; 3000 ppm is the maximum amount for 60 minutes
and 250 ppm is the maximum concentration that can be tolerated for several
hours by guinea pigs without serious disturbances (4).
Less extensive studies on acute inhalation toxicity of ethylene oxide
for various animal species have been cited (5-24) by Hollingsworth et al.
(3).
Ethylene oxide is an irritant/ a central nervous system depressant,
and a protoplasmic poison. Deaths due to respiratory paralysis may result
promptly from single vapor exposures causing deep anesthesia when animals
are exposed once to lower concentrations of ethylene oxide vapor; delayed
deaths may occur due to lung edema, secondary respiratory infection and/
or kidney and liver injury. Symptoms of excessive exposure observed in
animals include irritation of the eyes, nose, and throat; vomiting;
weakness; tremors; and shortness of breath.
After exposure of dogs, cats, rabbits, guinea pigs, rats and mice to
ethylene oxide vapor (concentrations greater than 1000 ppm for 2 hours), some
cats exhibited salivation and lacrimation, dogs vomited occasionally, and
breathing was somewhat accelerated in all animals. Following removal of the
animals from the exposure, corneal opacity was seen, especially in the
guinea pigs. Transient fits of coughing and nausea were observed in the
dogs and cats, Ihe animals that survived the more severe exposures (con-
centrations of 250 to 4000 ppm and exposures times of 1 to 48 hours) appeared
to recover completely, but showed delayed effects of apathy, dyspnea, in-
flanmation of the periosteum, paralysis of the hind legs, severe respiratory
distress, periodic convulsions and deaths. Autopsy of the animals revealed
congestion, hyperemia and emphysema of the lungs; plethora, congestion, and
1-27
-------
fatty degeneration of the liver; cloudy swelling of the tubules of the
kidneys; infrequent fatty degeneration of the muscle fibers and of the media
of the coronary blood vessels of the heart; and plethora of the spleen and
brain (5).
Early symptoms of excessive acute vapor exposure of humans to ethy-
lene oxide alone or in an admixture with carbon dioxide are irritation of
the eyes, nose, and throat. Symptons of nausea, vomiting, headache, short-
ness of breath, cyanosis, diarrhea, mental dullness, drowsiness, weakness,
incoordination, pulmonary edema, electrocardiogram abnormalities, lympho-
cytosis, and urinary excretion of bile pigments appear later (15-23).
Pure anhydrous liquid ethylene oxide does not cause priirary injury
to the dry skin of man, but rapid vaporization on the skin results in a
freezing reaction of the skin (24).
Prolonged, intitate skin contact with dilute or concentrated aqueous
solutions of ethylene oxide can cause severe delayed burns. After a
latent period of several hours, the concentrated solutions produced edema
and erythema. Shortly thereafter, vesiculation and/or impressive bleb
formation were observed in the cases of all aqueous solutions contacted.
Nausea and vomiting were observed when a 1% solution of ethylene oxide in
water had direct concact with skin for about two hours (23,24).
2.4 Other Toxic Effects
Hollingsworth et al. (3) have reported the effects of repeated exposure
to ethylene oxide as follows:
1-28
-------
When animals Nere subjected to repeated seven-hour exposures of
ethylene oxide vapor, five days a week, for six or seven months, guinea
pigs, rabbits, and monkeys tolerated 113 ppm and rats and mice tolerated
49 ppm without adverse effects. Repeated oral doses of 0.03 g/kg of
ethylene oxide given daily, 5 days a week, for a period of 30 days produced
no toxic effects in rats.
Irritation of the respiratory passage and injury to the lungs occurred
when animals were exposed repeatedly to 204, 357 and 841 ppm of ethylene
oxide vapor for seven hours a day, five days a week during a period of
182 days. Secondary respiratory infection caused the deaths of an appre-
ciable number of rats and mice under these circumstances. Injury to
the liver, kidneys, adrenals and testes was noted in the rats and guinea
pigs. Delayed reversible effects, characterized by impairment of func-
tion (both sensory and motor) of the nervous system at the level of the
lumbar and sacral region occurred. Paralysis, muscular atrophy of the
hind limbs and growth depression and organ weight changes were observed
in rats, rabbits and monkeys.
The Threshold Limit Value (TLV) recommended by ACGIH is 50 ppm
(approximately 90 mg/m ) (Gil).
2.5 Carcinogenicity
Carcinogenicity studies have been reported in the Public Health
Service Survey (G18, Vol. II-#829 and Vol. 1961-67-11203) and in an IARC
monograph (G9, Vol 11) as follows:
1-29
-------
In limited studies, no carcinogenic effects were found when ethylene
oxide was tested in mice by skin application, in rats by subcutaneous
injection and in dogs, rats and mice by inhalation. The experimental
details are outlined below.
Skin Application:
Thirty mice were painted three times weekly on the clipped dorsal
skin with ethylene oxide (0.1 ml. of a 10% solution in acetone) for life.
The median survival times was reported in IARC (G9) to be 493 days (25).
Subcutaneous Administration:
Twelve rats received maximum total doses of IgAg ethylene oxide in
arachis oil by subcutaneous injection for 94 days. The animals were observed
for lifetime; no local sarcomas were reported (26, as cited in G9).
Inhalation Study;
Three dogs (beagle), 30 mice and 20 rats were exposed to different
concentration levels of ethylene oxide from 6 weeks to a maximum of 6
months. The survival rate was very low in mice (35, as reported in G18).
Other Experimental System;
Positive results have been reported in mice exposed to shredded corn
cob bedding treated with ethylene oxide 150 days and then to untreated
bedding for the rest of the life span (maximal, 900 days). Sixty-three out
of 86 mice developed tumors at various sites. No tumors were reported in
female mice which were not exposed to treated bedding (27, as cited in G9).
The IARC working group (1975-76) on the evaluation of the carcinogenic
risk of chemicals to man comments on the above positive data that "This
observation does not allow an evaluation of the carcinogenicity of
1-30
-------
ethylene oxide"; and on the negative data that "Although no carcinogenic effect
was observed, the data do not allow an evaluation." No case reports or
epidemiological studies were available to the working group (G9/ Vol. 11).
2.6 Matagenicity
Information on the mutagenicity of ethylene oxide has been compiled
from two secondary sources: an IMC monograph (G9, Vol. 11) and an EPA
report (G28). Evaluation of the test results of these studies has been
provided in the latter source as follows:
Positive Tests Reviewed
Treatment with 9.55 mM ethanol solution of ethylene oxide for one
hour at 25°C produced reverse mutations in Salmonella typhimurium strain
TA1535 (28).
Treatment with a 0.025 M aqueous solution for 15 minutes produced
reverse mutations in the adenine-requiring mutant strain 38701 of Neurospora
crassa (29).
Ethylene oxide was found to be weakly active in the induction of sex-
linked recessive lethal mutations and translocations in D. melanogaster.
The chemical was administered to males by injection in single doses of a
0.055 or 0.09 M saline solution. This result was confirmed in another study.
The chemical was also found to be active in inducing minute mutants (small
chromosome deletions resulting in reduction of length and thickness of
bristles) in 0. melanogaster (30-32).
Negative/Inadequate Tests Reviewed
Ethylene oxide produced dominant lethal mutations in rats exposed for
4 hours to 1.83 g/m (1000 ppm) (33). Chromosome aberrations were induced
1-31
-------
in bone marrow cells of rats exposed by inhalation to 0.45 g/m (250 ppm)
ethylene oxide for 7 hours per day for 3 days (33). In both experiments
the presented data was judged to be inadequate for evaluation (G28).
Unreviewed Tests
Ethylene oxide has been reported to be inactive in the induction of
reversions to methionine and glutamate prototrophy in Streptomyces griseo-
flavus, weakly active in inducing prophage in Escherichia coli, and inactive
in inducing host-range nutations in bacteriophage T2h+ and the parent
bacteriophage T2. These tests were not reviewed because the mutational events
occurring have not been adequately characterized as screens for genetic
damage (G28).
Studies with Insufficient Data for Evaluation or Not Reviewed
Administered by inhalation at a single dose level of 1000 ppm for four
hours, ethylene oxide induced dominant lethal mutations in germ cells of
male Long-Evans rats (G28).
Ethylene oxide has also been reported to be mutagenic in several plant
systems. Chromosome breaks, breviaristatum mutants, eceriferum mutants, and
chlorophyll mutants were observed in sprouts of barley seeds treated with
ethylene oxide. Mutations were observed in wheat (Triticun
aestivum var. vulgare) after treatment of the seeds with ethylene oxide.
Chromosome aberrations were detected in germinating seedlings of Pterotheca
falconera treated with the chemical and recessive mutations were detected
in Eucalyptus species tereticornis, citriodoro, and nvalculata two generations
after treatment of seedlings. Chromosome aberrations (e.g., chromatic
breaks) were found in pollen grains of Tradescantia paludosa and in root
1-32
-------
tips of Vicia faba exposed to ethylene oxide. Chlorophyll mutations were found
in rice after treatment of the seeds with the chemical. Chromosome aberrations
have also been detected in maize treated with ethylene oxide (G28).
Human mutagenic episode for ethylene oxide has been reported in an
EPA document (35) as follows:
"Ehrenbert (36) studied the lymphocytic effects
on seven workers who were transiently exposed to a high
concentration of EtO for 2 hours after an industrial
accident involving an EtO spill. Since two of the seven
workers were hospitalized with lung damage, Ehrenbert (37)
estimated the level of exposure to be equivalent to 2 hours
of continuous exposure to 1500 ppm. Eighteen months
afterwards, peripheral blood lymphocytes were examined for
chromosomal aberrations, including chromosomal transloca-
tions, gaps, breaks, and aneuploidy. When compared with
10 control subjects with ho history of EtO exposure, the
incidence of these aberrations was elevated (p 0.05)."
2.7 Teratogenicity and Reproductive Effects
No information was found in searched literature for the teratogenicity
of ethylene oxide.
Hollingsworth et al. (3) observed atrophic effects on the testes in
eight male guinea pigs which were exposed by inhalation to 357 ppm EtO in
123 seven-hour doses during the 176-day study. All animals survived but
appreciable degeneration of the testicular tubules and replacement fibrosis
1-33
-------
was noted. In another test 20 male rats were exposed to 204 ppm EtO for
122 to 157 seven-hour periods during 176 to 226 days were noted to
have small testes and slight degeneration of tubules. In view of these
findings, the working group on ethylene oxide (35) concluded that "studies
conducted with guinea pigs and rats indicate that ethylene oxide can
adversely affect the male reproductive organs."
2.8 Metabolic Information
No information found in searched literafire.
2.9 Ecological Effects
The rate of pollen collection in bees (Apis mellifera) exposed to
fumigated pollen was reduced (G14). Aquatic toxicity rating: Tim 96:100-10
ppm (G16).
2.10 Current Testing
A study is presently underway at Carnegie Mellon University under
D.L. Geary and W.M. Snellings to investigate the possible health hazards of
long-term inhalation of ethylene oxide vapor.
Groups of rats are inhaling unspecified ethylene oxide concentrations
6 hours a day, 5 days a week for 2 years. Hematologic and blood clinical
chemistry evaluations, urinalysis, clotting times, ophthalmologic exams,
cytogenic analysis, gross necropsy and histopathological examinations will
be performed at each sacrifice interval. The animals will also be palpated
1-34
-------
for tissue masses periodically.
Mutagenesis, teratogenesis and reproductive effects will also be
evaluated (34).
Ethylene oxide (NCI #C50088) has been tentatively selected for car-
cinogenesis bioassay testings (date approved July 1966) (G12) in rats and
mice by inhalation.
I-3 5
-------
REFERENCES
1. Office of TXocic Substances, EPA. Review of the environmental fate of
selected chemicals. Task 3, Final report, Contract no. 68-01-2681,
May 1977.
2. U.S. Environmental Protection Agency. EPA Compendium of Registered
Pesticides, Vol. II, Fungicides and Nematicides, Washington, D.C.,
U.S. Government Printing Office, p. E-05-00.01 (1973).
3. Hollingsworth, R.L., Rows, V.K., Oyen, F., McCollister, D.D. and
Spencer, H.C. Toxicity of ethylene oxide determined on experimental
animals. Arch. Industr. Health 13:217-227 (1956).
4. White, C.P., Patty, F.A. and Yant, W.P. Acute response of guinea pigs
to vapors of some new ccrrmercial organic compounds: IV. Ethylene oxide,
Reprint 1401. Public Health Report 45:1832-1843 (1930).
5. Flury, F. Concerning ethylene oxide (T-gas) Arch. Exper. Path. u.
Pharmacol. 151:107-108 (1931).
6. Zernik, F. Concerning ethylene oxide: toxicity-application-protective
measures, Gaanask 5:3-6 (1933).
7. Walker, W.J.G. and Greeson, C.E. Toxicity of ethylene oxide, J. Hyg.
32:409-416 (1932).
8. Koelsch and Lederer. Toxicity of ethylene oxide. Zentralbl, Gewer-
behyg. 17:264-266 (1930).
9. Carpenter, C.P., Smyth, H.F., Jr., and Pozzani, U.C. Assay of acute
vapor toxicity and the grading and interpretation of results on 96
chemical compounds. J. Indust. Toxicol. 31:343-346 (1949).
10. Beck, G. and Susstrunk, M. Experiments on acute poisoning by cis-
and trans-dichloroethylenes and ethylene oxide, on the differences
in the actiois of the products, particularly the retarded action.
Arch. Gewerbepath. Gewerbehyg. 3:81-91 (1931).
11. Susstrunk, M. Acute intoxication by trans- and cis-dichloroethylenes
and ethylene oxide (at the same time a contribution to the knowledge of
narcosis). Thesis, Zurich, 1931: abstracted in Chem. Abstr. 28:1977
(1934).
12. Schwarz, L., and Deckert, W. Concerning the hygienic evaluation of T-gas
(ethylene oxide) as a pest control agent. Ztschr. Disinfekt. u.
Gesundheitsw. 22:531-552 (1930).
1-36
-------
13. Stehle, R.L., Bourne, W., and Lozinsky, E. Concerning the pharma-
oological action of ethylene oxide. Arch. Exper. Path. u. Pharmakol.
104:82-86 (1924).
14. Meyer, K.H. and Gottlieb-Billroth, H. Theory of narcosis by inhalation
of anesthetics. Ztschr. Physiol. Chem. 112:55-79 (1921).
15. Curroe, G.O., Jr. and Johnston, F. Glycols. American Chemical
Society Monograph, Series 114, New York, Peinhold Publishing
Corporation (1952).
16. Hess, L.G. and Tilton, V.V. Ethylene oxide: hazards and methods of
handling. Indust. Eng. Chem. 42:1251-1258 (1950).
17. Cotton, R.T. Carbon dioxide as an aid in the fumigation of certain
highly adsorptive cotroodities. J. Econ. Entomol. 23:231-233 (1930).
18. Metz, E. Poisoning by ethylene oxide (Cartox or T Gas). Samml.
Vergiftungsf. 10:37-38 (1939): abstracted in J. Indust. Hyg. Toxicol.
23:33 (1941).
19. Metz, E. Ethylane oxide poisoning (Cartox). Arztl. Sachverstand-
Ztg. 44:155-157 (1938): abstracted in J. Indust. Hyg. Toxicol.
20:197 (1938).
20. Blackwood, J.D. and Erskine, E.B. Carboxide poisoning. U.S. Navy
Mad. Bull. 36:44-45 (1939): abstracted in Chem. Abstr. 32:2208 (1938).
21. Von Oettingen, W.F. Ethylene oxide in supplement to occupation and
health. Encyclopedia of Hygiene, Pathology, and Social Welfare,
Geneva, International Labour Office (1939).
22. Von Oettingen, W.F. Poisoning: a guide to clinical diagnosis and
treatment, New York, Paul B. Hoeber, Inc. (1952).
23. Sexton, R.J. and Henson, E.V. Dermatological injuries by ethylene
oxide. J. Indust. Hyg. Toxicol. 31:297-300 (1949).
24. Sexton, R.J. and Henson, E.V. Experimental ethylene oxide human skin
injuries. Arch. Indust. Hyg. Occup. Mad. 2:549-564 (1950).
25. Van Duuren, B.L., Orris, L. and Nelson, N. Carcinogenicity of epoxides,
lactones and peroxy compounds. II. J. Nat. Cancer Inst. 35:707-717 (1965)
26. Walpole, A.L. Carcinogenic action of alkylating agents. Ann. N.Y. Acad.
Sci. 68:750-761 (1958).
27. Reyniers, J.A., Sacksteder, M.R. and Ashburn, L.L. Multiple tumors in
female germfree inbred albino mice exposed to bedding treated with ethy-
lene oxide. J. Nat. Cancer Inst. 32:1045-1057 (1964).
1-37
-------
28. Rannug, U., Goethe, R. and Wachtmeister, C.A. The mutagenicity of
chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloro-
acetic acid, conceivable metabolites of vinyl chloride. Chem.-biol.
Interact, (in press) (1976).
29. Ktflmark, G. and Westergaard, M. Further studies on chemically induced
reversions at the adenine locus of Neurospora. Herryiitas 39:209-224
(1953).
30. Nakao, Y. anc Auerbach, C. Test of a possible correlation between
cross-linking and chromosome breaking abilities of chemical mutagens.
Z. Vererbungsl. 92:457-461 (1961).
31. Watson, W.A.F. Further evidence of an essential difference between the
genetical effects of mono- and bifunctional alkylating agents. Mutat.
Res. 3:455-457.
32. Fahmy, O.G. and Fahmy, M.J. Gene elimination in carcinogenesis:
reinterpretation of the somatic mutatior. theory. Cancer Res.
30:195-205 (1970).
33. Embree, J.W. and Hine, C.H. Mutagenicity of ethylene oxide. Toxicol.
Appl. Pharraacol. 33:172-173 (1975).
34. Smithsonian Science Information Exchange, Chemical Teratogenesis, AW
26, November 1977.
35. Boyd, J.B. Ethylene oxide position document 1. Ethylene Cxide
Working Group, U.S. Environmental Protection Agency. October 1977.
36. Brewer, J.H., and Keller, G.H. A comparative study of ethylene oxide
and radiation sterilization of medical devices. Int. At. Energy
Agency 92(26):311-337 (1967).
37. Pertel, R. [Office of Special Pesticide Reviews, EPA]. September 9,
1977. ETO mutagenicity: human exposure. Memorandum to J. Boyd
[Office of Special Pesticide Reviews, EPA]. 2pp.
1-38
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PROPYLENE OXIDE
(Propane, 1,2-Epoxy-)
2.1 Bioaccumulation
There is no potential for bioaccunulation of propylene oxide due to
its high solubility (40.5% at 20°C, 59% at 25°C) (G9) and negative
log PQCt value (log PQCt - -0.13) (1).
2.2 Contaminants and Environmental Degradation or Conversion Products
IAFC monograph (G9) reports propylene oxide specifications from a
producer as follows: acetic acid 0.005%, water 0.01%, propionaldehyde
0.05%. Propylene oxide reacts with active hydrogen compounds (e.g., al-
cohols, amines) and with inorganic chloride in foods to form 1-chloro-
2-propanol (G9).
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances (G16)
±s the acute
Parameter
LD50
LCLo
LC50
LCTo
I£50
LD50
toxicity of propylene
Dosage
930 mgAg
4000 ppm/4H
1740 ppm/4H
2005 ppm/4H
1500 mgAg
690 mgAg
oxide as follows
Animal
rat
rat
mouse
dog
rabbit
guinea pig
*
•
Route
oral
inhalation
inhalation
inhalation
skin
oral
i-39
-------
Rowe et al. (2) have reviewed the toxicity of propylene oxide. Major
toxicity effects and sources cited in this article are as follows:
In a skin contact study/ cotton pads moistened with undiluted or
diluted (10% and 20% aqueous solutions) propylene oxide were applied to
rabbits' skin from 1 to 60 minutes and observed for six to seven days follow-
ing exposure. Hypermia and edema resulted from all preparations when the
duration of skin contact was six minutes or longer. The severe exposures
resulted in scar formation.
There is a hazard from inhalation of propylene oxide vapors in ex-
perimental animals ^s shown in Tables 1 and 2 below.
Table 1
Mortality of Female Rats Exposed to
Various Concentrations of Propylene Oxide
Vapor for Single Periods
PPM
16,000
8,000
4,000
2,000
itrations
Mg/L.
38,0
19.0
9.5
4.7
Period of
Exposure, Hr.
0.50
0.25
2.0
1.0
0.50
0.25
7.0
4.0
2.0
1.0
7.0
Rats
Total No.
10
15
10
10
10
10
10
10
10
5
10
No. that died
10
0
10
5
2
0
10
4
4
0
0
1-40
-------
Table 2
Jfortality of Female Guinea Pigs
Exposed to Various Concentrations of Propylene
Cod.de Vapor for Single Periods
Vapor Concentrations
PPM Ma/L.
16,000 38.0
8,000 19.0
4,000 9.5
2,000 4.7
Period of
Exposure, Hr.
1.0
0.5
4.0
2.0
1.0
7.0
4.0
2.0
7.0
Guinea Pigs
Total No. No.
5
5
10
5
10
5
5
5
5
that died
5
0
10
1
0
2
1
0
0
During the exposures the rats and guinea pigs exhibited eye irri-
tation, nasal irritation, difficulty in breathing, drowsiness, weakness
and occasionally some incoordination. The amount and extent of the
observed symptoms were dependent on the concentration and the duration of
exposure (2).
Dogs given single four hour exposures of different concentrations of
propylene oxide showed lacrimation, salivation and nasal discharge, vomiting
and death. When poisoning progressed far enough to produce vomiting, the
dog usually died. The mortality rate in dogs at various concentrations
is reported as follows (3) in Table No. 3:
1-41
-------
Table 3
Concentration Mortality % Mortality after 14 days
PPM Mg/m3
2,481 5,880 3/3 1st hr 100
2,030 4,810 1/3 1st hr, 67
2/3 1st day
2,005 4,750 1/3 1st hr 33
1,363 3,230 0/3 14th day 0
Postmortem examination of dogs reveals that those exposed to con-
centrations of 2030 and 2480 had marked congestion of the tracheal mucosa
and comparable vascular phenomena in the lungs. Spotty alveolar edema
and marked prevascular and peribronchial edema were present. Focal areas
of subepithelial edema in the terminal bronchioles and necrobiosis of
the bronchiolar epithelium were noted. Subpleural hemorrhage was occa-
sionally found. Subendo cardial ecchymoses were noted and are believed
to be a secondary effect of the terminal anoxia (3).
2.4 Other Toxic Effects
Guinea pigs, monkeys, rabbits and rats were exposed for 7 hours to
propylene oxide vapor, 5 days/week for 6 or 7 months. Rabbits and mon-
keys, but not guinea pigs or rats tolerated 1095 mg/m (460 ppm). Mon-
keys, rabbits, rats and male guinea pigs tolerated 464 mg/m (195 ppm).
In female guinea pigs increases in the average weight of the lungs
were observed. All four species tolerated 243 mg/m (102 ppm) without
adverse effect (2,G9). Propylene oxide is about one-third as toxic
as ethylene oxide when administered by ingestion or by inhalation, in
1-42
-------
all of the species studied (3,G9).
A paper by Mclaughlin (4) has been cited in an IAPC monograph (G9)
reporting three cases of corneal burns in man from propylene oxide vapor.
The TLV assigned by ACGIH is 100 ppm (approximately 240 mg/foi ) for
propylene oxide (Gil).
2.5 Carcinogenicity
Only one study (5) of the carcinogenic potential of propylene oxide
was found in a secondary source (G9). This study was reviewed by the 1976
IARC expert committee. Propylene oxide was carcinogenic in a limited study
in rats by subcutaneous injection and produced local sarcoma (G9). Ex-
perimental details outlined in the IARC monograph are as follows:
"Of 12 rats (age at start not specified) given to-
tal doses cf 1500 mg/kg bw propylene oxide in arachis
oil by s.c. injection within 325 days (dosing schedule
not specified), 8 developed local sarcomas after 507-
739 days. In a similar experiment in which total doses
of 1500 mgAg bw propylene oxide in water were injected
subcutaneously, 1/12 rats developed a local sarcoma af-
ter 158 days, and 2 developed local sarcomas after 737
days. In a concurrent experiment, ethylene oxide pro-
duced negative results."
2.6 Mutagenicity
Mutagenicity data of propylene oxide has been recently evaluated
1-43
-------
and reported in one EPA report (G28) as follows:
Propylene oxide has been demonstrated to induce reversions to
adenine prototrophy in Neurospora craasa w. 40 "distinctus" A (from
strain 38701). At the optimal concentration and time (0.5 M in a sus-
pension containing approximately 132 x 10 conidia for one hour), the
mutation frequency observed was 80/10 surviving conidia. In untreated
controls after one hour of incubation, the mutation frequency was 0/10
survivors. Although a dose-survival relationship was established for
propylene oxide during the optimization of the test concentration, there
was no data reported indicating that a dose-response effect in induction
of mutants had been observed (6). This test was classified "negative/
inadequate" as this is the result of a single test in which the chemical
was assayed at a dose chosen for optimal survival and mutagenicity.
Propylene oxide was reported to be active in inducing sex-linked
recessive lethal mutations (Muller-5 Test) in D. melanogaster Oregon-K.
Drosophila sperm were treated by a post-copulatory douche with the chem-
ical. The mutation rate was 1.2% (13 lethals from 12 males/1074 tested)
versus 0.06% (i lethal/1650 tests) iun untreated controls. Although
the result suggests a positive effect, this report is essentially an
abstract, and the data presented are insufficient for evaluation of this
test (e.g., no demonstration of dose-response and inadequate description
of the experimental method) (7).
Propylene oxide (330 mM) was reported to be inactive in inducing
host-range mutations in bacteriophage T2h . Mutants were identified as
phage able to infect T2h+-resistant Escherichia coli B/2 (8).
1-44
-------
In addition to Schalet's publication (7) the IARC monograph has cited
two Russian articles (9,10) which indicate that propylene oxide induced
recessive lethal mutations in Drosophila melanogaster. No experimental
details have been reported in the monograph.
Propylene oxide reacts with DNA at neutral pH to yield two principal
products, N-7-(2-hydroxypropyl)guanine and N-3-(2-hydrcxypropyl)adenine,
according to a paper (11) cited in the IARC monograph (G9).
2.7 Teratogenicity
No information found in searched literature.
2.8 Metabolic Information
No information found in searched literature.
2.9 Ecological Effects
Aquatic toxicity rating - Tim 96 over 1000 ppm (G16). Various plastic
and cellulose products used as food wrappings and containers when fumigated
contained as much as 1500 mg/kg of propylene oxide (12, as reported in
G9), which may be of concern for ecological effects when discarded.
2.10 Current Testing
Propylene oxi.de is currently under test by NCI in rats and mice by
the inhalation route. The NCI chemical number is C50099 (G12).
1-45
-------
REFERENCES
1. Office Of Toxic Substances, EPA. Review of the environmental fate
of selected chemicals. Task 3, Final report, Contract no. 68-01-2681
(1977).
2. Howe, V.K., Hollingsworth, R.L., Oyen, F., McCollister, D.D. and
Spencer, H.C. Toxicity of propylene oxide determined on experimental
animals. Arch, Industr. Hlth. 13:228-236 (1956).
3. Jacobson, K.H., Hackley, E.B. and Feinsilver, L. The toxicity of
inhaled ethylene oxide and propylene oxide vapors. Arch. Industr.
Hlth. 13:237-244 (1956).
4. Mclaughlin, R.S. Chemical burns of the human cornea. Amer. J. Opthal.
29:1355-1362 (1946).
5. Walpole, A.L. Carcinogenic action of alkylating agents. Ann. N.Y.
Acad. Sci. 68:750-761 (1958).
6. Kolmark, G. and Giles, N.H. Comparative studies of monoepoxides as
inducers of reverse mutations in Neurospora. Genetics 40:890-902
(1955).
7. Schalet, A. Mutagenic action of 1,2-propyiene oxide and ethyl sulfate
on mature sperm. Dros. Info. Serv. 28:155 (1954).
8. Cookson, M.J., Sims, P. and Grower, P.L. Mutagenicity of epoxides
of polycyclic hydrocarbons correlated with carcinogenicity of parent
hydrocarbons. Nature (London) New Biol. 234:186-187 (1971).
9. Rapoport, I.A. Alkylation of gene molecule. Dokl. Akad. Nauk SSR
59:1183-1186 a948).
10. Rapoport, I.A. Action of ethylene oxide, glycidol and glycols on gene
mutation. Dokl. Akad. Nauk SSR. 60:469-472 (1948).
11. Lawley, P.O. and Jarman, M. Alkylation by propylene oxide of deoxyribo-
nucleic acid, adenine, guanosine and deoxyguanylic acid. Biochem. J.
126:893-900 (1972).
12. Hirashima, T., Oguma, T., Hosogai, Y. and Fujii, S. Gaseous anti-
microbial agents. III. Determination of propylene oxide residue in
food wrappings and containers. J. Pd. Hyg. See. Japan 11:161-163 (1970).
1-46
-------
STATUS OF CARCENOGENICITY S1UDIES ON EPQXIDES AT
NATIONAL CANCER INSTITUTE*
PART III
Based on their level of exposure, potential carcinogenicity and repre-
sntative substructures, the following chemicals are on test or were previously
msidered by the Chemcal Selection Working Group (CSWG) for carcinogenesis
.oassay testings:
CAS No. Name Status
75218 Ethylene oxide CBDS No. C50088
7556y Propylene oxide CBDS No. C50099
106898 Epichlorohydrin CBDS No. C07001
8013U78 Epoxidized soy oils Already considered by CSWG as
part of printing ink class; CSWG
considered previous tests adequate
72208 Endrin Considered as part of organo-
haiide study.
96093 Styrene oxide Received final NCI approval;
will be tested at PCRC
The following four epoxides are representative structures which have also been
Lected by CSWG for the reasons shown:
flame of Compound Reason for Nomination
2-Epoxybutane It is the only remaining epoxide having an annual
production of greater than 108 grams that is not
covered by current NCI tests or previous CSWS action.
It is representative of simple short chaiK epoxides
and it is mutagenic but has been reported inactive
as a carcinogen.
rcidol It is a representative short chain epoxide with
potential for significant human exposure. Gly-
cidol is mutagenic but has been reported as inac- -
tive in carcinogenicity tests where the related
compound glycidaldehyde has been reported active.
!-Epoxyhexadecane This epoxide was chosen as a representative long-
chain, terminal nonoepoxide having potential for
significant exposure. Preliminary studies with
1-47
-------
Name of Compound
1,2-Epoxyhexadecane
(Continued)
3,4-Epdxycyclohexy.iiuethyi-
3,4-epoxycyclohexane
carcoxylate
Reason for Nomination
mice indicate it may be carcinogenic.
This was recommended as the only diepoxide
with potential for signiticant exposure that
has not yet been adequately tested; it is
closely related to 3,4-epoxy-b-tnethylcyclohexyl-
rnethyl-3,4-epoxy-6-methylcyclohexane carboxylate
which is carcinogenic to mouse sKin.
"Epoxides Class Study" conducted by a class working group of the chemical
Selection working Group.
1-48
-------
CM STRUCTURAL ANALOGS (1)
PART IV
•A number of alkyl epoxides have been tested for carcinogenicity
mostly by painting the skin of mice and observing the formation of papillo-
mas and carcinomas. Although many of these chemicals are not of major in-
dustrial importance and some may only represent laboratory curiosities,
it is important to realize that not all of these alkyl epoxides are car-
cinogenic; but it is not clear at this time what factors in chemical
structure limit such carcinogenicity.
•Regarding the carcinogenic potency of diepoxides, it can be stated
that nearly all diepoxides are far more carcinogenic than monoepoxides
and the reason is to be found in the capability of diepoxides to cause
cross-linking between chains of DNA. Although diepoxides have been sug-
gested at one time as chenotherapeutic agents for the treatment of cancer,
it is unlikely that these compounds will become of major industrial signi-
ficance.
Because of the far lower toxicity of monoepoxides, it seems of im-
portance to put the available literature on the carcinogenicity of these
compounds that have not been dealt with earlier in the dossier together
in table form (See Table 1).
Epoxides with additional functional groups have not been considered
as structural analogs in this discussion, but a great number of such
analogs like epichlorohydrin, glycidal, and epoxystearic acid have been
found carcinogenic. These compounds will have to be considered as a
1-49
-------
separate group of epoxides and a separate dossier will have to be pre-
pared.
1-50
-------
TABLE 1. CARCINOGENICITY OF ALKYL EPOXIDES (2, 3, 4)
Compound Concentration Tumors
in acetone _ .,, _
Papillomas Carcinomas
Hexaepoxysqualene 1% 10
1,2,3,4-Diepoxybutane 3% 10 6
1,2,4,5-Diepoxypentane 10% 10 3
1,2,5,6-Die?oxyhexane 5% 40
1,2,6,7-Diepoxyheptane 1% 91
1,2,7,8-DiepoxyoetanR 1% 74
l-ethyleneoxy-3,4-epoxycyclohexane 10% (Benzene) 5 4
1,2,3,4-Diepoxycyclohexane 10% 0 0
1,2,5,6-Diepoxycyclooctane 10% 0 0
l-ethyl-3,4-epoxycydohexane 10% 0 0
Ethyleneoxycyclohexane 10% 0 0
Epoxycyclohexane 10% (Benzene) 0 0
Epoxycyclooctane 10% 0 0
l,2-Epoxybutene-3 no solvent 2 1
1,2-Epoxybutane. 10% 0 0
1,2-Epxoydodacane 2% 00
1,2-Epoxyhexadecane 10% 2 1
30 male Swiss Millerton mice were painted 3x weekly with 100 mg
solution/paint for life.
1-51
-------
1. Written ccnrauttication by Dr. Hans FaUc, NIEHS, Research Triangle Park,
N.C. 27709.
2. Orris, L., Van Duuren, B.L., and Nelson, N. Carcinogenicity of oxy cccn-
pounds. Acta Un. Int. Cancer 19(3-4):644-647 C1963).
3. Van Duuren, B.L., Orris, L., and Nelson, N. Carcinogenicity of epoxides,
lactones, and peroxy compounds. Part II. J. Nat. Cancer Inst. 35:707-717
(1965).
4. Van Duuren, B.L., Langseth, L., Goldschmidt, B.M., and Orris, L. Carcino-
genicity of epoxides, lactones, and peroxy cotpounds. VI. Structure and
carcinogenic activity. J. Nat. Cancer Inst. 39_: 1217-1228 (1967).
1-52
-------
ALKYL PHTHALATES
TABLE OF CONTENTS
Page
Overview II-l
Alkyl phthalates, long chain
Part I - General Information
Bis(2-Ethylhexyl) phthalate II-3
Dicyclohexyl phthalate II-6
Diisodecyl phthalate II-8
Diisooctyl phthalate 11-10
Dioctyl pthalate 11-12
Ditridecyl phthalate 11-14
n-Octyl n-decyl phthalate 11-16
Summary of characteristics 11-18
Alkyl phthalates, short chain
Part I - General Information
Dibutyl phthalate 11-19
Diethyl phthalate 11-22
Dimethyl phthalate 11-24
Summary of characteristics 11-26
Specific References 11-27
Part II - Biological Properties
2.1 Bioaccumulation 11-28
2.2 Contaminants and Environmental 11-29
Degradation or Conversion
Products
2.3 Acute Toxicity 11-31
2.4 Other Toxic Effects 11-31
Il-i
-------
Page
Part II - Biological Properties (Continued)
2.5 Carcinogenicity 11-31
2.6 Mutagenicity 11-37
2.7 Teratogenicity 11-38
2.8 Metabolic Information 11-41
2.9 Ecological Effects 11-44
2.10 Current Testing 11-50
References 11-51
Il-ii
-------
ALKYL PHTHALATES
AN OVERVIEW
This category consists of alkyl esters of 1,2-benzene dicar-
boxylic acid. They are generally water-insoluble liquids.
Many of the alkyl phthalates are produced in large volumes; an-
nual production of both Cdi (2-eth;ylhexyl) phthalate) and diisodecyl
phthalate) exceed one hundred million pounds.
Alkyl phthalates are primarily used as plasticizers for resins,
including vinyl chloride resins. They also have numerous household
applications/ such as in model cements, paints and wood finishes.
The di(2-ethylhexyl) phthalate has been estimated to be released
into the environment at a rate of 440 million pounds annually,
while about 30 million pounds of dibutyl phthalate and 20 million
pounds of diethyl phthalate are released. It is estimated that
over 3 million U.S. workers are occupationally exposed to alkyl
phthalates.
Alkyl phthalates are relatively stable, breaking down only slowly
to monophthalates or phthalic acid. High bioaccumulation factors for
alkyl phthalates have been observed in aquatic invertebrates and plants.
Fish show much lower bioaccumulation of phthalates, apparently because
of superior abilities to metabolize and excrete phthalates. Widespread
occurrence of the phthalate esters in aquatic ecosystems has been re-
ported.
Although the alkyl phthalates are relatively toxic to fish and
aquatic invertebrates, they have a low order of actxte toxicity to
II-l
-------
mammals and birds. The shorter chain esters are more toxic to mam-
mals than the longer chain compounds. The mutagenicity and carcino-
genicity of these chemicals are not adequately established. However,
positive teratogenic results have been reported.
The chronic toxicity has been indicated in sub-lethal exposures
that inhibited reproduction in daphnia, reduced the survival of eggs
and fry of fish and reduced egg shell thickness in birds. Biological
significance levels and the levels and frequency of occurrence of
residues in fish have not been adequately determined.
II-2
-------
ALKYL PHTHALAIES - LONG CHAIN
PART I
GENERAL DEFORMATION
I. Bis(2-Ethylhexyl) phthalate
1.1 Identification CAS No.: 000117817
NIOSHNo.; TI03500
1.2 Synonyms and Trade Names
1,2-Benzenedicarboxylic acid, bis (2-ethylhexyl) ester; phthalic acid, bis
(2-ethylhexyl) ester; Compound 889; DEHP; di( 2-ethylhexyl) orthophthalate;
di (2-ethylhexyl) phthalate; di-sec-octyl phthalate; OOP; 2-ethylhexyl phtha-
late; Flexol OOP; Flexol plastic ' •ser OOP; Hercoflex 260; Octoil; Pitts-
burgh PX-138; RC plasticizer DOP; Witcizer 312; Truflex OOP; Staflex DOP
(G16,G23)
1.3 Chemical Formula and Molecular Weight
,COO
C24H 04 Mol. Wt. 390.54
fYY*} rrT /^TT //n TT * "WT \ ^^TT **~ jo "
(G23)
1.4 Chemical and Physical Properties
1.4.1 Description; Light-colored odorless liquid; combustible
(G21)
1.4.2 Boiling Point; 231° C at 5rtm (G25)
1.4.3 Melting Point; -46° C (G25)
1.4.4 Absorption Spectrotnetry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility; Insoluble in water;
Soluble in all proportions in mineral oil
(G21)
1.4.7 Octanol /Water Partition Coefficient;
log PQCt =3-4 (estimate) (G36)
II-3
-------
1.5 Production and Use
1.5.1 Production:
435 Million Ibs (1972)
302.492 Million Ibs (1975)
296.739 Million Ibs (1976)
(G28)
(G24)
(G24)
1.5.2 Use;
As a commercial plasticizer in vinyl chloride resins;
in vacuum pumps; as a plasticizer in polystyrene;
as a plasticizer for many resins and elastomers; in
automotive seating, interior trim, and landau roofs
(321, G23, G25, G32)
Category
paints, varnishes,
shellac, rust pre-
ventatives, etc.
flame retardant
chemicals
household aerosols
chemical deodorizers
adhesives and adhesr'.ve
products, incl. glue
Product Information:
no. of bis(2-ethylhexyl)
phthalate containing
products
49
No. of bis(2-etnylhexyl)
phthalate products in
category
11
67
2
3
total no. of products
in category
0.4%
1.9%
1.8%
0.6%
0.6%
-xlOO
(G27)
The 132 chemicals surveyed contained an average of 3.5% bis(ethylhexyl) phthalate
Bis (2-ethylhexyl) phthalate is present in:
aerosol paints
lacquers
woodfinishes
model cement
household cement
children's "Plastigoop" (G35)
1.6 Esposure Estimates
1.6.1 Release Pate:
441.6 Million Ibs
(G28)
] 6.2 NOHS Occupational Exposure:
Rank: 333
Estimated no. of persons exposed: 693,000*
*rcugh estimate
(G29)
II-4
-------
1.7 Manufacturers
BASF wyandotte Corp.
B.F. Goodrich Co.
Continental Oil Co.
Tennessee Eastman Co.
Exxon Chemical Co.
W.R. Grace & Co.
Tenneco Chemicals, Inc.
Monsanto Co.
Reichhold Chemicals, Inc.
Teknor Apex Co.
Union Carbide Corp.
USS Chemicals Div. of U.S. Steel Corp.
(G24)
II-5
-------
ALKEL PHTHAIATES - LONG CHAIN
II. Dicyclohexyl phthalate
1.1 Identification CAS No.: 000084617
NIOSH No.:
1.2 Synonyms and Trade Names
Phthalic acid, dicyclohexyl ester; DCHP (G21,G22)
1.3 Chemical Formula and Molecular Weight
COO'
Mol. Wt. 330.43
1.4 Chemical and Physical Properties
1.4.1 Description; Prisms (from alcohol); white granular solid;
nonvolatile; mildly aromatic odor; combustible
(G21,G22)
1.4.2 Boiling Point;
No information found in sources searched
1.4.3 Melting Point; 66° C (G22)
1.4.4 Absorption Spectrometry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility; Insoluble in water;
Soluble in alcohol, ether, and most organic
solvents
(G21,G22)
1.4.7 OctanolAfeter Partition Coefficient;
log P .. * 3 - 4 (estimate) (G36)
3 oct
II-6
-------
1.5 Production and Use
1.5.1 Production;
No information found in sources searched
1.5.2 Use; As a plasticizer for nitrocellulose, ethyl cellulose,
chlorinated rubber, polyvinyl acetate, polyvinyl chloride,
and other polymers; in specialty plastics; in adhesives
(G21,G25)
1.6 Esposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
Rank: 1963
Estimated no. of persons exposed: 25,000*
*rough estimate (G29)
1.7 Manufacturers
Monsanto Co.
Pfizer, Inc. (G24)
II-7
-------
ALKYL PHTOAIATES - LONG CHAIN
III. Diisodecyl phthalate
1.1 Identification CAS No.: 026761400
NIOSH No.:
1.2 Synonyms and Trade Names
DIDP (G21)
1.3 Chemical Formula and Molecular Weight
,000 3
C28H46°4 Mo1- Wt' 446
000
(G21,G25)
1.4 Chemical and Physical Properties
1.4.1 Description; Clear liquid with a mild odor
(G21)
1.4.2 Boiling Point; 250 - 257° C at 4 mm (G21)
1.4.3 Melting Point;
No information found in sources searched
1.4.4 Absorption Spectrometry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility. Insoluble in glycerol, glycols, and some amines;
Soluble in most other organics and oils
(G21,G25)
] 4.7 Octanol/Water Partition Coefficient;
log P =3-4 (estimate) (G36)
II-8
-------
1.5 Production and Use
1.5.1 Production; 125 Million Ibs (1970) (G25)
105.668 Million Ihs (1975) (G24)
143.129 MiUion Ibs (1976) (G24)
1.5.2 Use; As a commercial plasticizer in vinyl chloride resins;
in calendered film and sheeting; in coated fabrics; in
wire and cable extrusion
(G21,G32)
1.6 Exposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
Rank: 1136
Estimated no. of persons exposed: 100,000*
*rough estimate (G29)
1.7 Manufacturers
BASF wyandotte Corp.
Continental Oil Co.
Tennessee Eastman Co.
Exxon Chemical Co.,
W. R. Grace & Co.
Tenneco Chemicals/ Inc.
Monsanto Co.
Reichhold Chemicals, Inc.
Hooker Chemical Corp.
Tekncr Apex Co.
USS Chemicals Div. of U.S. Steel Corp. (G24)
II-9
-------
ALKYL PHIHALATES - LONG CHAIN
IV. Diiscoctyl Phthalate
1.1 Identification CAS No.:
NIOSH No.:
1.2 Synonyms and Trade Names
DIOP (G21)
1.3 Chemical Formula and Molecular Weight
C24H38°4 M°1' "** 390'54
C8H17
(G23)
1.4 Chemical and Physical Properties
1.4.1 Description; Isomeric esters obtained from phthalic
anhydride and the mixed octyl alcohols;
nearly colorless viscous liquid; mild
odor; combustible
(G21)
1.4.2 Boiling Point; 370° C (G21)
1.4.3 Melting Point: < -50° C (G25)
1.4.4 Absorption Spectrometry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility; Insoluble in water;
Soluble in oils
(G21,G25)
1.4.7 OctanolAfater Partition Coefficient;
leg P . = 3 - 4 (estimate) (G36)
3 oct
11-10
-------
1.5 Production and Use
1.5.1 Production; 32.3 Million Ibs (1972) (G28)
1.5.2 Use; As a commercial plasticizer in vinyl chloride resins; as
a plasticizer for cellulosic and aerylate resins and
synthetic rubber
vG^l;
1.6 Exposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
Rank: 2703
Estimated no. of persons exposed: 10,000*
*rough estimate (G29)
1.7 Manufacturers
Reichhoxd Chemicals, Inc.
USS Chemicals Div. of U.S. Steel Corp. (G24)
11-11
-------
ALKYL PHIHAIATES - LDNG CHAIN
V. Dioctyl phthalate
1.1 Identification CAS No.: 000117840
NIOSH No.: TI19250
1.2 Synonyms and Trade Names
Phthalic acid, dioctyl ester; o-benzenedicarixocylic acid, dicctyl
ester; Celluflex COP; dioctyl c-benzenedicarboxylate; n-dioctyl
phthalate; octyl phthalate; Polycizer 162; PX-138
(G16)
1.3 Chemical Formula and Molecular Weight
C24H38°4 Mol> Wt* 390-54
(G25)
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless, odorless, stable, oily liquid
(G25)
1.4.2 Boiling Point; 248° C (G25)
1.4.J Malting Point; -25° C (G25)
1.4.4 Absorption Spectrometry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility: Insoluble in water;
Soluble in all proportions in mineral oil
(G25)
1.4.7 Octanol/Water Partition Coefficient;
log P =3-4 (estimate) (G36)
oct
11-12
-------
1.5 Production and Use
1.5.1 Production;
No information found in sources searched
1.5.2 Use; As a comercial plasticizer in vinyl chloride
resins
(G32,G35)
1.6 Exposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
No information found in sources searched
1.7 Manufacturer
Eastman Kodak Go. (G24)
11-13
-------
ALKYL PHTHMATES - LONG CHAIN
VI. Ditridecyl phthalate
1.1 Identification CAS No.: 000119062
NIOSH No.:
1.2 Synonyms and Trade Names
DODP (G21)
1.3 Chemical Formula and Molecular Weight
COO C
COO C13H2?
C34H58°4 Mol. Wt. 530.83
(G21)
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless liquid; combustible (G21)
1.4.2 Boiling Point; > 285° C at 5 mm (G21)
1.4.3 Melting Point;
No information found in sources searched
1.4.4 Absorption Spectroroetry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility;
No information found in sources searched
1.4.7 Octanol/Water Partition Coefficient;
log P =3-4 (estimate) (G36)
vJQ*> t
1.5 Production and Use
1.5.1 Production; 23.9 Million Ibs (1972) (G28)
15.664 Million Ibs (1975) (G24)
10.472 Million Ibs (1976) (G24)
1.5.2 Use; AS a piasticizer (G21)
11-14
-------
1.6 Exposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
Rank: 2710
Estimated no. of persons exposed: 10,000*
*rough estimate (G29)
1.7 Manufacturers
Exxon Chemical Co.
W. R. Grace & Co.
Tenneco Chemicals, Inc.
Reichhold Chemicals, Inc.
Hooker Chemical Corp.
Teknor Apex Co.
USS Chemicals Div. of U.S. Steel Corp. (G24)
11-15
-------
ALKYL PHTOALATES - LONG CHAIN
VII. n-Octyl n-ciecyl phthalate
1.1 Identification CAS No.: 000119073
NIOSH No.;
1.2 Synonyms and Trade Names
No information found in sources searched
1.3 Chemical Foiinula and Molecular Weight
-C H,
. Wt- 418.62
1.4 Chemical and Physical Properties
1.4.1 Description; Clear liquid; mild characteristic odor;
combustible
(G21)
1.4.2 Boiling Point; 232 - 267° C at 4 ran (G21)
1.4.3 Melting Point;
No information found in sources searched
1.4.4 Absorption Spectrometry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility;
No information found in sources searched
1.4.7 Octanol/Water Partition Coefficient;
log P . = 3 - 4 (estimate) (G36)
oct
11-16
-------
1.5 Production and Use
1.5.1 Production!
No information found in sources searched
1.5.2 Use; As a commercial plasticizer in vinyl chloride
(G21
1.6 Exposure Estimates
1.6.1 Release Rate:
No information found in sources searched
1.6.2 NOHS Occupational Exposure:
Rank: 1999
Estimated no. of persons exposed: 24,000*
*rough estimate
(G29)
1.7 Manufacturers
Reichhold Chemicals, Inc.
Tehnor Apex Co.
USS Chemicals Div. of U.S. Steel Corp. (G24)
11-17
-------
KLXXL PfflHAIATES, LONG CHAIN
OF CHARACTERISTICS
Name
Bis(2-ethyl-
hexyl)
phthalate
Dicyclohexyl
phthalate
Diisodecyl
phthalate
Discoctyl
phthalate
Dioctyl
phthalate
Ditridecyl
phthalate
n-Octyl n-
~ decyl ~
phthalate
Solubility
i in H_O;COin
mineral oil
i in HJD; s in
ale, eth, and
most os
i in glycerol,
glycols, some
amines; s in
most os and
oils
i in H_O; s in
oils
i in H20;oO in
mineral oil
*
Estimated
Environmental
Release
^ oct (Million Ibs)
3-4 (esti- 441.6
mate)
3-4 (esti- *
mate)
3-4 (esti- *
mate)
3-4 (esti- *
mate)
3-4 (esti- *
mate)
3-4 (esti- ^
mate)
3-4 (esti- ^
mate)
Production
(Million
•^435
302.492
296.739
*
~125
105.668
143.129
32.3
^
23.9
15.664
10.472
^
Ibs)
(1972)
(1975)
(1976)
*
(1970)
(1975)
(1976)
(1972)
*
(1972)
(1975)
(1.976)
*
Estimated no.
of persons
exposed
(Occupational)
~ 693, 000
^,25,000
^100,000
^v-10,000
*
~10,000
~24,000
Use
Plasticizer for many re-
sins and elastomers; va-
cuum puvps; automotive
seating
Plasticizer for many
polymers; specialty plas-
tics; adhesive
Plasticizer in v yl
chloride resins; coated
fabrics; cable and film
Plasticizer in many resins
and synthetic rubber
Plasticizer in vinyl
chloride resins
Plasticizer
Plasticizer in vinyl
chloride resins
11-18
* No information found in sources searched.
-------
ALKZL PHfflALAISS - SHORT CHAIN
PART I
GENERAL INFORMATION
I. Dibutyl phthalate
1.1 Identification CAS No.: 000084742
NIOSH No.: TI08750
1.2 Synonyms and Trade Names
Benzene-o-dicarboxylic acid, di-n-butyl ester; di-n-butyl phthalate;
o-benzenedicarboxylic acid, dibutyl ester; phthalic acid, dibutyl ester;
DBP; Celluflex DBP; Elaol; Hexaplas M/&; Palatinol C; Polycizer DBP; PX
104; Staflex DBP; Witicizer 300
(G16,G23)
1.3 Chemical Formula and Molecular Weight
Mol. Wt. 278.35
LAI Cl6H22°4
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless, odorless, stable, oily liquid;
combustible; nonvolatile
(G21,G25)
1.4.2 Boiling Point: 340° C (G22)
1.4.3 Melting Point;
No information found in sources searched
1.4.4 Absorption Spectrometry :
"\ alcohol
log 6 = 3.98, 3.18 (G22)
1.4.5 Vapor Pressure; 1 nm at 148.2° C (G22)
1.4.6 Solubility; Soluble in water (0.45g/100 ml at 25°C)
Soluble in all proportions in alcohol,
ether and benzene
(G22,G19 in 1)
1.4.7 Octanol/Water Partition Coefficient
log PQct =2.2 (estimate) (G36)
11-19
-------
1.5 Production and Use
1.5.1 Production: 29.1 Million Ibs (1972) (G28)
12.264 Million Ibs (1975) (G24)
13.702 Million Ibs (1976) (G24)
1.5.2 Use; As a plasticizer in nitrocellulose lacquers, elastomers; in
explosives, na.il polish and solid rocket propellants;
as a solvent for perfume oils; as a perfume fixative; as a
textile lubricating agent; in safety glass; in insecticides
and chigger repellent; in printing inks; as a resin solvent;
in paper coatings; in adhesives
(G21)
Consumer Product Information;
No. of dibutyl phthalate
No. of dibutyl products in category
phthalate containing total no. of products
Category products _ in
cleaning agents and 4 0.2%
compounds
paints, varnishes, shel- 67 0.6%
lac, rust preventatives,
etc.
flame retardant chemi- 12 2.0%
cals
household aerosols 5 0.1%
adhesives and adhesive 14 2.6%
products, incl. glue
caulking and spackle 5 7.7%
floor waxes 1 0.5%
The 108 products surveyed contained an average of 1.9% dibutyl phthalate
(G27)
Dibutyl phthalate is present in:
aerosol antiperspirants and deodorants
nail enamels, base coats and top coats
tractor and implement finishes
rubber sealants
floor waxes
emergency light markers (G35)
1.6 Exposure Estimates
1.6.1 Release Rate: 29.5 Million Ibs (G28)
11-20
-------
1.6 Exposure Estimates (Continued)
1.6.2 NOHS Occupational Exposure;
Rank: 259
Estimated no. of persons exposed: 1,006,000*
*rough estimate (G29)
1.7 Manufacturers
Sherwin Williams
Argus Chemical Corp.
BASF Wyandotte Corp.
CJjicinnati Milacron Inc.
Continental Oil Co.
Diamond Shamrock Corp.
Exxon Corp.
Filo Color and Chemical Corp.
FMC Corp.
B. F. Goodrich Co.
W. R. Grace & Co.
Hooker Chemical Corp.
Kay-Fries Chemical, Inc.
Monsanto Co.
Pfizer, Inc.
Reichhold Chemicals
Ronm and Haas Co.
Teknor Apex Co.
Tenneco Chemicals, Inc.
Tennessee Eastman Co.
Union Camp Corp.
United States Steel Corp.
Commerical Solvents Corp.
Union Carbide Corp.
(G25,G24,G31)
11-21
-------
ALKYL PHTHAIATES - SHORT CHAIN
II. Diethyl phthalate
1.1 Identification CAS No.: 000084662
NIOSH No.: TI10500
1.2 Synonyms and Tirade Names
1,2-Benzenedicarboxylic acid, diethyl ester; ethyl phthalate; Anozol;
Neantine; Palatinol A; Phthalol; Placidol E; Solvanol; DEP; phthalic
acid, diethyl ester
(G21,G16)
1.3 Chemical Formula and Molecular Weight
Mol. Wt. 222.24
(G22)
COOC2H,.
1.4 Chendcal and Physical Properties
1.4.1 Description; Colorless to water white, practically odorless,
oily liquid; bitter, disagreeable taste;
oanbustible (G23,G21)
1.4.2 Boiling Point; 295° C (G23)
1.4.3 Melting Point: NO information found in sources searched
1.4.4 Absorption Spectrometry ;
-\ alcohol _ .__ -_,.
A max " 225' 275 rm;
log £ = 3.9, 3.1 (G22)
1.4.5 Vapor Pressure: 1 nm at 108.8° C (G22)
1.4.6 Solubility; Insoluble in water;
Soluble in acetone and benzene;
Soluble in all proportions in alcohol;
ether and many other organic solvents
(G22,G23)
1.4.7 Octano3,Afetter Partition Coefficient
log P_. =1.8 (estimate) (G36)
OCu
11-22
-------
1.5 Production and Use
1.5.1 Production; 19.0 Million Ibs (1972) (G28)
11.661 Million Ibs (1975) (G24)
16.135 Million Ibs (1976) (G24)
1.5.2 Use; As a solvent for nitrocellulose, cellulose acetate; as
a plasticizer; as a wetting agent; in insecticidal sprays;
an a camphor substitute; in plastics; as a perfume fixative
and solvent; as an alcohol denaturant; in mosquito repel-
lents; as a plasticizer in solid rocket propellants
Consumer Product Information; (G21)
Diethyl phthalate is present in:
tarnish preventatives for gold, silver and brass.
colognes, perfumes, bathoils, shampoo
CG35)
1.6 Exposure Estimates
1.6.1 Release Rate; 19.3 Million Ibs (G28)
1.6.2 NOHS Occupational Exposure:
Rank: 171
Estimated no. of persons exposed: 1,240,000
1.7 Manufacturers
Kay-Fries Chemicals, Inc.
Monsanto Co.
Pfizer, Inc.
Eastman Kodak Co.: Tennessee Eastman Co. Div.
(G24)
11-23
-------
ALKYL PHTHAIATES - SHORT CHAIN
III. Dimethyl phthalate
1.1 Identification CAS No.: 000131113
NIOSH No.: TI15750
and Trade Names
Avolin; 1 , 2-benzenedicarboxylic acid, dimethyl ester; dimethyl benzene-
orthodicarboxylate; CMP; Ent 262; Fermine; methyl phthalate; Mipax; OTM;
Palatinol M? phthalic acid, dimethyl ester; phthalic acid, methyl ester;
Solvanom; Solvarone
(G16)
1.3 Chemical Formula and Molecular Weight
COOCH3
Mol. Wt. 194.19
COOCH3
(G22)
1.4 Chemical and Physical Properties
1.4.1 Description: Colorless to pale yellow oily liquid; odor-
less to slight aromatic odor; combustible
(G21,G22,G23)
1.4.2 Boiling Point; 283.8° C (G22)
1.4.3 Melting Point: 0-2° C (G22)
1.4.4 Absorption Spectrometry :
-v alcohol ~oc __.
^ max = 225' 274 nm;
log £ = 3.92, 3.10 (G22^
1.4.5 Vapor Pressure; 1 im\ at 100.3° C (G22)
1.4.6 Solubility; Insoluble in petroleum ether, and other
paraffin hydrocarbons;
Soluble in benzene, water (0.5g/100 ml) ;
Soluble in all proportions in alcohol, ether
and chloroform
(G22,G23,G19
In 1)
11-24
-------
1.4 Chemical and Physical Properties (Continued)
1.4.7 Octanol Abater Partition Coefficient:
log PQct =1.5 (estimate) (G36)
1.5 Production and Use
1.5.1 Production; 6.771 Million Iba (1975)
8.836 Million U» (1976) (G24)
1.5.2 Use: As a plasticizer for nitrocellulose and cellulose acetate,
resins, rubber and in solid rocket propellants; in lacquers;
in plastics; in rubber; in coating agents; in safety glass;
in nolding powders; in insect repellents; in perfumes
Consumer Product Information; (G21)
Dimethyl phthalate is present in:
plastic fillers (G35)
1.6 Exposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure
Rank: 1691
Estimated no. of persons exposed: 36,000*
*rough estimate (G29)
1.7 Manufacturers
Kay-Fries Chemicals, Inc.
Monsanto Co.
Pfizer, Inc.
Eastman Kodak Co.: Tennessee Eastman Co. Div.
Tanatex Chemical Corp.
(G24)
11-25
-------
Name
Dibutyl
phthalate
Diethyl
phthalate
Dimethyl
phthalate
ALKYL PHTHAIATES, SHORT CHAIN
OF CHARACTERISTICS
Solubility
ss in H~O;CO in
ale, eth and bz
i in H«0; s in
ace ana bz;OO in
ale, eth and many
other os
ss in H-O, i in
peth, and other
paraffin hydrocar-
bons; s in bz;
in ale, eth, and
chl
Log P
oct
2.2
(estimate)
1.8 (esti-
mate)
1.5 (esti-
mate)
Estimated
Environmental
Release
(Million IDS)
29.5
19.3
Production
(Million Ibs)
29.i (1972)
12.264 (1975)
13.702 (1976)
19.0 (1972)
11.661 (1975)
16.135 (1976)
6.771
8.836
(1975)
(1976)
Estimated no.
of persons
exposed
(Occupational)
Use
.1,006,COO Plasticizer; solvent; in-
secticide; ink; coatings;
adhesives
1,240,000 Solvent; plasticizer;
insecticide; fixative;
wetting agent
36,000 Plasticizer/ insect re-
pellent
* No information found in sources searched.
II- 26
-------
SPECIFIC REFERENCE FOR PART I
1. Autian/ J. Ibxicity and Health Threats of Phthalate Esters: Review of the
Literature Environ. Health Perspec. 4 (1973)..
11-27
-------
AUCYL PHTHAIATES
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccimilation
Metcalf et al. (1) carried out studies to determine the uptake of
labeled DEHP directly from water by various aquatic plants and animals.
They also evaluated the magnification properties of DEHP in a laboratory
model ecosystem that included a terrestrial-aquatic interface and a
seven-element food chain. The authors concluded that DEHP closely
resembles DDT in the rate of uptake and storage, that DEHP partitions
strongly in lipids of plants and animals and is concentrated in moving
through the food chains. At the end of the 33-day model ecosystem study,
Oedogonium (algae) had bioconcentrated DEHP by a factor of 53,890,
Physa (snails) by 21,480, Culex (mosquito larvae) by 107,670, and Gam-
busia (fish) by 130. Failure to bioaccumulate DEHP in Gambusia, indicates
that DEHP is metabolized by fish. Similar experiments with guppies show
that they metabolize DEHP rapidly while invertebrates and plants degrade
DEHP at a much slower rate (1). These results appear to account for high
bioaccumulation in invertebrates and plants.
A laboratory study reported the accumulation of DEHP by fathead minnows
to levels 160 to 1130 times the concentration in water. 12.3 days after
the fish were transferred to fresh water, 50% of the DEHP was eliminated (2)
11-28
-------
Bioaocruraulaticxi of DNBP by aquatic invertebrates was studied by ex-
posing the organisms to DNBP containing 14C-labeled tracer (3,4). From
what appear to be almost identical experiments, the two papers reported
different bioaccumulation factors. Sanders, Mayer and Walsh (3) report
the 14-day bioaccumulation factors of 5000 and 6700 for waterfleas (Daphnia
magna) and scud (Gammarus pseudolimneuis), respectively. Mayer and Sanders
(4) report these figures as 400 and 1400, respectively. However, the
data from Sanders et al. are from flow-through bioassays and those from
Mayer and Sanders are unspecified and may be from static bioassays.
Environmental samples that were analyzed for phthalates substantiated
the laboratory predictions of phthalate bioaccumulation. Mayer, Stalling
and Johnson (5) reported concentrations of 3.2 ppm EEHP in channel catfish.
Tadpoles were found to contain 0.5 ppm ENBP (5). A survey of 145 commercial
catfish farms revealed that 95% of the fish analyzed contained CEHP re-
sidues. The average DEHP concentration was 3.15 ppm (6). Water concen-
tration levels -were not reported.
The log octanol-water partition ratios of the phthalates are in the
range expected to cause bioaccumulation. High bioaccumulation factors are
indeed observed with aquatic invertebrates and plants (up to 100,000).
Bioaccumulation factors are much lower with fish (130-1130) apparently
owing to their superior ability to metabolize and excrete the phthalates.
2.2 Contaminants and Environmental Degradation or Conversion Products
In an aquatic model ecosystem di-n-octyl phthalate exhibited a
half-life of about five days. Major degradation products in the water
were phthalic acid and nono-octyl phthalate (8).
11-29
-------
14
In another study, C-DEHP rapidly decreased in the guppy (Lebistis
reticulatus) from 88.5% of the total radioactivity after one day to 37.1%
after two days 'vith concomitant increase of polar metabolites (45, as
reported in 1). Products were phthalic acid (23.8%) and small amounts
of a metabolite believed to be phthalic anhydride. Degradation of DEHP
was much slower with the water flea, snail and the aquatic plant Elodea.
Products were similar to those from the guppy.
Specific data concerning individual esters follows:
Dibutyl Phthalate
4 BOD: 19% of theoretical after 5 days at 20°C
Ibtal theoretical oxygen demand = 2.25 (gmAg)
Reacts with oxidizing agents
(G15)
Di-2-ethylhexyl Phthalate
Impurities in product: 2-ethylhexanol, phthalic acid, mono-
ethylhexylphthalate, water, 2-ethylhexylbenzoate. Reacts with
oxidizing materials, unreactive towards peroxide and ozone.
Activity towards hydroxyl radical: t^ ,2= 1 ^aY
It hydrolyzes fairly rapidly at pH 10 (t1/2 ~ 8 days) but
much more slowly at lower pH values.
(G14,G15)
Diisodecyl phthalate
Reacts with oxidizing materials
(G15)
Diisoctyl Phthalate
Reacts with oxidizing materials
(G15)
11-30
-------
n-Octyl-n-decyl Phthalate
Reacts with oxidizing materials
(G15)
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances (G16)
reports the acute toxicity of phthalate esters as shown in Table 1.
The alkyl phtnalates have a low order of acute toxicity in manuals.
The shorter chain esters are more toxic than the longer chain compounds
(9).
Some of the acute toxic effects of phthalate esters may be attri-
butable to contamination with phthalic anhydride (10).
2.4 Other Toxic Effects
The effectis of repeated doses of alkyl phtnalates on humans and
various laboratory animals are summarized in Table 2. Data for this table
are taken directly from the secondary source cited; the primary reference
refers to the article which originally reported the result. Nearly
all of the investigations concluded that the phthalates constitute a
chemical family of very low order of toxicity, as measured by ingestion
methods (11).
2.5 Carcinogenicity
Two reviewers reported no evidence of carcinogenicity for these ma-
terials. Krauskopf, in 1973/ reviewed the literature on the oral toxi-
city of the phthalate esters. Though numerous long term feeding studies
11-31
-------
TABLE 1
ACTTTE DOSAGES
Ccnpoimd
Dibutyl Phthalate
Diethyl Phthalata
Dimethyl Phthalate
Diethylhexyl Fhthalate
Dioctyl Phthalate
OF ALKXL PHTHALATES (G16)
TDLo CCNS)
LD50
LD50
LD50
LDLO
LD50
LD50
LCLO
LD50
LD50
LD50
TDLO (GIT)
LD50
LDLO
LD50
LD50
LD50
TDLO (GIT)
Dosage
140 mgAg
3050 mgAg
5058 mgAg
2749 mgAg
1000 mgAg
3375 mgAg
1580 mgAg
1000 ppm
4400 mgAg
2400 mgAg
8500 mgAg
143 mgAg
31 gmAg
300 mgAg
14 gm/kg
34 gmAg
10 gm/kg
143 mgAg
Animal
human
rat
rat
mouse
rabbit
rat
mouse
cat
rabbit
guinea pig
thicken
man
rat
rat
mouse
rabbit
guinea pig
man
Route
oral
intraperi-
toneal
intraperi-
toneal
intraperi-
toneal
oral
intraperi-
toneal
intraperi-
toneal
inhalation
oral
oral
oral
oral
oral
intravenous
intraperi-
toneal
oral
skin
oral
TQXICriY ORDER
(i.p.)
Mouse (i.p.)
Rabbit (oral)
Dibutyl
Dimethyl
dimethyl
diethyl
Diethyl \ Dimethyl
diethyl
diethylhexyl
Diethylhexyl
11-32
-------
TABLE 2
Ccnpound
Species
Ditutyl Phthalate rats
(DBF)
2 DBF
rats
3 DBF
rats
4 DBF
rats
OF CHRONIC TOXIC EFFECTS OF PHTHALATE ESTERS
Dose
100 mgAg/day
Period
5 generations
(seme for 21
months)
300 mgAg/day 3 generations
(some for 21
months)
500 ing/kg/day
1.25%
3 generations
(some for 15
months)
2-5 mgAg/day 6 months
0.01% day
0.05% day
1.25% day
0.25% (350-
llOmgAg
body weight
1 year
1 year
1 year
1 year
1 year
11-33
References
Effects
No poisonous or carcin-
ogenic effects at all dose
levels. Normal weight
gains and reproductive
patterns.
Primary
12
No effect; recommended
maximun level of 2 mg/1
in reservoir due to toxi-
city; taste and odor
threshold at 5 mg/1
no effect
no effect
50% died in 1 week;
lesions observed
no
No effects (acute oral
lethal dose = 8 gAg)
50% fatal in 1 week;
other 50% sim'.lar to con-
trols. No gross or micro-
scopic changes; DBF meta-
bolized by pancreatic
lipases
13
12
14
Secondary
11
11
11
11
-------
TABLE 2 (Continued)
Compound
5 DBF
c DEHP
7 DEHP
8 DEHP
rat
rat
rat
9 DEHP
10 DEHP
rat
rat
Dose
Period
1.25%
0.25%
500 mgAy/day
(oral)
0.5% of diet
(oral)
0.13% of diet
(oral)
0.4%
0.04%
0.5 mgAg/day
(oral)
0.5% of diet
(ora])
1 year
4 generations
2 years
2 years
6 months
2 years
0.1%
References
Effects
At 1.25% death occurred in five
of ten animals during first week
but the survivors at this level
and all animals at 0 * 25% level
showed no sign of clinical or
tissue toxicity
Normal reproduction. Mo anoma-
lies during parturition or
nursing
All body weights and organ
weights unaffected. No patho-
logical changes
No effects
Primary
14
Secondary
9
12
15
16
11
11
11
11-34
No effects
Mortality: no effect due to
DEHP
Body weight: no effect due to
DEHP
Food intake: no effect for
first year; but 0.5% group
ate only 75% of control
group during second year
No effect: 0.1% in rats for
2 years
Organ weight: no difference,
except for slight increase of
liver and kidney with 0.5% diet
Pathology: no effect
13
15
11
11
-------
•EABIE 2 (Continued)
1
11 DEHP
12 DEHP
13 DEHP
14 DEHP
15 DEHP
rat
rat
mouse
mouse
16 DEHP
17 DEHP
18 Dinethyl Phtha-
late
Reference
Ccnpound
>
Species
rat
Dose
variable
(oral)
Period
13 weeks
dog
dog
unspecified
1.0 rug/kg/day
(intravenous)
3.7 mg/kg/day
variable
(oral)
200-400 mg/
kg/day
(inhalation)
(intraperito-
neal)
5.0 gm/day
(oral)
0.13% of diet
(oral)
unspecified
(inhalation)
Effects
19 injections
in 63 days
Chronic un-
specified
At doses higher than 200 mg/
kg/day, there was growth re-
tardation, testicular degener-
ation and tubular atrophy
No affects on growth rate, or-
gan weights, hematology or be-
havior. No biochemical or
pathological changes
No effects below 60 mg/kg/day
Primary
18
18
15,17,
18
Growth rates depressed; enlarged
livers and kidneys
1 hr., 3 tines/ No signs of unusual effects or
week for 12 behavior; autopsies revealed signs
weeks of diffuse chronic inflammation in
the lungs similar to a burn
21
11 weeks
14 weeks
1 year
repeated
Some cumulative effect is evi- 20
denced by the fact that the i.p.
U350 decreased from 25.41 ml/kg
the first week to 3.06 ml/kg at
the end of 11 weeks
Slight loss in rate of weight 15
gain; no other effects
No effects 16
Irritation of nasal mucous mem- 24
branes and upper respiratory
tract. May lead to CNS depres-
sion and eventual paralysis
Secondary
9
19
10
10
11
11
10
11-35
-------
2 (Continued)
£ Conpound Species
19 UMP rat
20 DMP
rabbit
21 Dioctyl Phthalate mouse
22 Di mixed heptyl rat, mouse
& nonyl phtha-
lates
23 Diisodecyl
Phthalate
rat, dog
Dose
4%-8% in diet
(oral)
4 mlAg
(dermal)
(intraperito-
neal)
0.125% in diet
(oral)
0.25%
0.5%
1.0%
1% in diet
(oral)
Period
2 years
90 days
11 weeks
5 days/wk
90 days
14 weeks
References
Effects
Slight reduction in growth.
Noticeable kidney damage at
8% level
50% of population died in 90
days. 90-day dermal 1D50 =
4
Primary
24
20
20
Some cumulative effects are
evidenced by the fact that the
ID50 decreased from 6.40
the first week to 1.37
after 10 weeks
Definitely no effect at 0.125% 22
Slight anemia at 0.25% and above
Increased kidney and liver weights
at 0.5% and above
Growth retardation in males at 1%
No histological changes observed. 23
Slightly elevated liver/body
weight ratio in male dogs. Livers
markedly heavier in rats
Secondary
10
10
10
11
19
11-36
-------
are cited, the author stated that "no carcinogenic characteristics were
found by any of the investigators" (11).
Later in the same year, Autian stated that "no animal data have yet
demonstrated that any of the phthalate esters act as carcinogenic agents.
Likewise, their role as possible co-carcinogens has not been established"
(10).
Dogs given 19 oral doses of 0.03 mlAg of di-ethylhexyl phthalate
followed by 221 doses of 0.06 mlAg over the course of one year showed
no carcinogenic effects (17, as reported in 10). However, no evalua-
tion about the cercinogenicity of DEHP can be made because of the
short experimental duration.
2.6 Matagenicity
In 1973, Autian (10), in reviewing the literature on phthalate
esters stated that "no published information is available on the muta-
genic effects of phthalate esters." Since then, a dominant lethal assay
study in mice has been reported (26), as described below.
Ten male mice were treated intraperitoneally with DEHP at one-
third, one-half, and two-thirds of the acute LD50 dose (12.78, 19.17
and 29.56 mlAg respectively). The results revealed significant re-
ductions in mean live fetuses and mean implants per pregnancy which were
indicative of a dominant lethal mutation for the compound
A bacterial mutagenesis study is reported in the abstract of a
Japanese article. DEHP was reported to be non-mutagenic in bacterial
tests. However, the monoester, which is a metabolite of DEHP, showed
II-37
-------
DMA damage-provoJcing activity in Bacillus subtilis and mutagenicity in
E. Coli (27).
2.7 Teratogenicity
Positive results ware reported in three studies. One is a feeding
study with mice, the other two are intraperitoneal studies using rats and
chicks.
An abstract of a Japanese article (27) reports that DEHP was adminis-
tered orally to pregnant mice at 1/12 - 1/3 of the LD50 dose, once a
day during days 6-10 of gestation. Many fetal deaths were observed at
higher doses on day 7. Very few deaths were recognized in the groups
treated on dayr9 and 10 even with the highest dose. A significant number
of external and skeletal malformations were found in the group with 7.5
ml/kg on day 8.
The intraperitoneal study (28) in the rat was performed as follows:
Relatively high (0.3 - 10.0 ml/kg) doses of several phthalate esters
were injected intraperitoneally into pregnant Sprague-Dawley rats three
times during gestation, on days 5, 10, and 15. Table 3 shows the numbers
and precentages of resulting malformed embryos. Abnormalities noted
included the absence of tails and eyes and twisted legs. Less dramatic
skeletal anomalies were also noted.
Despite the nigh doses used in the rat experiment, the investigators
believe that the najor anomalies are impressive because of the unusual
dose regime followed. Rat organogenesis begins at about day 8 and is,
for many organ systems such as the brain and limb buds, complete by day
11-38
-------
TABIE 3
GROSS AND SKELETAL MALFORMATIONS
PRODUCED BY PHIHAIATE ESTERS (28)
Volume
Injected
mlAg
None
10.00
10.00
10.00
5.00
1.125
0.675
0.338
1.245
0.747
0.374
1.686
1.012
0.506
1.017
0.610
0.305
1.250
0.750
0.375
2.296
1.378
0.689
10.00
5.00
10.00
5.00
Number of
Resorptions
0
4 ( 6.8%)
7 (11.5%)
4 ( 6.8%)
3 ( 6.4%)
17 (32.1%)
0
21 (33.3%)
55 (96.5%)
52 (89.7%)
16 (27.6%)
2 ( 3.6%)
0
28 (44.4%)
23 (36.5%)
2 ( 3.6%)
4 ( 7.3%)
16 (25.8%)
3 ( 5.5%)
5 ( 9.6%)
13 (24.1%)
8 (14.5%)
4 ( 7.8%)
5 ( 8.3%)
2 ( 3.8%)
15 (26.8%)
5 ( 8.2%)
Number of Gross.
Abnormalities
0
0
1 ( 1.9%)
1 ( 1.8%)
0
4 ( 11.1%)
4 ( 7.5%)
4 ( 9.5%)
2 (100.0%)
5 ( 83.3%)
1 ( 2.4%)
0
0
0
0
0
0
0
2 ( 3.9%)
0
1 ( 2.4%)
1 ( 2.1%)
0
15 ( 27.3%)
8 ( 15.7%)
9 ( 22.0%)
0
Number of Skeletal
Abnormalities c
Treatment Groups
Untreated controls
Distilled water
Normal saline
Cottonseed oil
Dimethyl phthalate
Dimethoxyethyl phthalate
Diethyl phthalate
Dibutyl phthalate
Diisolbutyl phthalate
Butyl carbobutoxy-
methyl phthalate
Dioctyl phthalate
Di-2-ethylhexyl phthalate
a. Numbers in parentheses represent percent resorption based on total number of implantations.
b. Numbers in parentheses indicate percent gross abnormalities based on total number of fetuses.
c. Numbers in parentheses represent percent skeletal abnormalities based on total number of stained fetuses.
0
0
4
3
0
9
6
4
2
4
13
13
8
5
8
7
6
8
5
4
5
4
4
0
0
0
0
( 14.3%)
( 10.7%)
( 75.0%)
( 35.3%)
( 25.0%)
(100.0%)
(100.0%)
( 92.9%)
( 81.3%)
( 47.1%)
( 26.3%)
( 33.3%)
( 24.1%)
( 20.7%)
( 33.3%)
( 17.2%)
( 14.8%)
( 21.7%)
( 16.0%)
( 13.8%)
TT-39
-------
10. Thus, the injections on days 5, 10, and 15 would miss the critical
period sought by roost researchers in teratology. Another problem was
the high incidence of dead (resorbed) fetuses which may have masked
many abnormalities (28).
The chick study involved injection of several phthalate esters
either into the yolk sac or allantoic cavity , or direct application to
the chorioallantoin membrane of developing embryos. A syndrome of
neural and musculo-skeletal anomalies was observed. Doses and stages
of administration were not available at th time of this writing (29,
30 as reported in 31).
Besides teratogenic effects, phthalates have been found to have
other reproductive effects. In a study by Peters and Cook (32), preg-
nant rats were injected with dibutyl or di-2-ethylhexyl phthalate at
2 or 4 mlAg- Di-methyl phthalate was injected at 0.5, 1 or 2 ml/kg.
DEHP prevented implantation in 7 out of 10 rats injected at 3, 6 and 9
days of gestation at 2 or 4 ml/kg. Excessive bleeding and maternal
mortality were noted at parturition. DBP caused a 50% reduction in the
number of young weaned per litter and a decrease in the number of im-
plantations. DMP did not cause a significant decrease in the number
of young weaned.
When labeled di-2-ethylhexyl and diethyl phthalates were administered
to pregnant rats intraperitoneally, traces of the chemicals and/or
metabolites were found in the maternal blood, the placenta, the amniotic
fluid, .and in the fetus. This suggests that the reports of teratogenesis
11-40
-------
and fetal deaths could be the result of the direct effect of phthalic
esters on developing embryonic tissue (33).
2.8 Metabolic Information
Numerous articles describing absorption, distribution, metabolism
and excretion of phthalate esters have appeared. Metabolism of alkyl
phthalates may involve initial hydrolysis to monoester with subsequent side
chain oxidation to the alcohol, ketone and acids. With the exception of
dimethyl phthalate, phthalic acid has been found to be a minor metabolic com-
ponent of the phthalate esters (34).
Butylglycol butyl phthalate, when treated in an isolated perfused
rat liver system gives glycol phthalate as a metabolite (35) but DEHP
is not metabolized by this system (36). In another study (37) DEHP
was partially hydrolyzed to the monoester after oral admin* ^tration to
rats, and the residual alkyl moiety subjected to omega an* ontega-less-
one oxidation. The alcohols can be further oxidized to the corresponding
carboxylic acid or ketone and the acid may be subsequently subjected to
beta oxidation. Hydrolysis of DEHP may occur in the liver or, alterna-
tively, in the small intestine. In vitro studies indicate, however, that
DEHP is hydrolyzed more rapidly by pancreatic lipase than by rat-liver
homogenate (37).
In rats, intravenously administered DEHP appears to be extensively
metabolized to water-soluble products (not well characterized) which are
11-41
-------
excreted primarily in the urine and feces. These results, according to
the investigators, indicate that metabolism of DEHP by rats does not
consist of simple de-esterification of the dialkyl ester, but rather
that at least four chemically similar water soluble metabolites are
formed (38).
Rat, kidney, lung and liver tissue enzymatically hydrolyze DEHP
in vitro to MEHP and 2-ethylhexanol. Liver mitochondria and microsomes
have been strongly implicated as the site of this degradation. It
would appear that a number of esterases or lipases are capable of
hydrolyzing DEHP (according to the authors) (39).
A study (40) was made of the in vitro hydrolysis of the dimethyl,
diethyl, di-n-butyl, di-n-octyl, di-(2-ethylhexyl), and dicyclohexyl
esters by both hepatic (from rat, baboon and ferret) and intestinal
preparations from various species (rat, baboon, ferret and man). Both
the hepatic and intestinal preparations from these species hydrolyzed each
of the phthalate diesters to their corresponding monoester derivatives.
The results thus show a species similarity in the metabolism of phthalate
diesters by man, a rodent, a non-rodent, and a nonhuman primate species.
Furthermore, the authors state that their results suggest that orally in-
gested phthalate diesters would most probably be absorbed from the gut
of these species primarily as the corresponding monoester derivative.
The metabolites appearing in the urine of rats fed with DEHP have
been isolated and characterized (Table 4) by Albro et al. (34). Metabolites
found were those expected frcm omega and omega-less-one oxidation of DEHP
11-42
-------
TABLE 4
UREflE METABOLITES OF DEHP FED TO RATS*
(1.)
H-
H-
H
H
(2.)
f
r
H
:-OH
H
H
(3.)
xoy-j-c-oH
!tiA-
0
II
C-OH
H Q
T
H
(4.)
4.
C-OCHj-C-CHj-G-OH
iijCHj
*Albro/ P.W., Thonas, R. and Fishbein, L. Metabolism of clethyehexyl
£dithalate by rats; Isolation and characterization of the urinary
netobolities, J. Chronat. 76:321-330 (1973).
11-43
-------
without attack on the aromatic ring. The metabolites do not form glucu-
ronides. Free phthalic acid amounted to less than 3% of the urinary
metabolites. The conclusion on glucuronides may require further inves-
tigation according to Carter et al. (39), since in another study (41)
the ester glucuronide of the related compound rnonobutyl phthalate has
been identified.
Albro and Mx>re (42) have identified (Table 5) rat urinary metabolites
of orally administered dimethyl, di-n-butyl and di-n-octyl phthalates.
Phthalic acid was a very minor metabolite except in the case of dimethyl
phthalate. Hydrolysis to monoesters becomes more significant as they
become more polar (methyl > butyl > n-octyl^ethylhexyl). The remaining
metabolites are those of subsequent oxidation of the side-chain to the
alcohol, ketone and acid. The intact diester was excreted as a trace com-
pound when dibutyl phthalate was fed to rats and as a significant component
when dimethyl phthalate was similarly fed.
The metabolism of dibutyl phthalate (DNBP) has been recently inves-
tigated (43) in the rat. Phthalic acid, monobutyl phthalate, mono
(3-hydroxybutyl) phthalate and mono (4-hydroxy butyl) phthalate have been
identified as metabolites in the urine. Of a single oral dose of DNBP,
80-90% was metabolized and excreted in the urine within 48 hours.
2.9 Ecological Effects
The toxicity of phthalic acid esters in aquatic organisms has been
evaluated by standard static and flow-through bioassay procedures. The
96-hr LC5Q to scuds (Gannarus pseudolimnaeus) and crayfish (Qrconectes
nais) was 2.1 mg/1 and > 10.0 mg/1, respectively (4). Acute toxicity of
11-44
-------
TABLE 5
METABOLITES OF DIFFERENT PHTHKLftlE ESTEPS*
Cotpound
Dimethyl phthalate
Di-n-fautyl phthalate
Di-n-octyl phthalate
11
0
Metabolites
1.
2.
3.
1.
2.
3.
4.
5.
6.
7.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Free phthalic acid (14.4%)
I-tonotiethyl phthalate (77.5%)
Dimethyl phthalate (8.1%)
Phthalic acid
Dibutyl phthalate (Intact)
Mono-butyl phthalate
R = -O^COCH-
R = - (ay 2aioHCH3
R = -(CH2)3CH2OH
R » -(Oi2)3COOH
Monooctyl phthalate
Phthalic acid
R = -CH2COOH
R = -(CH2)2CCOH
R = -(CH2)3COOH
R = -(CH2)4COOH
R = -(OygCOOH
R = -(CH2)6COOH
R = - (ay 7COOH
R = - (CK~) ,OXH.,
/ D ->
Rw. //^tT \ /^ L T^tC3/ ^tJ
— — I*— tl^ ) -v-nUi»-n-
R = -(CH0)^CH,OH
*Albro, P.W. and Moore, B. Identification of the nvetabolites of sirrple
phthalate diesters in rat urine. J. of Chrom. 94:209-218 (1974).
11-45
-------
di-n-butyl phthalate to aquatic organisms, as reported by Mayer and
Sanders (4), is shown in Table 6. The 96-hr LC_ value of DEHP was
-fQ
greater than 10 mg/1 for both fish and invertebrates (4).
TABI£ 6
ACUTE TOXECITY OF DI-n-BUTYL PHTHALATE
TO AQUATIC ORGANISMS
Species
Fathead minnow
(Pimephales pronelas)
Bluegill
(Lepomis macrochirus)
Channel catfish
(Ictalurus punctatus)
Rainbow trout
(Salmo gairdneri)
Scud
(Gammarus pseudolimnaeus)
Crayfish
(Orconetes nais)
24 hrs.
7.00
value, mg/1
48 hrs.
1.49
1.23
3.72
0.73
2.91
96 hrs.
1.30
0.73
2.91
6.47
2.10
7 10.00
Alkyl phthalates have found their way into human food (45,46) in bo-
vine and other tissues (47-49), air, soil (50), water (5,51) and aquatic
organisms (5,6). The widespread occurence of the phthalate esters in
aquatic ecosystems has also been reported by the U.S. Bureau of Sport Fish-
eries and Wildlife (6,44,59).
Fish from various locations in the United States have been analyzed
for DEHP by Stalling et al. (53). Residue levels ranged from 0.2 to 10.0
on a whole fish basis, as shown in Table 7.
11-46
-------
PHTHALA1E ES1ER RESIDUES POUND IN
SELECTED SAMPLES FROM NORTH AMERICA
Source
Mississippi and Arkansas
(agriculture and industrial
areas)
Fairport National Fish
Hatchery, Iowa (water sup-
ply from industrial area
of Mississippi River)
Black Bay, Lake Superior,
Ontario (rural and industrial
area)
Hanrnond Bay, Lake Huron,
Michigan (forested area)
Lake Huron, Michigan
Missouri River McBaine,
Missouri
Water
Water
(turbid)
Residue, ng/g (ppb)
Sample
Channel
catfish
Channel
Catfish
Dragonfly
naiads
Tadpoles
Walleye
Water
Sediment
Water
DBF
Trace
200
200
500
100
0.040
DEHP
1,000-
7,500
400
200
300
800
300
200
____
0.09
5.0
4.9
DEHP has also been found in catfish (6) in quantities greater than 3 ppm. 95 per
cent of the samples from Mississippi and Arkansas contained residue.
Phthalates in the Charles and the Merrimack rivers have been quanti-
tively assessed by Kites (51) as shown in Table 8 below.
TABLE 8
PHTHALATE CONCENTRATION IN THE CHARLES RIVER
River Mile Depth, ft
7 4
Phthalate
concn, ppb
1.9, 1.8
11-47
-------
TABLE 8 (Continued)
Phthalate
River Mile Depth, ft concn, ppb
3 4 1.1, 1.1
1 4 0.88, 0.89
1 11 0.97, 0.98
Phthalate esters have been reported as being present in Kewda, to-
bacco leaf and lily of the valley, but the chemical structures of the es-
ters have not been elucidated (10).
Analyses for phthalate esters by the .DA (58) indicate that the major
contamination occurs in dairy products, but the level of contamination
found was judged to be toxicologically insignificant.
Phthalate esters may interact with fulvic acid which is present in
humic substances in soils and waters. The fulvic acid-phthalate ester
complex is soluble in water, and thus the relatively insoluble esters can
readily be solubilized and transported away from the original site of pol-
lution (10,50). This phenomenon could possibly result in greater availa-
bility of phthalate esters to aquatic organisms (5).
Even though most of the phthalate esters have low volatility, they
will volatilize from plastic materials, as for example, in the case of
automobiles containing vinyl furnishings (10).
Effects of phthalate esters on aquatic organisms have been reported in
the literature as follows:
Di-n-butyl phthalata (DNBP) slightly inhibits the hatching of brine
shrimp eggs at 10.3 ppm. Diethyl phthalate inhibited hatching slightly at 61.5
ppm;and dimethyl phthalate did not inhibit hatching at 60.1 ppm (55, as re-
ported in 54).
11-48
-------
The no effect concentration for sac fry mortality was judged to lie
between 5 and 14 ppb DEHP in water (54).
The effects of phthalate esters on aquatic organisms have demonstrated
that, brine shrimp are quite insensitive/ but that sac fry of rainbow trout
are more sensitive then adults during extended dynamic exposures (54).
DNBP was a heart rate depressor in goldfish at 1 ppm to 12 ppm, but
DEHP did not produce this effect at 200 ppm. (56/57, as reported in 54).
DEHP did not affect the growth rate of fathead minnows during 56 days
of exposure at concentrations as high as 62 ppb/ but DEHP was accumulated
115 to 886-fold from the water (54).
DEHP and DNBP were fed to ring doves at 10 ppm in the diet. No effect
due to DEHP was observed/ but with DNBP/ egg shell thickness was decreased
by 10% and the rate of water loss from the egg was decreased by 23%. When
the doves were returned to a normal diet, the eggshell thickness rapidly re-
turned to normal (54).
Mayer et al. (5) reported that a concentration of only 3,ng/l of DEHP
in the water was sufficient to significantly decrease growth and reproduction
of the crustacean Daphnia magna.
DEHP is reported (4) to be detrimental to the reproduction of aquatic
organisms at low concentrations. Waterfleas continuously exposed to 3, 10,
and 30 ug/1 of DEHP for a complete life cycle (21 days) showed reduced re-
production. Total production of offspring was inhibited by 60, 70, and 83% in
the respective treatment levels.
The effects of DEHP on reproduction in Zebra fish (Brachydamio rerio)
and guppies (Poecilia reticulatus) were determined with a 90-day dietary ex-
posure (4). The number of spawns was greater in the treated Zebra fish, but
11-49
-------
the control fish produced more eggs per spawn than those fish exposed to DEHP.
Fry survived, was significantly reduced and the least number of guppy fry were
born to parents fed DEHP. An 8 percent incidence of abortions was noted, as
shown in Table 9 below.
TABUS 9
REPRODUCTION IN ZEBRA FISH (BRACHYDAMIO REPIO)
DEHP Concentration mg/g
Species
Zebra fish
Guppies
Reproductive variable
Number of spawns
Eggs per spawn
Percent fry survival
Fry per female
Percent abortions
0
6
20.3
51.1
33
0
50
8
15.2
31.7
100
14
10.1
11.5
29
8
2.10 Current Testing
Di(2-ethyihexylphtnalate; (NCI #C52733) is currently being tested by NCI in
rats and mice by feeding (G12).
11-50
-------
REFERENCES
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Uptake and fate of di-2-ethylhexyl phthalate in aquatic organisms
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2. Harris, V.T., and Eschmeyer, P.H. Sport Fishery and Wildlife
Research. 1972. Bureau of Sport Fisheries and Wildlife, Fish and
Wildlife Service, U.S. Department of the Interior (1974).
3. Sanders, H.D., Mayer, F.L., Jr. and Walsh, D.F. Toxicity residue
dynamics, and reproductive effects of phthalate esters in aquatic
invertebrates. Environ. Res. 6:84-90 (1973).
4. Mayer, F.L., Jr. and Sanders, H.O. Toxicology of phthalic acid
esters in aquatic organisms. Env. Hlth. Persp. 3:153-157 (1973).
5. Mayer, F.L., Stalling, D.L. and Johnson, J.L. Phthalate esters as
environmental contaminants. Nature 238:411-413 (1972).
6. Gaudet, J. (ed.) Report of the 1970 workshop on fish feed technology
and nutrition. Bureau of Sport Fisheries and Wildlife, Fish and
Wildlife Service, U.S. Department of the Interior (1970).
7. Fishbein, I. and Albro, P.W. Chromatographic and biological aspects
of the phthalate esters. J. Chromatog. 70:365-412 (1972).
8. Saubron, J.R., Metcalf, R.L., and Lu, P. Plasticizers in the environ-
ment; fate of di-n-octyl phthalate in to*o model ecosystems and uptake
and metabolism of OOP by aquatic organisms. Arch. Environ. Contain.
Toxicol. 3(2):244-255 (1975).
9. Gesler, R.M. Toxicology of di-2-ethylhexyl phthalate and other phthalic
acid ester plasticizers, Env. Hlth. Persp. 1:73-79 (1973).
10. Autian, J. Toxicology and health threats of phthalate esters: review
of the literature. Env. Hlth. Persp. 4:3-26 (1973).
11. Krauskopf, L.G. Studies on the toxicity of phthalates via ingestion.
Env. Hlth. Pexsp. 1:61-72 (1973).
12. Lefaux, R. Practical toxicology of plastics. CRC Press, Chemical
Rubber Co., Cleveland, Ohio (1968).
13. Maslenko, A.A. Hazards of dibutyl phthalate and dioctyl phthalate
as reservoir pollutants. Gig. Sanit. 33(6):102 (1968).
11-51
-------
14. Smith, C.C. Toxicity of butyl stearate, dibutyl sebacate, dibutyl
phthalate, and methoxyethyl oleate. Arch. Ind. Hyg. 7:310 (1953).
15. Harris, R.S. et al. Unpublished work; Mass. Inst. Technol., Univ.
of Rochester, and W.R. Grace and Co. (1948).
16. W.R. Grace and Co., Dioctyl phthalate, Technical Brochure (1948).
17. Carpenter, C.P., Weil, C.S. and Smyth, H.F., Jr. Chronic oral toxicity
of di(2-ethylhexyl) phthalate for rats, guinea pigs, and dogs. Arch.
Ind. Hyg. 8:219 (1953).
18. Shaffer, C.B., Carpenter, C.P. and Smyth, H.F., Jr. Acute and sub-
acute toxicity of di(2-ethylhexyl) phthalate with note upon its meta-
bolism. J. rnd. Hyg. Toxicol. 27:130 (1945).
19. Shibko, S.I. and Blumenthal, H. Toxicology of phthalic acid esters
used in food-packaging material. Env. TT.th. Persp. 1:131-137 (1973).
20. Brown, V.K.H., Muir, C.M.C. and Thorpe, E. Toxicology of sane al-
cohol mixtures containing 7 to 9 and 9 to 11 carbon atoms and the
corresponding phthalate esters. Arch. Toxicol. 26:84 (1970).
21. Lawrence, W.H. et al. Toxicity of plastics used in medical practice I.
Investigation of tissue response in animals by certain unit packaged
polyvinyl chloride administration devices. J. Pharm. Sci. 52:958 (1963),
22. Gaunt, I.P., Colley, J., Grass, P. and Lansdown, A. Acute (rat and
mouse) and short term (rat) toxicity studies on dialkyl 79 phthalate.
Food Cosmet. Toxicol. 6:609 (1968).
23. Dewey and Alma, Chemical Division of W.R. Grace and Co., Unpublished
data submitted to FDA (1968).
24. Patty, F.A. Industrial Hygiene and Toxicology, Vol. II, Interscience
Publishers, New York, p. 1903 (1967).
25. Epstein, S.S. and Shafner, H. Chemical mutagens in the hunan environ-
ment. Nature 219:285 (1968).
26. Dillingham, E.O. and Autian, J. Teratogenicity, mutagenicity and
cellular toxicity of phthalate esters. Env. Hlth. Pers. 1:81-89 (1973).
27. Yagi, Y. Tutikawa, K. and Shimoi, N. Teratogenicity and mutagenicity
of a phthalate ester. Teratology 14:259-260 (1976).
28. Singh, A.R., Lawrence, W.H. and Autian, J. Teratogenicity of phthalate
esters in rats. J. Pharm. Sci. 61:51-55 (1972).
11-52
-------
29. Guess, W.L., Haberman, S., Rowan, D.F., Bower, R.K. and Autian, J.
Characterization of subtle toxicity of certain plastic components
used in manufacture of the polyvinyls. Amer. J. of Hosp. Pharm.
24:494-501 (1967).
30. Haberman, S., Guess, W.L., Rowan, D.F., Bowman, R.O. and Bower, R.K.
Effects of plastics and their additives on human serum proteins, anti-
bodies and developing chick embryos. Sec. Plastics Eng. J. 34:62-69
(1963).
31. Bower, R.K., Haberman, S. and Minton, P.D. Teratogenic effects in
the chick embryo caused by esters of phthalic acid. J. Pharm. Exp.
Ther. 171:314-324 (1970).
32. Peters, J. and Cook, R. Effects of phthalate esters on reproduction
in rats. Env. Hlth. Pers. 3:91-94 (1973).
33. Singh, A.R., Lawrence, W.H. and Autian, J. Maternal-fetal transfer
of 14C-di-2-ethylhexyl phthalate and 14C-diethyl phthalate in rats.
J. Pharm. Sci. 64(8):1347-1350 (1975).
34. Albro, P.W., Thomas, R. and Fishbein, L. Metabolism of diethylhexyl
phthalate by rats: isolation and characterization of the urinary
metabolites. J. of Chromatography 76:321-330 (1973).
35. Jaeger, R.J. and Rubin, R.J. Phthalate ester metabolism in the
isolated, perfused rat liver system. Env. Hlth. Persp. 1:49-51 (1973).
36. Jaeger, R.J. and Rubin, R.J. Extraction, localization and metabolism
of di-2-ethylhexyl phthalate from PVC plastic medical devices.
Env. Hlth. Persp. 1:95-102 (1973).
37. Daniel, J.W. and Bratt, H. The absorption, metabolism and tissue
distribution of di(2-ethylhexyl) phthalate in rats. Toxicology 2:51-65
(1974).
38. Schulz, C.O. and Rubin, R.J. Distribution, metabolism and excretion of
di-2-ethylhexyl phthalate in the rat. Env. Hlth. Persp. 1:123-129
(1973).
39. Carter, J.E., Roll, D.B. and Petersen, R.V. The in vitro hydrolysis
of di-(2-ethylhexyl) phthalate by rat tissues. Drug Metab. and Disp.
2(4):341-344 (1974).
40. Lake, B.C., Phillips, J.C., Linnell, J.C. and Gangolli, S.D.
The in vitro hydrolysis of some phthalate diesters by hepatic and
intestinal preparations from various species. Tox. and Appl. Pharm.
39:239-248 (1977).
11-53
-------
41. Thompson, R.M., Gerber, N., Seibert, R.A. Desideno, D.M. Drug
Metab. Disp. 1:489 (1973).
42. Albro, P.W. and Moore, B. Identification of the metabolites of
simple phthalate diesters in rat urine. J. of Chromatography
94:209-218 (1974).
43. Williams, D.T. and Blanchfield, B.J. The retention, distribution,
excretion and metabolism of dtbutyl phthalate-7-14C in the rat.
J. of Agr. and Food Chem. 23(5):854-858 (1975).
44. Progress in Sport Fishery Research, Resource Publication 106, Wash-
ington, D.C. (1970).
45. Cerbulis, J. and Ard. J.S. Methods for the isolation of di-octyl
phthalate from milk lipids. J. Assoc. Offie. Anal. Chem. 50:646
(1967) .
46. Perkius, E.G. Characterization of the nonvolatile compounds formed
during thermal oxidation of corn oil. II. Phthalate esters. J.
Amer. Oil Chemists Sec. 44:197 (1967).
47. Taborsky, R.G. Isolation studies on a lipoidal portion of the
bovine pineal gland. J. Am. Food Chem. 15:1073 (1967) .
48. Nazir. D.J., Beroza, M. and Nair, P.P. Isolation and identification of
di(2-ethylhexyl) phthalate—a component of heart muscle mitochondria.
Fed. Proc. 26:142 (1967).
49. Jaeger, R.J. and Rubin, R.J. Plasticizers from plastic devices:
extraction, metabolism and accumulation by biological systems.
Science 170:460 (1970).
50. Ogner, G. and Schutzer, M. Humic substances: fulvic acid—dialkyl
phthalate complexes and their role in pollution. Science 170:317
(1970) .
51. Kites, R.A. Phthalates in the Charles and the Merrimack Rivers.
Environ. Hlth. Persp. 5:17-21 (1973).
52. Marcel, Y.L. and Noel, S.A. Contamination of blood stored in plastic
packs. Lancet 1970-1:35 (1970).
53. Stalling, D.L., Hbgan, J.W., and Johnson, J.L. Phthalate ester
residues—their metabolism and analysis in fish. Environ. Hlth.
Persp. 5:159-173 (1973).
54. Hartung, R. Research report, Toxicological and Environmental issues
associates with phthalic acid esters, for Manufacturing Chemists
Association. December 13, 1976.
11-54
-------
55. Sugawara/ N. Effect of phthalate esters on shrimp Bull. Environ.
Contain. & Toxicol. 12(4) :421-424 (1974).
56. Pfuderer, P. and Francis, A.A. Phthalate esters: heart rate depres-
sors in goldfish. Bull. Environ. Contam. & Ibxicol. 13(3):275-279
(1975).
\
\
57. Pfuderer, P., Jansen S. and Rainey, W.T., Jr. The identification of
phthalic acid esters in the tissues of cyprinodont fish and their
activity as heart rate depressors. Environ. Research 9:215-223 (1975).
58. Food and Drug Administration. Compliance Program Evaluation, Phthalate
esters in foods survey, EY1974 (7320.13B). Bureau of Foods Jan. 8, 1975.
59. Harris, V.T. and Eschmeyer, P.H. Sport Fishery and Wildlife Research
1972. Washington, D.C. 1974.
11-55
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-------
CHLORINATED BENZENES, MONO- AND PI-
TABLE OF CONTENTS
Page
Overview III-l
Part I - General Information
Chlorobenzene III-3
m-Dichlorobenzene III-5
o-Dichlorobenzene III-7
p_-Dichlorobenzene 111-10
Summary of Characteristics 111-13
Specific References 111-14
Part II - Biological Properties
Chlorobenzene
2.1 Bioaccumulation 111-15
2.2 Contaminants and Environmental 111-15
Degradation or Conversion
Products
2.3 Acute Toxicity 111-17
2.4 Other Toxic Effects 111-18
2.5 Carcinogenicity 111-19
2.6 Mutagenicity 111-19
2.7 Teratogenicity 111-20
2.8 Metabolic Information 111-20
2.9 Ecological Effects 111-21
2.10 Current Testing 111-22
References 111-23
Ill-i
-------
Page
Part II - Biological Properties (Continued)
o-Dichlorobenzene
2.1 Bioaccumulation 111-26
2.2 Contaminants and Environmental 111-27
Degradation or Conversion
Products
2.3 Acute Toxicity 111-28
2.4 Other Toxic Effects 111-29
2.5 Carcinogenicity 111-30
2.6 Mutagenicity 111-31
2.7 Teratogenicity 111-32
2.8 Metabolic Information 111-32
2.9 Ecological Effects 111-32
2.10 Current Testing 111-34
References 111-35
p_-Dichlorobenzene
2.1 Bioaccumulation 111-37
2.2 Contaminants and Environmental 111-38
Degradation or Conversion
Products
2.3 Acute Toxicity 111-39
2.4 Other Toxic Effects 111-40
2.5 Carcinogenicity 111-42
2.6 Mutagenicity 111-43
2.7 Teratogenicity 111-43
2.8 Metabolic Information 111-44
2.9 Ecological Effects 111-45
2.10 Current Testing 111-46
References 111-47
Ill-ii
-------
CHLORINATED BENZENES/ MONO- AND DI-
AN OVERVIEW
This category consists of monochlorobenzene and o-, m-, and
p_-dichlorobenzene. Monochlorobenzene and o- and m-dichloroben-
zenes are colorless liquids while £-dichlorobenzene is a volatile
white crystalline material. All of these compounds are insoluble
in water but soluble in major organic solvents.
In 1976, over 325 million pounds of monochlorobenzene, 48
million pounds of o-dichlorobenzene and 36 million pounds of p_-di-
chlorobenzene were produced. Chlorinated benzenes are used in sol-
vent applications/ industrial processes and many consumer products.
In the NOHS Survey of Occupational Exposure, the monochloro-, p_-
dichloro- and o-dichloro- benzenes ranked 195, 383, and 114, re-
spectively, out of approximately 7000 agents; over a million workers
are believed to be exposed to them. Nearly 100 million pounds of the
o- and -dichlorobenzenes are estimated to be released annually into
the environment. The release rate for monochlorobenzene was not found.
Chlorinated benzenes have been detected in the environment.
Their potential for bioaccumulation is considered great owing to their
high octanol-water partition coefficients and the stability and low
reactivity of the molecule. Chlorinated benzenes mainly give phenolic
metabolites which are usually excreted as glucuronides, sulfate or
mercapturic acid conjugates.
Liver, kidney, respiratory and neurological effects have been
observed after exposure to chlorinated benzenes. There are no adequate
III-l
-------
studies available on which to evaluate the carcinogenicity of
chlorinated benzenes, but an association has been reported between
exposure to the dichlorobenzenes and leukemia. No conclusion can
be drawn from current mutagenicity data on chlorinated benzenes,
and no information on the teratogenicity of these chemicals is avail-
able.
III-2
-------
CHLORINATED BSNZttNES (MONO- AND DI-)
PART I
GENERAL INFORMATION
I. Chlorobenzene
1.1 Identification CAS No.: 000108907
NIOSH No. : CZ01750
1.2 Synonyms and Trade Names
Monochlorobenzene; phenyl chloride; benzene chloride;
chlorbenzene ; chlorbenzol ; MCB
(G16)
1.3 Chemical Formula and Molecular Weight
C£HCC1 Mol. Wt. 112.56 (G22)
o b
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless, volatile liquid;
almond-like odor; flammable
(G21)
1.4.2 Boiling Point; 132° C (G22)
1.4.3 Melting Point; -45.6° C (G22)
1.4.4 Absorption Spectrometry ;
245,251,258,264, 272nm
log € = 1.95,2.34,2.13,2.45,2.32 (G22)
1.4.5 Vapor Pressure; 10 mm at 22.2° C (G22)
1.4.6 Solubility; Insoluble in water;
Very soluble in benzene, chloro-
form, carbon tetrachloride and
carbon disulfide;
Soluble in all proportions in
alcohol and ether
1.4.7 Octanol/Water Partition Coefficient;
Log PQCt =2.84 (G36)
III-3
-------
1.5 Production and Use
1.5.1 Production:
576.749
484.914
306.030
329.072
Million Ibs
Million Ibs
Million Ibs
Million Ibs
(1966)
U970)
(.1975)
(1976)
(G24)
1.5.2 Use;
In manufacture of phenol, chloronitrobenzenes,
aniline; as a solvent carrier for methylene di-
isocyanate; as a solvent for paints; as a pesti-
cide intermediate; as a heat transfer medium
(G21,G23)
1.6
Quantitative Distribution of Uses;
Intermediate (including o- and p_-
nitrochlorobenzene)
Solvent
DPO and derivatives
Rubber intermediate
DDT- silicones, isocyanates and others
Consumer Product Information;
Chlorobenzene is present in; marine primer
Exposure Estimates
1.6.1 Release Rate:
Percent
35
30
10
10
15
100
(2)
(G35)
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
Rank: 195
Estimated no. of persons exposed: 1,093,000
(G29)
1.7 Manufacturers
Allied Chemical Corp.
Dow Chemical Co.
Monsanto Co.
Montrose Chemical Corp. of Calif.
PPG Industries, Inc.
ICC Solvent Co., Inc.
Standard Chlorine Chemical Co.
(G25,l)
III-4
-------
CHLORINATED BENZENES (MONO- AND DI-)
II. m-Dichlorobenzene
1.1 Identification CAS No.: 000541731
NIOSH No.:
1.2 Synonyms and Trade Names
1,3-Dichlorobenzene
1.3 Chemical Formula and Molecular Weight
C6H4C12
Mol wt. 147.01
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless liquid
1.4.2 Boiling Point; 173° C
1.4.3 Melting Point; -24.7° C
1.4.4 Absorption Spectrometry ;
A
log
1.4.5 Vapor Pressure;
1.4.6 Solubility;
» 250, 256, 263, 270, 278
= 1.90, 2.15, 2.40, 2.52, 2.43
1 mm at 12.1° C
(G21)
(G22)
(G21)
(G22)
(G22)
(G22)
(G22)
Insoluble in water;
Soluble in alcohol, ether, and
benzene;
Soluble in all proportions in ace-
tone, ligroin and carbon tetrachloride
1.4.7 Octanol/Water Partition Coefficient
Log P ^ = 3.38
^ oct
(G22)
(G36)
III-5
-------
1.5 Production and Use
1.5.1 Production:
No information found in sources searched
1.5.2 Use; As a fumigant and insecticide
(G21)
1.6 Exposure Estimate
1.6.1 Release Rate:
No information found in sources searched
1.6.2 NOHS Occupational Exposure
Rank:
No information found in sources searched
Estimated no. of persons exposed:
No information found in sources searched
1.7 Manufacturers
Aceto Chemical Co., Inc.
American Hoechst Corp.
Mitsubishi International Corp.
Standard Chlorine Chemical Co., Inc.
(G37)
III-6
-------
CHLORINATED BENZENES (MONO- AND DI-)
III. o-Dichlorobenzene
1.1 Identification CAS No.: 000095501
NIOSH NO.: CZ45000
1.2 Synonyms and Trade Names
Chloroben; cloroben; DCB; o-dichlorobenzene; o-dichlor benzol;
1,2-dichlorobenzene; Dizene; Dowtherm E; ODB; ODCB; ortho-
dichlorobenzol
1.3 Chemical Formula and Molecular Weight
Cl
Cl
CgH4Cl2 Mol. Wt. 147.01 (G23)
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless liquid, pleasant odor;
a mixture of isomers containing
at least 85% o.- and varying
percentages of p_- and m-
(G21)
1.4.2 Boiling Point; 180.5° C (G22)
1.4.3 Melting Point: -17.0° C (G22)
1.4.4 Absorption Spectrometry;
= 250, 256, 263, 270, 277 nm;
\ alcohol
max
log £ = 1.98, 2.13, 2.36, 2.44, 2.37
(G22)
1.4.5 Vapor Pressure: 1 mm at 20° C (G22)
1.4.6 Solubility: Insoluble in water;
Soluble in alcohol, ether, benzene;
Soluble in all proportions in
acetone, ligroin, carbon tetrachloride
(G22)
1.4.7 Octanol/Water Partition Coefficient;
Log PQct =3.38 (G36)
III-7
-------
1. 5 Production and Use
1.5.1 Production: 51.386 Millions Ibs (1966)
66.219 Millions Ibs (1970)
54.679 Millions Ibs (1975)
48-594 Millions Ibs (1976) (G24)
1.5.2 Use: In manufacturing of 3,4-dichloroaniline; as
a solvent for a wide range of organic mater-
ials and for oxides of nonferrous metals;
as a solvent carrier in production of tolu-
ene diisocyanate; in the manufacture of
dyes; as a fumigant and insecticide; in de-
greasing hides and wool; in metal polishes;
in industrial odor control; in drain clean-
ers
(G21)
Quantitative Distribution of Uses;
Percent
Organic synthesis, mainly for pesticides 53
Toluene diisocyanate process solvent 20
Solvent, including paint removers and 15
engine cleaners
Dye manufacture 8
Miscellaneous 4_
100
(G25)
Consumer Product Information;
o-Dichlorobenzene is present in:
radiator cleaner
leather dye
conditioner for lawn mower engines (G35)
1.6 Exposure Estimates
1.6.1 Release Rate; 27.0 Million Ibs
1.6.2 NOHS Occupational Exposure;
Rank: 114
Estimated no. of persons exposed: 1,978,000
(G29)
III-8
-------
1.7 Manufacturers
Allied Chemical Corp.: Specialty Chemicals Div.
Dow Chemical Co.
Monsanto Co.
PPG Industries, Inc.
Montrose Chemical Corp.
ICC Industries, Inc.
Standard Chlorine Chemical Co.
Chemical Products Corp.
Specialty Organics
(G24,l)
III-9
-------
CHLORINATED BENZENES (MONO- AND DI-)
IV. p_-Dichlorobenzene
1.1 Identification CAS No.: 000106467
NIOSH No.: CZ45500
1.2 Synonyms and Trade Names
Di-cloricide, p_-chlorobenzol; 1,4-dichlorobenzene; Para-
cide; Paradi; Paradow; Paramoth; PDB; PDCB; Santichlor
(G16)
1.3 Chemical Formula and Molecular Weight
Cl
>i
C6H4C12 Mol. Wt. 147.01
(G23)
1.4 Chemical and Physical Properties
1.4.1 Description; White crystals; volatile (sub-
limes readily); penetrating odor (G21)
1.4.2 Boiling Point: 174° C (G22)
1.4.3 Melting Point; 53.1° C (G22)
1.4.4 Absorption Spectrometry;
= 258, 266, 273, 280 nm;
\ alcohol
max
log C = 2.24, 2.46, 2.60, 2.51
(G22)
1-4.5 Vapor Pressure; o.4 mm at 25° C (1)
1.4.6 Solubility: Insoluble in water;
Soluble in ether, benzene, carbon
disulfide, chloroform;
Soluble in all porportions in
alcohol, acetone
(G22)
111-10
-------
1.4.7 Octanol/Water Partition Coefficient
Log P
oct
3.39
(G36)
1.5 Production and Use
1.5.1 Production:
66.307 Million Ibs U966)
69.606 Million Ibs CL970)
45.755 Million Ibs (J.975)
36.699 Million Ibs (1976)
(G24)
1.5.2 Use:
As a moth repellent, general insecticide, germicide,
space odorant; in the manufacture of 2,5-dichloro-
aniline and dyes; as an intermediate; in pharmacy and
agriculture (.fumigating soil)
(G21)
Quantitative Distribution of Uses
Space odorant
Moth control
Miscellaneous
Percent
50
40
10
100
(G25)
Category
Consumer Product Information:
Total no. of £-
dichlorobenzene
containing products
No. of p_-dichlorobenzene
products in category
3s
di
Cleaning agents
and compounds
Chemical deodori-
zers
51
total no. of products
in category
0.2%
16.0%
-xlOO
The 54 products surveyed contained an average
of 85.3% p_-dichlorobenzene
1.6 Exposure Estimates
1.6.1 Release Rate:
71.0 Million Ibs
(G27)
(G28)
1.6.2 NOHS Occupational Exposure;
Rank: 383
Estimated no. of persons exposed: 544,000*
* rough estimate (G29)
III-ll
-------
1.7 Manufacturers
Allied Chemical Corp.: Specialty Chemicals Div.
Dow Chemical Co.
Dover Chemical Co.
PPG Industries, Inc.
Monsanto Co.
Montrose Chemical Corp.
Standard Chlorine Chemical Co.
Specialty Organics
(G24,l)
111-12
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CHLORINATED BENZENES (MONO- AND DI-)
SUMMARY OF CHARACTERISTICS
Name
Benzene,
chloro-
Benzene,
o-dichloro
Solubility
i in H20; vs in
bz, chl, CC1., CS2;
oo in ale. and etn.
i in H?0; s in ale,
eth, bzj oo in ace,
lig, oci4
Estimated
Environmental
Release
^ oct (Million Ibs)
2.84 *
3.38 27.0
Production
(Million Ibs)
576,729 (1966)
484.914 (1970)
306.030 (1975)
329.072 (1976)
51.386 (1966)
66.219 (1970)
54.679 (1975)
48.594 (1976)
Benzene,
p-dichloro
Benzene t
m—dichloro
i in H2O;
bz, CS2, chl.
ale, ace.
s in eth,
oo in
3.39
71.0
i in H^O; s in ale,
eth, bz;oo in ace,
lig, CC14
3.38
66.307 (1966)
69.606 (1970)
45.755 (1975)
36.699 (1976)
Estimated no.
of persons
exposed
(occupational)
1,093,000
1,978,000
544,000
Use
Mfg. of phenol; chloro-
nitrobenzene, aniline;
solvent carrier for
methylene diisocyanate;
solvent for paints; pesti-
cides intermediate; mar-
ine primer; heat transfer
medium
Mfg. of 3,4-dichloroani-
line; solvent for wide
range of org. mats, and
for oxides of nonferrous
metals; solvent carrier
in prod, of toluene
diisocyanate; dye mfg;
fumigant and insecticide;
degreasing hides and wool;
metal polishes; industrial
odor control
Moth repellent; general
insecticide; germicide;
space odorant; mfg.
of 2,5-dichloroaniline;
dyes; intermediates;
pharmacy; agriculture
(fumigating soil)
Fumigant; insecticide
No j nfometion found in sources searched.
111-13
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QILORINATED BENZENES (PCND- AND DI-)
SPECIFIC REFERENCES FOR PART I
1. EPA. 560/2-77-004, Investigation of selected potential environmental con-
taminants: Halogenated benzenes. Office of Toxic Substances, U.S. Environ-
mental Protection Agency, (1977).
2. Chemical Profile, ttonochlorobenzene, Chemical Marketing Reporter, October 31,
1977.
111-14
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CHLOROBENZENE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
Chlorobenzene was tested for bioaccumulation in a model aquatic
ecosystem by Lu and Metcalf (1). The model ecosystem contained:
300 Daphnia; 200 4th instar mosquito larvae; 6 snails; strands of algae;
and miscellaneous plankton. Radio-labelled (14C ) chlorobenzene was
added to the water phase, and three fish were added one day later.
When an additional day had passed, the ecosystem components were ex-
tracted for chlorobenzene. Biological magnification values found
were as follows: fish, 645; mosquito larvae, 1292; snail, 1313;
Daphnia, 2789; and algae, 4185.
In a study of chlorinated benzene content of human adipose
tissue of residents of the Tokyo area, chlorobenzene was less than
10 ppb in all samples. Exposure rates were not estimated (2,3).
That chlorobenzene bioaccumulates is consistent with its high
octanol-water partition coefficient and the stability and low reac-
tivity of the molecule.
2.2 Contaminants and Environmental Degradation or Conversion Products
The BOD of chlorobenzene is reported as 1% of theoretical (G15).
This result indicates resistance to biodegradation. At ordinary tem-
perature and pressure it is unaffected by the presence of air, mois-
ture, or light and shows no tendency to dechlorination (G17).
Possible contaminants (formed during manufacture of the chemical)
are o- and p_-dichlorobenzene (G17) .
111-15
-------
The following reports show that chlorobenzene degrades
slowly in the environment:
The chemical is oxidized to 3-chlorocatechol by Pseudomon-
as putida but oxidation occurs only if the organism is initially
grown on toluene for 15 hr and then on the chemical for 20 hr (5,
as reported in 4). It appears that P^ putida can oxidize chloro-
benzene only if it is already adapted to an aromatic carbon source.
The biodegradability index (ratio of polar products of deg-
radation to nonpolar products) ranges from 0.014 to 0.063, which
again indicates substantial resistance to biodegradation. In
mosquito fish, the biodegradability index of 0.014 for chloro-
benzene was between that of DDT (0.012) and aldrin (0.015) (1).
The BOD with sewage microflora was only 0.03 g/g for chloro-
benzene (compared with 1.20g/g for benzene),which likewise shows a
very slow rate of degradation for the compound (6,as reported in 4)
Owing to its high vapor pressure (15.5 mm at 30°C), chloro-
benzene will volatilize when released to the environment, even
when released in water (7, as reported in 4). Its fate in the
atmosphere is, therefore, of special interest. In a study of
rate of degradation of the chemical in a simulated atmosphere
(8, as reported in 4), it was found that the chemical decomposed
relatively slowly.
Hydrolysis of chlorobenzene (to phenols) does not seem like-
ly owing to its low water solubility and the low reactivity of
aromatic chlorine.
All of the foregoing data are consistent in showing chlo-
robenzene to be a non-reactive, persistent chemical in the en-
vironment, both in water and air.
TTT-1 £.
-------
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances
(G16) reports the following acute toxicity data for chlorobenzene:
Parameter Dosage (jug/kg) Animal Route
LD50 2910 rat oral
LDLo 4000 rat s.c.
LD50 2830 rabbit oral
The EPA report on halogenated benzenes (4) gives the following
acute toxicity data for this compound:
Parameter Dosage Cmg/kg) Animal Route
LD50 1445 mouse oral
LD50 2390 rat oral
LD50 2250 rabbit oral
LD50 5060 guinea pig oral
LC50 20 mouse inhal.
LC50 0.05 guinea pig inhal.
Acute poisoning in laboratory animals is characterized by symptoms
primarily originating in the nervous system, including hyperexcitability,
restlessness, muscle spasms or tremors followed by varying degrees
of CNS depression. Respiratory failure is the most frequent cause
of death (9, as reported in 4). Subcutaneous injection of 4-5 g/kg
of chlorobenzene in rats caused no immediate effects, but resulted in
death within a few days. Autopsy revealed liver and kidney necrosis.
Larger doses produced CNS depression and acute ataxia. 7-8 g/kg of
chlorobenzene was fatal to rats in a few hours, (10, as reported in
4}. Inhalation of 20 mg/1 of chlorobenzene in rabbits was fatal
111-17
-------
for all animals in comparison with 30 mg/1 for benzene (11, as re-
ported in 4). Exposure to chlorobenzene vapor in humans causes
headaches, irritation of the eyes and upper respiratory tract, numb-
ness and eventual loss of consciousness (.9, as reported in 4).
2.4 Other Toxic Effects
Functional disorders of circulatory organs in workers employed
in the production of chlorobenzene have been reported (12). Symptoms
included pain in the area of the heart, bradycardia, irregular vari-
ations in EKG, and decreased contractile function of the myocardium.
Specific alterations which occurred in external respiration caused
secondary disorders in the circulatory organs (12). In the majority
of cases, exposure lasted over three years and did not exceed the
maximum allowable concentration.
Rats exposed to 1.0 mg/m^ of chlorobenzene, 24 hours/day for
approximately 2 months experienced liver, lung and kidney damage,
blood dyscrasias, and a change in the regulating influence of the
CNS (13, as reported in 4).
Inhalation exposure to chlorobenzene (0.1-1.5 mg/1) in guinea
pigs for 2 months decreased the activity of red cell enzymes (14,
as reported in 4). Repeated subcutaneous injection of 0.9 mg/kg
chlorobenzene in rabbits resulted in liver and kidney damage, blood
dyscrasia and CNS depression. Oral administration of 0.001-0.1 mg/kg
chlorobenzene to male white rats daily for five months caused CNS
depression and tne higher dose caused liver and kidney damage (15,
as reported in 4).
111-18
-------
Chlorobenzene (orally administered, 250 mg/kg for 3 days) caused
a doubling in rat liver
-------
After 24 hours, all spores were dead. At six hours, the maximum
yield of back mutations observed exceeded the controls by a factor
of 187 (low dose) and 1400 (high dose) (17, as reported in 4).
Chlorobenzene caused chromosomal damage and mitotic
inhibition in root tips of higher plants.
Chlorobenzene was not found to be mutagenic in the fungus
Aspergillus ridulans (1).
2.7 Teratogenicity
No data on the teratogenicity of Chlorobenzene were found in
the searched literature. Evidence has been presented that
pentachlorobenzene is teratogenic (4) .
2.8 Metabolic Information
Chlorobenzene is oxidized mainly to 4-chlorophenol and 4-
chlorocatechol and excreted in the urine as sulfate, mercapturic
acid and glucuronic acid conjugates. About 25% of an oral dose
of 0.5 g/kg in rabbits was eliminated via expiration and the
remainder was excreted by the kidneys in 1-2 days. Approximately
equal quantities (32%) of 4-chlorophenol and 4-chlorocatechol
have been isolated from a 24-hour urine specimen in man and a
smaller percentage (16%) was recovered as 4-chlorophenyl mer-
capturic acid. In contrast, the percent of dose recovered as
mercapturic acid conjugate in the monkey, dog, mouse and rat was
significantly higher (>40%) (4).
Direct evidence for the generation of a reactive epoxide
intermeuiate from bromobenzene (4) suggests that a similar inter-
mediate is formed in the metabolism of other halogenated benzenes,
which may be the metabolite that reacts with cellular proteins.
111-20
-------
2.9 Ecological Effects
Chlorinated benzenes have been detected in waste waters, drink-
ing waters, rivers and lakes as well as in the soil (.4). From an
EPA study that estimated loss of materials during batch manufacture
of chlorobenzene by a plant Cpresumed to be typical) (.21, as reported
in 4), the following are estimates of chemicals vented to the en-
vironment annually, assuming the figures given for the plant selected
apply to the entire U.S. production of chlorobenzene, about 400 mil-
lion Ib/year:
Chemical Quantity Vented, Ib. Destination
Hydrogen 560,000 air
chloride
Monochloroben- 352,000 water stream
zene
Dichloroben- 1,480,000 water stream
zenes
Usage of chlorobenzene as an intermediate will result in addi-
tional venting of the chemical to the environment. For example,
0.02 - 0.3 mg/1 was found in the atmosphere of a new DDT manufactur-
ing plant in Romania (22, as reported in 4); this indicates leaks in
piping and inadequate ventilation are occurring even in new plants.
Loss from scrubbers is another source of environmental contamination
(23, as reported in 4).
Murray State College, Kentucky has reported chlorobenzene (and
higher chlorinated benzenes) in textile finishing plant effluents
(24, as reported in 4). The chemical has been found in U.S. drink-
ing water, with the highest level being 5/xg/l (25, as reported in 4).
It has also been found in 9 of 10 cities surveyed: in ground water,
111-21
-------
in supposedly unco.ntaminated upland water, and in waters contami-
nated by industrial, municipal or agricultural wastes (25, as re-
ported in 4) .
In a 15-day static test of chlorobenzene (.at 17 - 20°C) on
aquatic organisms serving as food for freshwater fish, 25 mg/1 was
toxic to saprophytic microflora Cbased on BOD) and nitrogen-fixing
bacteria (based on nitrification processes); 1.0 mg/1 was toxic to
crayfish and Daphnia magna; and 20 mg/1 was toxic to the oligochaetes
Limnodrilus hoffmeister and Tubifex tubifex, and the chironomid
larvae Stictochironomus. Crayfish were tolerant of 0.5 mg/1 which
was the concentration suggested as permissible (26).
Of four species of fish—fathead minnows (Pimephales promelas),
bluegill (Lepomis machrochirus) , goldfish (.Carassius auratus) and
guppies (Lebistes reticulatus)—tested at 25°C, bluegills were the
most sensitive to chlorobenzene with 24-, 48-, and 96-hr TLms of
24.0 mg/1 (.27) .
2.10 Current Testing
Chlorobenzene (NCI IC554886) has been tentatively selected for
long-term bioassay testing by the NCI (G12).
111-22
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REFERENCES
1. Lu, P. and Metcalf, R. Environmental fate and biodegradability of
benzene derivatives as studied in a model aquatic ecosystem. Env.
Health Pers. 10:269-284 (1975).
2. Morita, M. and Ohi, G. Paradichlorobenzene in human tissue and
atmosphere in Tokyo metropolitan area. Environ. Pollut. 8:267-
274 (1975).
3. Morita, M., Mimura, S., Ohi, G., Yagyu, H., and Nishizawa, T.
A systematic determination of chlorinated benzenes in human adipose
tissue. Environ. Pollut. 9:175-179 (1975).
4. Office of Toxic Substances, EPA. Investigation of selected environ-
mental contaminants: halogenated benzenes. Final report, Contract
no. 68-01-4183, July 1977.
5. Gibson, A.L. Tests of bark-penetrating insecticides to control the
Douglas fir beetle. Econ. Entomol. 50:266-268 (1957).
6. Heukelekian, H. and Rand, M.C. Biochemical Oxygen Demand of
pure organic compounds. Sewage Ind. Wastes 27:1040 (1955).
7. Garrison, A.W. and Hill, S.W. Organic pollutants from mill persist
in downstream waters. Amer. Dyestuff Rep. 21-25:February 1972.
8. Dilling, W.L., Bredeweg, C.J., and Tefertiller, W.B. Organic photo-
chemistry—simulated atmospheric photodecomposition rates of
methylene chloride: 1,1-trichloroethane, trichloroethylene, tetra-
chloroethylene and other compounds. Environ. Sci. Tech. 10:351-
356 (1976).
9. Girard, R., Tolot, R., Martin, P., and Bourret, J. Serious, blood
disorders and exposure to chlorine derivatives of benzene (a re-
port of 7 cases. J. Med. Lyon (50(1164): 771-73 (1969).
10. Von Oettingen, W.F. The halogenated aromatic hydrocarbons. In:
The Halogenated Aliphatic, Olefinic, Cyclic, Aromatic and Aliphatic
Aromatic Hydrocarbons, Including the Halogenated Insecticides,
their Toxicity and Potential Dangers. U.S. Department of Health,
Education and Welfare, Public Health Service, Rockville, Maryland,
No. 414:283-299 (1955).
11- Rozenbaum, N.D., Block, R.S., Kremneva, S.N., Ginzburg, S.L.,
and Pozhariskii, I.V. Use of chlorobenzene as a solvent from the
standpoint of industrial hygiene. Gig. Sanit. 12(1):21-24 (1947).
12. Dunaevskii, G.A. Functional condition of circulatory organs in
workers employed in the production of organochlorine compounds,
Gig.T. Prof. Zabol 16(3):48-50 (1972).
111-23
-------
13. Khanin, A.G. Pathohistological changes in the central nervous
system and internal organs of experimental animals after chronic,
24-hour inhalation of toxic substances. T. Tsent, Inst. Vrachei.
135:97-106 (1969).
14. Lecca-Radu, M. Modifications of blood carbonic anhydrase and
leucccytic indophenol oxidase in chronic benzene and mono-
chlorobenzene intoxication. Igiena 3:231-239 (1959).
15. Varshavskaya, S.P. Comparative toxicological characteristics
of chlorobenzene and dichlorobenzene (ortho- and para-
isomers) in relation to the sanitary protection of water bodies.
Gig. Sanit. 33(10):17-23 (1967).
16. Preussman, R. Chemical carcinogens in the human environment.
Hand. Allg. Pathol. 6:421-594 (1975).
17. Keskinova, D.V. The effect of dimethylcyclodiazomethane in
chlorobenzene solution on mutagenesis in Actinomyces antibioticus
400. GenetiJca 4 (8): 121-125 (1968).
18. Carlson, G.P. and Tardiff, R.G. Effect of chlorinated benzenes
on the metabolism of foreign organic ccmDounds. Toxicol.
Appl. Pharmacol., 36:383-394 (1976),
19. Reid, W.D. and Krishna, G. Centrolobular hepatic necrosis related
to covalent binding of metabolites of halogenated aromatic hydrocarbons
Exp. Molec. Pathol. 18:80-99 (1973). u^ticons.
20. Heid, W.D., Ilett, K.F., Click, J.M. and Krishna, G. Metabolism and
binding of aromatic hydrocarbons in the lung; relationship to experimental
bronchiolar necrosis. Am. Rev. Resp. Dis. 107:539^551 (1973).
2i. EPA, Assessment of industrial hazardous waste practices-
organic chemicals, pesticides and explosives industry.
USEPA Report SW-1.18C (1976) .
22. Gabor, S. and Raucher, K. Studies on the determination of the
maximum permissible concentrations of benzene and monochloro-
benzene. J. Hyg. Epidemiol. Microbiol. Immunol. 4(2):223-231
(1960) .
23. Lewis, P.F. Chlorinated benzenes. Department of Health,
Education and Welfare, Public Health Service, Division of
Chemical Technology, Rockville, Maryland, January 1975.
24. Erisman, H. and Gordon, M. Identification of organic con pounds
in textile plant effluents. Presented at the First Chemical
Congress of the North American Continent, Mexico City, Mexico,
November 30-December 5. Murray State College, Murray, Kentucky
(1975).
25. EPA. Preliminary Assessment of Suspected Carcinogens in Drinking
Water: Report to Congress. USEPA Report PB-250 961. National
Technical Information Service, Springfield, Virginia,
December 1975.
III-24
-------
26. Lobacheva, L.L. On the effect of dichloroethane and chlorobenzene
on water organisms. Rybn. Khoz. 7:71-74 (1957).
27. Pickering, Q.H. and Henderson, C. Acute toxicity of some
important petrochemicals to fish. Water Pollut. Control Fed.
38(9):1419-1429 (1966).
111-25
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O-DICHLOROBENZENE
2.1 Bioaccumulation
The propensity for o-dichlorobenzene to bioaccumulate is
considered great. The log of the octanol/water partition co-
efficient is 3.38 (G15). The halogenated aromatic structure
confers stability on the molecule, which helps ensure its
environmental persistence and its resistance to biodegradation.
Although specific test data on the compound are not available,
indications are very strong, from data on closely related compounds,
that o-dichlorobenzene will bioconcentrate. For example, blood and
fat samples taken from inhabitants of the Tokyo, Japan area were
found to contain the closely related para isomer of the compound;
fat levels were 0.2-11.7 /ig/g and blood levels (on whole blood basis)
8-12^ug/ml (1). In a small model aquatic ecosystem, the following
ecological magnification factors were observed for chlorobenzene
with the species indicated: mosquito fish 645, mosquito larvae
1292, snails 1313, Daphnia 2789, and algae 4185. The log octanol/
water partition ratio of o-dichlorobenzene (3.38) is much higher
than that of chlorobenzene (2.176) (2) suggesting a greater potential
for bioaccumulation. It has also been observed that the para isomer
of the compound can bioconcentrate in trout muscle (3). Dichloro-
benzene has been identified in samples of sprat (Clupea sprattus) (4)
A mixture of 7 chlorinated hydrocarbons (including o-dichloro-
ben^ene), all known to be pollutants of Rhine water, when adminis-
c£.:cd orally to rats, was found in the fat at levels 50 to 100
times that in the administered dose. Generally, highly chlorinated
aromatic compounds accumulate to a greater extent than less-
111-26
-------
chlorinated aromatics (5).
2.2 Contaminants & Environmental Persistence
The technical grade contains 1.3% of the meta- and para- isomers
and the crude grade contains 17% of the meta- and para- isomers (G9).
Other impurities are 1,2,4-trichlorobenzene, monochlorobenzene, and
chlorotoluene (G14).
o-Dichlorobenzene is unreactive toward peroxides in water and
ozone in air, but is very reactive to hydroxyl radical; the t,,2 ^s
about 3 days (G14). Products of these reactions were not given. The
affinity of the compounds for fatty tissues would tend to result in
bioaccumulation and, therefore, increased persistence in the environ-
ment. However, only traces of the chemical have been detected in wa-
ter effluents or supplies (see Section 2.9) . The compound has been
reported to be degraded by sewage sludge organisms (7, as reported in 6)
However, this process is probably very slow since the 3OD of
chlorobenzene was 0.03 g/g (8, as reported in 6) and it was noted
that the introduction of chlorine atoms in an organic molecule
lowered the BOD; i.e., the BOD of the dichlorobenzene should be less
than the 0.03 g/g of chlorobenzene. o-Dichlorobenzene at levels
up to 300 mg/1 appears to codistil from water readily since it
volatilized completely from aerated distilled water in less than
4 hours (9, as reported in 6). Without aeration the chemical
volatilized in less than 3 days. Once in air, the chemical is sub-
ject to OH attack. Degradation products in water were not
detected.
111-27
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Dosage
707 ppm/4H
800 ppm/24H
2000 mgAg
330 mgAg
520 mgAg
Investigation of
Animal
rat
guinea pig
guinea pig
rabbit
mouse
Selected Potential
Route
inhalation
inhalation
oral
intravenous
intravenous
Environmental
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances (G16) reports
the lowest lethal concentrations in air (LCLo) and lowest lethal dosage
by other routes (LDLo) for > 99% o-dichlorobenzene as follows:
Parameter
LCLo
LCLo
LDLo
LDLo
LDLo
The EPA repo:
Contaminants; Halogenated Benzenes (6) gives the oral LD50 for several
experimental animals as follows:
Animal LD5Q (mq/kq)
mouse 2000
rat 2138
rabbit 1875
guinea pig 3375
Acute exposure of sewage workers to o-dichlorobenzene effluents
from a dry cleaning establishment above the plant resulted in eye and upper
respiratory tract irritation and vomiting. (10, ac reported in 6) .
o-Dichlorobenzene is toxic in many species oZ manuals, the extent of
toxicity depending on the species and route of administration. Intravenous
administration of 0.25 - 0.50 itu/kg body weight to rabbits was fatal within
24 hours and 1.00 mlAg was fatal within 20 seconds (11, as reported in 6).
£xposure of dogs to o-dichlorobenzene vapor at 2 ml/m (0.04%) did not result
in adverse effects but 4 ml/m (0.08%) produced somnolence (12, as reported in
6). Exposure of mice to a similar concentration of oj-dichlorobenzene resulted
111-28
-------
in CNS stimulation for about twenty minutes followed by CMS depression, muscular
twitching, slow and irregular respiration, cyanosis near the end of an hour
and death within 24 hours. Rats and guinea pigs appear more resistant than
mice (12,as reported in 6). The clinical symptoms of acute poisoning in rats
are hyperenia, increased salivation, ataxia, paraparesis, paraplegia and
dyspnea. Similar symptoms of acute poisoning are observed in rabbits including
hyperemia of visible mucous membranes, increased salivation and lacrimination,
ataxia, paraparesis, paraplegia, initial excitation followed by sleepiness
and dyspnea (14) .
2.4 Other Toxic Effects
Daily administration of 18.8 - 188 mg/kg of o-dichlorobenzene to
rats via stomach tube 5 days/week for 192 days did not produce any adverse
effects. At 376 mg/kg, positive findings consisted of a moderate
increase in liver and kidney weight, and a slight decrease in spleen weight.
Microscopic examination of the liver revealed slight to moderate cloudy
swelling (13). Repeated 7 hour exposures to 93 ppm of o-dichlorobenzene in
air for 6-7 months had no adverse effects in the rat, guinea pig, rabbit
and monkey (13). o-Dichlorobenzene was absorbed through the skin and was toxic
after repeated cutaneous administration. Subcutaneous injection produced
localized edema and necrosis of adjoining tissue. Repeated subcutaneous
injections in rats resulted in blood dyscrasias characterized by agranulocytosis,
with little or no effact on red blood cells (12 as reported in 6).
Sensitization to o-dichlorobenzene has been reported in man
upon exposure to skin, manifested as eczerratoid dermatitis (6).
Inhalation of 800 ppm of o-dichlorobenzene for 11 to 50 hours in
rats was irritating to the eyes and nose, produced slight changes in
I.Tl-29
-------
the tvfoxL*r epithelium of the kidney and caused confluent massive
necrosis of the liver (11, as reported in 6). Oral administration to white rats at
0.001 rag - 0.1 r^/kg f&r five months caused blood dyscrasias and increased
prothrombin time (14, as reported in 6). Abnormalities in conditioned reflexes
rfere also observed. oHDichlorobenzsne increases A-aminolevulinic acid synthetase,
the rate-lifting factor in the enzymatic synthesis of porphyrins, and in rats
caused porphyria (6).
A correlation has been observed between the extent of covalent binding
of halogenated benzene metabolites to protein in vitro and in vivo, and the
severity of liver necrosis. Both binding and necrosis were extensive for
o-dichlorbbenzene in contrast to pj-dichlorobenzene (6).
The Threshold Limit Value (TLV) reccmnended by ACGIH (1976) is 50 ppm
(approximately 300 mg/m ) (Gil).
2.5 Carcincgenicity
No.studies of the carcinogenicity of this compound lasting longer than
«
7 months'couId be found in the searched literature. Inhalation exposure to
49 ppm, -7. hours/day, 5 days/week of o-dichlorobenzene in the mouse and 93 ppm
in the rat and guinea pig for a period of approximately 6*5 months did not
result in tumor formation. Oral administration of pj-dichlorobenzene at 376
mg/kg to female white mice 5 days/week for approximately 6h months did not
result in tumor formation.
In another study, an unspecified isomer of dichlorobenzene gave a
slight response activity in mice, in the sebaceous gland and hyperplasia
tests in mice. In both cases, 0.1 ml of a lg/100 ml solution of
Oj-dichlorobenzene was applied 3 times to the skin of 3-4 month old, male
and female Swiss mice. The sebaceous gland test was based on the dis-
appearance of the glands after application of the compound. The hyperplasia
111-30
-------
tests involved thickening of the skin epithelium after application. On an
arbitrary scale of 0 to 4 (negative to strongly positive) pj-dichlorobenzene
scored 0.9 on the former test and 0.7 on the latter. The significance of
even strongly positive results in these tests with respect to carcinogenicity
is unclear (15, as reported in 6).
Four cases of leukemia occurring in humans exposed to o or pj-
dichlorobenzene as solvents for other chemicals or in chlorinated benzene
mixtures have been reported (G9, Vol. 7). No evidence of exposure to
benzene was found. Two cases of chronic lyrnphoid leukemia and two cases of
acute myeloblastic leukemia were reported. In the two subjects with chronic
lynphoid leukemia, one had been exposed to a glue containing 2% Oj-dichlorobenzene
from 1945-1961, and the other had been exposed from 1940-1950 to a solvent
containing (80%) a-, (2%) m-, and (15%) j>-dichlorobenzene, which was used
for cleaning electrical parts. One of the two cases of acute myeloblastic
leukemia had been exposed to the same mixture of m- and pj-dichlorobenzene
taken from the same factory and used for the cleaning of clothes (2 liters/
year for several years); and the other case was a 15-year old girl who had
"for some time" removed stains from her clothes with a product containing
37% oj-dichlorobenzene (6).
2.6 Mutagenicity
A single exposure to 1-5/^1 of o-dichlorobenzene did not induce
reversions to histodine prototrophy in eight strains of Salmonella
typhimurium in the absence of a mammalian metabolizing system (16).
The metabolites of o-dichlorobenzene were not evaluated in this study.
This experiment has been criticized on the grounds that a spot test is
inappropriate for insoluble conpounds (16) although data were presented in
this study indicating that similar insoluble compounds can diffuse
through agar and thus cone into contact with bacteria.
111-31
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A single test for rnutagenicity of o-dichlorobenzene in Aspergilus
nidulans gave inconclusive results (17).
2.7 Teratogenic ity
No information can be found in searched literature for this compound.
Evidence has been presented that pentachlorobenzene is teratogenic (6).
2.8 Metabolic Information
Following oral administration (0.5 mg/kg) to rabbits, o-dichlorobenzene
is oxidized mainly to 3,4-dichlorophenol (40 percent). Some 3,4-dichloro-
phenyl mercapturic: acid (5 percent) and 3,4- and 4,5-dichlorocatechol are
also formed (4 percent). The phenolic metabolites are excreted mainly as
oj-glucuronides and sulfates in 5 to 6 days (18 as reported in 6).
Phenobarbital, an inducer of microsomal mixed-function oxidase
activity, stimulated the metabolism of o-dichlorobenzene approximately
2-fold; this was blocked by SKF-525A, an inhibitor of microsomal
metabolism (19).
Direct evidence for the generation of a reactive epoxide intermediate
from bromobenzene suggests that a similar intermediate is formed in the
metabolism of other halogenated benzenes which may be the metabolite that
reacts with cellular proteins (6).
2.9 Ecological Effects
About 0.9 million Ib/yr of o-dichlorobenzene are discharged to water
during production. About 40 percent of the total annual production of
£2.4 million Ib is estimated to be for dispersive uses (G14).
The chemical was detected in 3 of 10 drinking water supplies sampled,
and one that was quantified contained 1 ppb (20). The ready co-distillation
of the chemical fron water (Section 2.2) should diminish the amounts of this
111-32
-------
chemical in water with a corresponding increase of levels in the air.
No information on the occurrence of o-dichlorobenzene in soil and
sediments, or in microorganisms and plants was found. No data on ecological
effects have been found. Available data are related to experimental exposure
of organisms to the chemical at levels well above those likely to occur
in the environment. Some of these data follow:
o-Dichlorobenzene can cause deformities and mutagenic effects on
higher plants (G14). o-Dichlorobenzene is not toxic to the microorganism
Ustilago moydis (G14). It did not affect BOD at concentrations below
0.2 ppm; however, at this level the chemical inhibited the ammonification
phase in saprophytic microflora (14). At 5 ppm in water in a 24-hour test,
the chemical produced visible distress in trout, bluegill, and sea lamprey
larvae (all 4 inches long) at 1/2, 2, and 3 hours, respectively (21).
The chemical has been found in sprats and in Rhine River water (see Section
2.1).
Levels of chemical required to kill fish are exemplified by the
following median lethal concentrations in the 96 hour fish bioassay,
static method (22).
Bluegill (Leponis maarochirus) 27 mg/1
Tidewater silverside (MenidTa beryllina) 7,3 mg/1
Although Ch-dichlorobenzene has not been reported in the environment,
the closely related para isomer has been found in human blood and fat
(see Section 2.1). The ortho isomer is likely to behave similarly and
therefore has the potential of being absorbed (by inhalation) by humans.
111-33
-------
2.10 Current Testing
2-Dichlorbbenzene has been tentatively selected for testing by the
NCI. Route and species are not specified (G12).
111-34
-------
REFERENCES
1. Morita, M. and Ohi, G. Paradichloro-benzene in human tissue and atmosphere
iji Tokyo Metropolitan Area. Environ. Pollut. 8:267-274 (1975).
2. Lu, P.Y. and Metcalf, R.L. Environmental fate and biodegradability
of benzene derivatives as studied in a model aquatic ecosystem.
Envir. Hlth. Perspec. 10:269-284 (1975).
3. Neely, W.B., Branson, D.R. and Blau, G.E. Partition coefficient to
measure bioconcentration potential of organic chemicals in fish.
Environ. Sci. Technol 8U3): 1113-in5 (1974).
4. TMT^^ G. and Baumannofstad, E. Extermination of fat-soluble
chlorinated compounds in fish. Fresenius Z. Anal. Chen., 282:
395-399 (1976).
5. Jacobs A., Blangetti, M. and Hellmund, E. Accumulation of noxious
chlorinated substances from Rhine river water in the fatty tissue of
rats. Von Wasser 43 259-74 (1974). C.A. 165547Q.
6. ocfice of Toxic Substances, EPA. Investigation of selected potential
environmental contaminants: halogenated benzenes. Final report,
Contract no. 68-01-4183. July 1977.
7. Gubser, H. Purification of chemical wastewaters. Gas Wasser
Abwasser, 49, (1969).
8. Heukelekian, H. and Rand, M.C. Biochemical oxygen demand of pure
organic compounds. Sewage Ind. Wastes, 27:1040 (1955).
9. Garrison, A.W. and Hill, S.W. Organic pollutants from mill persist in
downstream waters. Araer. Dyestuff Rep. 21-25, February 1972.
10. Dupont, R. Origin of a discomfort experienced by workers during the
cleaning of a sewer. Arch. Malad. Profess. 1:312-14 (1938).
11. Cameron, G.R., Thomas, J.C., Ashmore, S.A., Buchan, J.L., Warren, E.J.
and McKenny-Hughes, A.W. The toxicity of certain chlorine derivat-'-^s
of benzene with special reference to o-dichlorobenzene. J. Path.
Bact. 44:281-296 (1937).
12. Riedel, H. Arch. Gew. Path. Gew. Hyg. 10:546 (1941). Cited by Von
Oettingen, W;F. The halogenated aromatic hydrocarbons. In: the
halogenated aliphatic, olefinic, cyclic, aromatic and aliphatic
aromatic hydrocarbons, including the halogenated insecticides, their'
toxicity and potential dangers. U.S. Department of Health, Education
and Welfare, Public Health Service, Rockville, Maryland, No. 414:283-299,
May 1955.
111-35
-------
13. Hollingsworth, R.L., Rowe, V.K., Oyen, F., Torkelson, T.R. and
Adams, E.M. Toxicity of o-dichlorobenzene. Studies on animals
and industrial experience. Arch. Industr. Hlth 17:180-187 (1958).
14. Varshavskaya, S.P. Comparative toxicological characteristics of
chlorobenzene end dichlorobenzene (ortho- and para- isomers) in
relation to the sanitary protection of water bodies. Gig. Sanit.
33(10):17-23 (1967).
15. Guerin, M. and Cuzin, J. Skin tests on mice for determining the
carcinogenic activity of cigarette tobacco stroke tar. Bull.
Assoc. Franc. 1'Etude du Cane. 48(1):112-121 (1961).
16. Anderson, K.J., Leighty, E.G. and Takahashi, M.T. Evaluation of
herbicides for possible mutagenic properties. J. Agr. Food
Chera. 20:649-656 (1972).
17. Prasad, I. Mutagenic effects of the herbicide 3,4-dichloro-
propionanilide and its degradation products. Can. J. Microbiol.
16:369-372 (1970).
18. Williams, R.T. The metabolisn of halogenated aromatic hydro-
carbons. In: Detoxication Mechanisms, 2nd Ed. John Wiley and Sons,
New York, p 237-258 (1959).
*
19. Reid, W.D. and Krishna, G. Centrolobular hepatic necrosis related
to covalent binding of metabolites of halogenated aromatic
hydrocarbons. Exp. Molec. Pathol. 18:80-99 (1973).
20. EPA, Preliminary assessment of suspected carcinogens in drinking
water, Report to Congress, December 1975. Washington, D.C.
21. Applegate, V.C., Howell, J.H. and Hall, A.F. Toxicity of
4,346 chemicals to larval lampreys and fishes. U.S. Department
of the Interior, Washington, D.C. p. 1-25 (1957).
22. Dawson, G.W., Jennings, A.L. et. al. The acute toxicity of
47 industrial chemicals to fresh and salt water fishes. J. Hazard.
Mater. 1:303-318 (1977).
111-36
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2-DICHLORDBENZENE
2.1 Bioaccumulation
The propensity for g-dichlorobenzene to bioaccumulate is considered
great. The log of the octanol/water partition coefficient is 3.38 (G15).
The halogenated aromatic structure confers stability on the molecule, which
helps ensure its environmental persistence and its resistance to bicdegradation.
Though specific test data on the compound are not available, indications
are very strong that p_-dichlorobenzene will bioaccumulate. For example,
blood and fat samples taken from inhabitants of the Tokyo area were found
to contain the compound; fat levels were 0.2-11.7 ug/g and blood levels
(on whole blood basis) 8-12 ug/ml (1). In a small model aquatic ecosystem,
the following ecological magnification factors were observed for chlorobenzene
with the species indicated: mosquito fish 645, mosquito larvae 1,292, snails
1,313, Daphnia 2,789, and algae 4,185. The log octanol/water partition ratio
of p_-dichlorobenzene (3.38) is much higher than that of chlorobenzene (2.176)
(2) suggesting a greater potential for bioaccumulation. It has also been
observed that pj-dichlorobenzene can bioconcentrate in trout muscle. The
fish to water ratio for the compound was reported to be 215 (3). Dichloro-
benzene (isomer unspecified) has been identified in samples of sprat
(Clupea sprattus) (4). A mixture of 7 chlorinated hydrocarbons (including
c^-dichlorobenzene), all known to be pollutants of Rhine water, when administ™
ered orally to rats, was found in the fat at levels 50 to 100 times that
in the administered dose. Generally, highly chlorinated aromatic compounds
accumulate to a greater extent than less-chlorinated aromatics (5).
111-37
-------
2.2 Contaminants & Environmental Persistence
The technical grade liquid contains 0.08% by weight of the meta and
ortho isoners. Another impurity is inonochlorobenzene (G9, G14).
pj-Dichlorobenzene is unreactive towards peroxide in water and ozone in
air, but is very reactive to hydroxyl radical; the t,/ is about 3 days (G14).
Products of these reactions were not given. The affinity of the compound for
fatty tissues would tend to result in bioaccuntulation and, therefore, increased
persistence in the environment. However, only traces of the chemical
have been detected in water effluents or supplies (see Section 2.9).
o-Dichlorobenzene has been reported to be degraded by sewage sludge organisms
(6, as reported in 9). However, this process is probably very slow since
the BOD of chlorobenzene was only 0.03 g/g (7, as reported in 9) and it was
noted that the introduction of chlorine atoms into an organic molecule lowered
the BCD; i.e. the BOD of the dichlorobenzene should be less than the 0.03 g/g
of chlorobenzene.
pj-Dichlorobenzene at levels up to 300 mg/1 appears to co-distill from
water readily since it volatilized ccnpletely fron aerated distilled water
in less than four hours (8, as reported in 9). Without aeration the chemical
volatilized in less than three days. Once in air, the chemical is subject
to OH attack. Degradation products in water were not detected (8, as reported
in 9).
111-38
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2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances
(G16) reported the LD50 in rats for oral administration as
500 mg/kg and 2500 mg/kg for i.p. administration of commer-
cial grade (> 99%) p-dichlorobenzene. The oral LD50 in mice
was reported as 2950 mg/kg and 2800 mg/kg in guinea pigs. The
EPA report, Investigation of Selected Potential Environmental
Contaminants: Halogenated Benzenes (9) gives the ID50 for several
experimental animals: ,
Animal LD50 (mg/kg) Route
mouse 3220 oral
rat 2512 oral
rabbit 2812 oral
guinea pig 7593 oral
mouse 5145 s.c.
'Moderate"exposure of humans to p-dichlorobenzene resulted in
severe headaches, profuse rhinitis and periorbital swelling
for approximately 24 hours after exposure. At higher concen-
trations, anorexia, nausea, vomiting, weight loss and yellow
atrophy of the liver were reported.
Exposure of male rabbits to p-dichlorobenzene vapors (100 mg/1)
for thirty minutes resulted in a range of symptoms from simple
111-39
-------
eye and nose irritation to the more usually encountered syn-
drome involving intense eye and nose irritation, a pronounced
"marked time" reflex, muscle twitches, tremors, loss of
righting reflex, definite horizontal or vertical nystagmus and
rapid, labored breathing (10). Male and female Wistar rats
(150-300 gin) exposed for 20 minutes to p_-dichlorobenzene vapors
(100 mg/1) showed affects similar to those observed in the
rabbit. After each exposure there was complete narcosis with
attendent tremors and twitches of the extremities. Male guinea
pigs similarly exposed to p_-dichlorobenzene exhibited the same
symptoms as rabbits and rats, the symptoms lasting for l-lh
hours (10).
2.4 Other Toxic Effects
Exposure of male workers who manufactured pj-dichlorobenzene for
1-7 months resulted in loss of weight, exhaustion, decrease of appetite
and blood dyscrasia (11, as reported in 9). Exposure to £-dichlorobenzene
in mothball vapor in two humans for 3-4 months is reported to have
resulted in weight loss, loose bowels, tarry stools, numbness, abdominal
swelling, jaundice and clumsiness (12, as reported in 9).
Inhalation of 0.95-2.05 mg/1 of p_-dichlorobenzene for
7 hour/day, 5 days/week for 16 days in male and female rats,
guinea pigs and rabbits had no adverse effects on growth or
survival. Increases in the weight of liver, kidneys and
spleen were noted. Cloudy and granular swelling of the liver
vvas observed in exposed rats. No adverse effects were observed
upon exposure of experimental animals to 0. 58 mg/1 of
p-dichloroben^ene (13) .
Ill -40
-------
In another study rabbits exposed to 4.6-4.8 mg/1 of
p-dichlorobenzene for 8 hours/day exhibited muscular weakness.
tremors, nystagmus, edema of the cornea and transitory edema
of the optic nerve. Some animals died after a few days
while a few withstood 62 days exposure (14, as reported in 9).
Rats subjected similarly to toxic concentrations of £-dichlorobenzene
(100 mg/1) for 5-9 days exhibited a greater degree of CNS
depression and increased irritation of mucosa. Granulocytopenia
was also present (10) .
Oral administration of p-dichlorobenzene (500 mg/kg) to
adult male rats, 5 days/week for 4 weeks, resulted in marked
cloudy swelling and necrosis in the central area of the liver
lobules and marked cloudy swelling of the renal tubular epi-
thelium with cast formation. No adverse effects were observed
after 10-100 mgAg dosages (15).
Oral administration of 376 mg/kg of p-dichlorobenzene
to female rats 5 days/week for 27 weeks produced
an increase in liver, spleen, and kidney weight, slight
cirrhosis and focal necrosis of the liver. At 188 mg/kg
an increase in liver and kidney weight was observed. No
adverse effects were observed at 18.8 mg/kg of p-dichlorobenzene (15).
Rabbits fed a 25% solution of p-dichlorobenzene in olive
oil at 500-1000 mg/kg, 5 days/week for 7-8 months, exhibited
weight loss, tremors, weakness and slight changes in the
liver characterized by cloudy swelling and a very few areas
of focal caseous necrosis (15).
111-41
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No increase A-aminolevulinic acid synthetase, the rate-
limiting factor in the enzymatic synthesis of porphyrins,
was observed in rats given p-dichlorobenzene (250 rag/kg p.o.)
for three days, although porphyria was produced upon administration
of 770 mg/kg of this compound for five days. Slight increases
in hepatic glucuronyl transferase and azoreductase activity
and EPN detoxification were observed following p.o. adminis-
tration of jg-dichlorobenzene (40 mg/kg) (22, as reported in 9).
A correlation has been observed between the extent of
covalent binding of halogenated benzene metabolites to
protein in vitro and in vivo» and the severity of liver necrosis.
In contrast to o_-dichlorobenzene, protein binding and liver
necrosis was low for the para-isomer (21).
Intramuscular injection of guinea pigs with p_-dichlorobenzene
(125-250 mgAg) for 10-12 days resulted in weight loss, intense
steatosis of the liver, decreased liver glycogen and increased blood
serum transaminase (16, as reported in 9).
®
The Threshold Limit Value (TLV) "reconrended by the ACGIH (1976)
is 75 ppm (approximately 450 mg/m3) (Gil).
2.5 Carcinogenicity
No studies of the carcinogenicity of this compound involving exposures
longer than 7 months could be found in the searched literature.
The EPA report (9) cites carcinogenicity studies on p_-dichlorobenzene
by Hollingsworth et al. (1956), although the original paper does not give
any information about carcinogenicity.
111-42
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No tumors were observed in inhalation experiments with guinea pigs,
rabbits, mice and monkeys at 96-798 ppm p_-dichlorobenzene, administered
8 hours/day, 5 days/week for 6-7 months. No tumors were observed in rats
given (18.8-376 mg/kg) pj-dichlorobenzene via stomach tube, 5 days/week
for 6-7 months (15, as reported in 9).
In another study 10 mice received 9 doses of p_-dichlorobenzene
(0.4 rag/injection) subcutaneously at varying intervals over a period
of two months. Four mice died within a month. By the 77th day, one
out of six remaining mice exhibited a sarcoma with secondary growths
in the lymph glands and peritoneum (17). Because of the small number
of animals and short observation period it is difficult to determine
the significance of this observation.
2.6 Mutagenicity
Exposure of Aspergillus nidulans (meth-) to 200 ug/tal
of p_-dichlorobenzene for sixty minutes was reported to induce
an increase in the frequency of reversion to methionine pro-
totrophy from 3 to 11 out of 10 spores. The increase in
reversion was significantly greater than that observed for o-
dichlorobenzene. Since only one dose was tested, the data are not
fully conclusive evidence of mutagenicity (18).
2.7 Teratogenicity
No information has been found in the searched literature for this
compound, although evidence has been presented that pentachlorobenzene
is teratogenic (19, as reported in 9).
111-43
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2.8 Metabolic Information
p_-Dichlorobenzene administered orally to rabbits (0.5
mg/kg) is oxidized mainly to 3,4-dichlorophenol (35%). No
mercapturic acid or catechols were detected although quinol
was found. The phenolic metabolite is mainly excreted as
glucuronide and sulfate conjugates in 5-6 days (20, as re-
ported in 9} .
Phenobarbital, an inducer of microsomal mixed-function
oxidase activity, stimulated the rate of metabolism of p_-
dichlorobenzene, while SKF-525A, an inhibitor of microsomal
metabolism, decreased the oxidation of this compound (21).
p_-Dichlorobenzene increased the urinary excretion of por-
phyrin and its precursors in the male rats given this compounc
(770 mg/kg) for five days.
Fish, cjnphibians, and insects possess enzyme-systems
that are capable of metabolizing halogenated benzenes. Trace
amounts of 2,5-dichlorophenol were detected in the frog,
Ran a pipiens, after administration of p_-dichlorobenzene (23,
as reported in 9).
111-44
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2.9 Ecological Effects
About 1.2 million Ib/yr of the chemical are discharged
to water during production. About 90 percent of the total annually produced
77.3 million Ib is estimated to be for dispersive uses (G14).
The widespread use of the chemical in the home and
city (as a space odorant and in moth control (G14) appears
to be largely responsible for the finding of p-dichlorobenzene
in the blood (8-12 jug/ml) and fat (0.2-11.7 jug/g) of
Tokyo residents (8) (See Section 2.1i. It appears that
persons using household products containing the chemical may
be exposed via inhalation to high concentrations of the chemical.
Some reported concentrations (;u g/ m ) of the chemical
in the home were: inside wardrobe 1700, inside closet 315,
bedroom 105 (1) . Concentrations in the anfcient air of central Tokyo
were 2.7-4.2, in suburban Tokyo 1.5-2.4 (i). Effects of this
exposure, however, have not been reported.
Traces of the chemical H™* been detected in 4 of 10 drinkino water
supplies sampled, and one that was quantified contained
0.5 ppb (24). The ready co-distdllation of the chemical from
water (section 2.2) should diminish the levels of this
chemical in water with a corresponding increase of levels in the
air.
No information on the occurrence of the chpnvi/vi.l in soil and
sediments, or in microorganisms and plants was found in the
searched literature.
111-45
-------
No data on ecological effects were found. The data that have been
reported are related to experimental exposure of organisms to
the chemical, and these are at levels above those in the environ-
ment. Some cf these data follow:
Dichlorobenzene can cause deformities and
mutagenic effects on higher plants (614).
The chemical is not toxic to the micro-
organism Ustilago maydis (G14). It did
not affect BOD at concentrations below
0.2 ppm; however, at this level the
chemical inhibited the ammonification
phase in saprophytic microflora (11).
Narcotic effects were observed within 6
minutes after frogs and toads were exposed
to vapors of the chemical (15). Three of 10
ducks died after 28 days on a diet containing
0.5% of the chemical; the remaining ducks
survived the 35-day subacute oral toxicity
test (15).
2.10 Current Tesr.ing
p-Dichlorobenzene has been tentatively selected for testing
by the NCI. Route and species are not specified. Testing
is currently in progress by N. Ito at Nagoya City University
Medical School, Nagoya, Japan in mice p.o. in diet (G13).
111-46
-------
References
1. Morita, M. and Ohi, G. Para-dichlorobenzene in human tissue and 7
atmosphere in Tokyo metropolitan area. Environ. Pollution. 8:26
274 (1975).
2. Lu, P.Y. and Metcalf, R.L. Environmental fate and biodegradability of
benzene derivatives as studied in a model aquatic ecosystem. Envir.
Hlth. Perspec. 10:269-284 (1975).
3. Neely, W.B., Branson, D.R. and Blau, G.E. Partition coefficient to
measure bioconcentration potential of organic chemicals in fish.
Envir. Sci. Technol. 8(13): 1113-1115 (1974).
4. Lunde G. and Baumannofstad, E. Determination of fat-soluble chlorinated
compounds in fish. Fresenius Z. Anal. Chem. 282:395-399 (1976),
5. Jacobs A., Blangetti, M. and Hellmund, E. Accumulation of noxious
chlorinated substances from Rhine river water in the fatty tissue of
rats. VoraWasser 43:259-274 (1974). C.A. 165547Q
6. Gubser, H. Purification of chemical wastewaters. Gas Wasser Abwasser
49 (1969).
7. Heukelekian, H. 3nd Rand, M.C. Biochemical oxygen demand of pure
organic compounds. Sewage Ind. Wastes, 27:1040 (1955).
8. Garrison, A.W. and Hill, S.W. Organic pollutants from mill persist in
downstream waters. Amer. Dyestuff Rep. 21-25, February 1972.
9. Office of Toxic Substances, EPA. Investigation of selected potential
environmental contaminants: halogenated benzenes. Final report,
Contract no. 68-01-4183, July 1977.
10. Zupko, A.G. and Edwards, L.D. A toxicological study of g-dichlorobenzene,
J. Amer. Phar. Ass. 38:124-131 (1949).
11. Varshavskaya, S.P. Comparative toxicological characteristics of
chlorobenzene and dichlorobenzene (ortho- and para-isomers) in relation
to the sanitary protection of water bodies. Hyg. Sanit. 33(10):17-23
(1967).
12. Cotter, L.M. Paradichlorobenzene poisoning from insecticides. N,Y.
State J. Med. 53:1690-1692 (1953).
13. Hollingsworth, R.L., Rowe, V.K. Oyen, F., Torkelson, T.R. and Adams,
r.M. Toxicity of oj-
-------
14. Pike, M.H. Ocular pathology due to organic compounds. J. Mich. State
Mad. See. 43:581-584 (1944).
15. Hollingsworth, R.L., Rowe, V.K., Oyen, F., Boyle, H.R. and Spencer,
H.C. Toxicity of paradichlorobenzene. Determinations on experimental
animals and human subjects. Arch. Industr. Hlth. 14:138-147 (1956).
16. Frada, G. and Cali, V. Toxicity of paradichlorobenzene. Folia Med.
(Naples) 41:349-355 (1958).
17. Parsons, D.L. On early tumour formation in pure-line mice treated with
carcinogenic compounds and the associated blood and tissue changes.
J. Path. Bact. 54:321-330 (1942).
18. Prasad, I. Mutagenic effects of the herbicide 3', 4x-dichloropro-
pionanilide and its degradation products. Can. J. Microbiol. 16 = 369-
372 (1970).
19. Khera, K.S. and Villeneuve, D.C. Teratogenicity studies on halogenated
benzenes (pentachloro-, pentachloronitro- and hexabrono-) in rats.
Toxicol. 5(1):117-122 (1975).
20. Williams, R.T. The metabolism of halogenated aromatic hydrocarbons.
In: Detoxication Mechanisms, 2nd Ed. John Wiley and Sons, New York,
p.237-258 (1959).
21. Reid, W.D. and Krishna, G. Centrolobular hepatic necrosis related to
covalent binding of metabolites of halogenated aromatic hydrocarbons.
Exp. Molec. Pathol. 18:80-99 (1973).
22. Carlson, G.P. and Tardiff, R.G. Effect of chlorinated benzenes on the
metabolism of foreign organic compounds. Toxicol. Appl. Pharmacol.
36:383-394 (1975).
23. Safe, S., Jones, D., Kohli, J. and Ruzo, L.O. The metabolism of
chlorinated aromatic pollutants by the frog. Can. J. Zool. 54:1818-
1823 (1976).
24. EPA, Preliminary assessment of suspected carcinogens in drinking water,
Report to Congress, December 1975.
25. Gavaudan, P. and Gavaudan, N. Narcosis of batrachians and inhii>Jtj.on
of the cleavage of sea-urchin eggs by cyclic hydrocarbons which modify
karyokinesis and plant cytodiereses. Compt. Rend. Soc. Biol. 136:
237-9 (1942).
111-48
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CHLORINATED PARAFFINS, 35-64% CHLORINE
TABLE OF CONTENTS
Page
Overview IV-1
Part I - General Information IV-3
Part II - Biological Properties
2.1 Bioaccumulation IV-8
2.2 Contaminants and Environmental IV-9
Degradation or Conversion
Products
2.3 Acute Toxicity IV-10
2.4 Other Toxic Effects IV-11
2.5 Carcinogenic!ty IV-11
2.6 Mutagenicity IV-11
2.7 Teratogenicity IV-11
2.8 Metabolic Information IV-11
2.9 Ecological Effects IV-11
2.10 Current Testing IV-12
References IV-13
IV-i
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CHLORINATED PARAFFINS 35-64% CHLORINE
AN OVERVIEW
Chlorinated paraffins (CP) are commercial products which are
prepared by chlorination of paraffin oils and paraffin waxes.
These products are mixtures of related compounds and are expected
to vary depending on feedstocks and manufacturing conditions. In
1976, U.S. production of chlorinated paraffins in the 35-64% chlo-
rine range was 60.2 million Ibs.
These compounds are industrially used as high pressure lubri-
cants, flame retardants and plasticizers. They have numerous con-
sumer uses in paints, varnishes, flame retardants and household
aerosols among other products.
It is estimated that 50.3 million pounds of 35-64% chlorinated
paraffins are annually released into the environment, and that ap-
proximately 1.75 million workers are occupationally exposed to the
wax annually.
It has been shown in Rainbow trout that the higher the molecular
weight of the chlorinated paraffin mixture the higher the bioaccumula-
tion in fish tissue. When juvenile Atlantic salmon were fed with cer-
tain chlorinated paraffins a high mortality rate was observed. Other-
wise, little information could be found in the literature searched on
the environmental effects or stability of these chemicals.
Chlorinated paraffins have been generally considered as relatively
non-toxic. However, fatty degeneration of the liver and changes in
the spleen in rats following ingestion of these compounds have been
IV-1
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reported in a Russian article. In addition, toxic contaminants
may be present in commercial paraffin products. No information on
their carcinogenic^ty, nmtagenicity and teratogenicity was found in
the searched literature.
IV-2
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CHLDRINftlED PARAFFINS, 35-64% CHLORINE
PART I
GENERAL INFORMATION
1.1 Identification
All chlorinated paraffin (CP) products are mixtures of isoners and
congeners of chlorinated hydrocarbons. The particular structures and
their proportions in a CP mixture depend on three factors: the nature
of the paraffin mixture used as raw material; the extent of chlorination
and the method of chlorination. The principal raw materials em-
ployed in the manufacture of CPs are paraffins, which are petroleum frac-
tions consisting mainly of straight-chain hydrocarbons. Certain CP
products, derived from paraffins of average molecular weight about 150,
are liquids. CP products which are derived from paraffins, of average
molecular weight 320, are hard, waxy solids. A purified petroleum fraction,
consisting predoninantly of eicosane (C2QH42) has been used as a raw
material (G17).
Paraffins can be chlorinated to a maximum of about 70% chlorine by
weight, which corresponds to about one chlorine atom per carbon of the
paraffin chain (G17). Useful properties are found in the 35-70% chlorine
range. Table 1 lists several comercial chlorinated paraffin mixtures,
their starting materials, average molecular formula and chlorine content.
A representative chlorinated paraffin component, chlorinated eicosane,
is shown below.
Cl Cl Cl Cl Cl Cl Cl Cl Cl
Cl Cl Cl Cl Cl Cl Cl Cl Cl
Estimates of the number of components in CP mixtures were not found
in the searched literature.
IV-3
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Table 1. Average Conpositions of Typical Catmercial Chlorinated Paraffins (adapted from G17)
Conmercial Paraffins
Raw
material
Chlorine Chemische Inperial Chemische
content, Av mol Diamond Hercules Farbwerke Vferke Chemical Werke
% formula Alkali Co. Powder Co. Hochst HUls Industries Witteu
paraffin
wax
paraffin
wax
40 C_.,H/t-Cl, Chlorowax
23 42 6
40 C—H-j-Cl,. Chlorowax
LV
Chlorafin Chlor-
42 paraffin 40
Cereclor 42
paraffin
40
,.0,.
14 26 4
Chlor-
paraffin 40
paraffin
wax
48-54
C23H40C18
Cereclor 48
paraffin
wax
48-54 C2QH34C18 Chlorowax
Cereclor 54
paraffin
wax
48-54
Chlor- Chlor- Cereclor
paraffin paraffin P 50
50 52
Chlorparaffin
K 53
paraffin
60-65
Chlor- Chlor-
paraffin paraffin
64 60
IV-4
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1.2 Synonyms and Trade Names
Paraffin, chlorinated; chlorcosane; cereclor; chlorowax; chlorez;
see also Table 1
1.3 Chemical and Physical Properties
1.3.1 Description;
Depending on the chain length and chlorine
content, chlorinated paraffins range from oily
liquids to viscous liquids to waxy solids.
The mixtures are tasteless, odorless and non-
flammable. (G2)
1.3.2 Meltirg Point;
The solid product of 70% chlorine content
prepared from a paraffin wax of average
molecular weight 320 has a melting range of
85-90°C. (G17)
1.3.3 Vapor Pressure;
For several products the vapor pressures are
reported as less than 10 urn H at 65 C. (G17)
1.3.4 Solubility;
Insoluble in water and lower alcohols;
soluble in chlorinated and aromatic organic
solvents. Also soluble in common oils and
plasticizers. (G17)
1.4 Production and Use
1.4.1 Production;
43.8 Million Ibs (1972)
57.545 Million Ibs (1975)
60.210 Million Ibs (1976) (G24)
1.4.2 Use:
Used in high pressure lubricants; as flame
retardant in plastics and textiles; as plasticizer
for polyvinyl chloride in polyethylene sealants;
detergents; food packaging. (2, G21)
IV-5
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CONSUMER PRODUCT INFORMATION
Number of Products Percentage of Products
Containing Chlor- in Category Containing
Category inated Paraffins Chlorinated Paraffins
Chlorinated paraffin wax
Paints, varnishes, shellac,
rust preventatives, etc. 33 0.3%
Flame retardant chemicals 31 5.2%
Household aerosols 1 0.03%
65 products surveyed averaged 22.1% chlorinated paraffin wax
Chlorinated paraffin
Paints, varnishes, shellac,
rust preventatives, etc. 15 0.1%
Flame retardant chemicals 4 0.6%
Household aerosols 1 0.03%
Adhesives and adhesive pro-
ducts, incl. glue 1 0.2%
21 products surveyed averaged 5.7% chlorinated paraffin
Chlorowax 40
Paints, varnishes, shellac,
rust preventatives, etc. 19 0.2%
Flame retardant chemicals 1 0.2%
Household aerosols 1 0.03%
21 products surveyed averaged 2.3% chlorowax 40
Chlorinated n-paraffins
Flame retardant chemicals 13 2.2% (G27)
13 products surveyed averaged 92.6% chlorinated n-paraffins
IV-6
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1.5 Exposure Estimates
1.5.1 Release Rate:
50.3 Million UDS. (G28)
1.5.2 NOHS Occupational Exposure;
Ra\ik: Chlorinated paraffin wax: 66
Estimated number of persons exposed: 1,757,000 (G29)
1.6 Manufacturers
Ferro Corp.
Hercules, Inc.
ICC Industrial, Inc.
ICI United States, Inc.
Neville Chemical Co.
Pearsall Chemical Corp.
Plastifax, Inc.
Riverside Chemical Co.
IV-7
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CHLORINATED PARAFFINS, 35-64% CHLORINE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
Rainbow trout were fed a CP product mixed into the diet
for 82 days (1). The diet contained 10 ppm of "Chlorowax
500C", a 50% chlorine product. Tissue residues were
determined by gas chromatography.
CP residues steadily increased throughout the experiment
to a maximum of 1.1 ppm at 82 days. The authors noted
differences in the gas chromatographic elution pattern of the
tissue residues as compared to the starting mixture. The higher
molecular weight components of the chlorinated paraffin
mixture were more residual in fish tissue. This was shown
by a shift toward later-eluting CP components in the fish as
the experiment progressed.
Uptake of two chlorinated paraffin mixtures by juvenile
Atlantic salmon has been studied (2). The two CP products were
of 42 and 70% chlorine content. Each was administered in two
ways: adsorbed on silica and mixed in food. Two fish were
exposed to CP-coated silica particles and 10 fish were fed
CP-containing food. Fish CP residues were determined as total
chlorine, and were expressed in ppm total chlorine (based
on wet weight). In the silica experiments, two fish (combined
weight 5-7 g) were exposed to a total of 2 mg of chlorinated
IV-8
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paraffin adsorbed on 2 g of silica in 2 liters of water. After
48 hours of exposure/ the fish had body residues of 0.44 and
0.22 a g/g from the 42 and 70% chlorine products, respectively.
After 144 hours the corresponding tissue residues were 0.75
and 0.46 ppm. In this experiment the control fish had
0.34 jU g/g of chlorine of an unspecified nature.
In the fish feeding trials, experimental levels of 10 and
100 ppm of the two chlorinated paraffins were fed in the diet of
juvenile salmon for 33, 109 and 181 days. After 33 days
the fish fed the 42% product had body residues of 0.11 and
0.51 ppm at the respective feeding levels of 10 and 100 ppm.
In the 70% chlorinated paraffin group, tissue residues were
0.29 and 0.49 ppm after 33 days.. The control group had a
chlorine residue of 0.3 ppm at this time. At later sampling
times none of the tested groups, including the controls, had
any detectable chlorinated residue.
2.2 Contaminants and Environmental Degradation or Conversion
Products
The definition of what is a contaminant in a product which
is a mixture of many components is not clear. If chlorinated
paraffins are taken to mean mixtures of partially chlorinated
straight-chain alkanes, then any branched-chain isomers or
alicyclic or aromatic impurities will be contaminants. Such
IV-9
-------
materials may be present from the petroleum-derived raw
materials used in the production of chlorinated paraffins,
but no confirmation or denial of these possibilities has been
found in the searched literature. Reported contaminants of
chlorinated paraffin mixtures include carbon tetrachloride (G17)
chlorine (G14), hydrogen chloride (G14), epoxy compounds
(G14), various metals (G14) and stabilizers such as
glycols, phosphates or derivatives of tin, lead and cadmium
(G17). These stabilizers are added to the commercial
products to inhibit thermal dehydrochlorination.
Under non-biological conditions, the chlorinated paraffins
are quite stable. At temperatures above 100 C or in the
presence of strong bases they will lose hydrogen chloride to
give chlorinated olefins. They have very low volatility
and negligible water solubility. Upon application to water
it is expected that chlorinated paraffins will be adsorbed
onto the sediment.
Bacteria are reported to degrade chlorinated paraffins
(G14), but the degradation products are not known.
2.3 Acute Toxicity
Oral LD50 values of 21 and 26 g/kg have been reported
for the mouse and the rat, respectively (3). There is no
evidence that these products are associated with skin irritation
or sensitization. Eye irritation in animals has been noted (3).
IV-10
-------
2.4 Other Toxic Effects
No information on other toxic effects was found in
primary sources. A secondary source (G14) reported a Russian
article claiming that repeated dosing (< 1 year, inhalation)
in the mouse produced fatty degeneration of the liver and various
generative (sic) changes in the spleen. No information on dosage
is available.
2.5 Carcinogenicity
No information found in searched literature.
2.6 Mutagenici-y
No information found in searched literature.
2.7 Teratogenicity
No information found in searched literature.
2.8 Metabolic Information
No information found in searched literature.
2.9 Ecological Effects
In a long term feeding study (up to 181 days) juvenile
Atlantic salmon suffered higher mortality than controls when
fed diets containing "Cereclor 42" and "Chlorez 700" at 10 and
IV-11
-------
100 ppm in the diet as shown below (2) . No explanation is
given for the reverse dose response in the Cereclor 42 data
LT50 of juvenile Atlantic salmon in the
feeding experiment
Cereclor 42, 10 p g/g 47
100
Chlorez 700, 10 //g/g 71
100 g/g 39
No gross toxicological effects were noted in fingerling
rainbow trout when fed a diet fortified with 10 ppm "Chlorowax
500C" for up to 82 days, although their weight gain was signi-
ficantly less than that of the controls (1) .
2 . 10 Current Testing
Chlorowax 40 and Chlorowax 500C, 35-64% chlorinated paraf-
fins, have been tsntatively selected for carcinogenesis bioassay
study by National Cancer Institute (approved in September 1977)
(G12) .
IV-12
-------
REFERENCES
1. Lombard©,. P., Dennison, J.L. and Johnson, N. Bioaccumulation
of chlorinated paraffin residues in fish fed Chlorowax 500C.
J. Assoc. Off. Anal. Chem. 58:707-710 (1975).
2. Zitko, V. Uptake of chlorinated paraffins and PCB from
suspended solids and food by juvenile Atlantic salmon.
Bull. Environ. Contam. Toxicol. 12:406-412 (1974).
3. Zitko, V., and Arsenault, E. Cholorinated paraffins:
properties, uses and pollution potential. Canada Fish
Mar. Service Tech. Rept. No. 491 (1974).
IV-13
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CHLOROMETHANE
TABLE OF CONTENTS
Page
Overview V-l
Part I - General Information V-3
Specific References V-5
Part II - Biological Properties
2.1 Bioaccumulation V-6
2.2 Contaminants and Environmental V-6
Degradation or Conversion
Products
2.3 Acute Toxicity V-7
2.4 Other Toxic Effects V-8
2.5 Carcinogenicity V-9
2.6 Mutagenicity V-9
2.7 Teratogenicity V-9
2.8 Metabolic Information V-9
2.9 Ecological Effects V-10
References V-12
V-i
-------
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CHLOROMETHANE
AN OVERVIEW
Chloromethane (or methyl chloride) is a colorless gas at
room temperature and pressure. It has a slight odor that is not
sufficiently characteristic or unpleasant to warn of exposure to
dangerous concentrations. It is soluble in water, alcohol, ether,
acetone, benzene, chloroform and acetic acid.
Production of chloromethane in the U.S. is primarily by reac-
tion of hydrogen chloride with methanol. In several plants the
chloromethane is further reacted with chlorine to produce methylene
chloride, chloroform, or carbon tetrachloride. In 1976, the produc-
tion of chloromethane totaled 377 million pounds. From 1965-1975
production increased by 5.3% per year. The Chemical Marketing Re-
porter (March 29, 1976) projected an annual rise in production of 6%
through 1980.
Chloromethane is used primarily as an industrial intermediate in
the production of silicones and tetramethyliead. Additional minor uses
are as a catalyst solvent in butyl rubber manufacture, in the produc-
tion of methyl cellulose, as a propellant in high pressure aerosols and
as an anesthetic. In the past, it has been used extensively as a re-
frigerant.
It is estimated that currently about 5% of the annual production
(over 18 million pounds per year) is released into the environment.
According to NIOSH, about 31,000 workers are exposed to chloromethane.
Chloromethane is reported to be a natural product, formed in
the oceans and by combustion of vegetation (e.g., argicultural burning
V-l
-------
and forest fires). Combustion of polyvinyl chloride in waste is
believed to be a larger source of release to the environment than
losses of the industrially synthesized product. It is widespread
in the atmosphere and may play a minor role in the destruction of
stratospheric ozone.
Exposure to chloromethane has been implicated in damage to the
central nervous system, liver, kidneys, and lungs. Chloromethane
exhibits mutagenic properties in the Salmonella reversion test with-
out microsomal" enzyme activation. No reports on carcinogenicity,
teratogenicity and chonic toxicity were found.
V-2
-------
CHLOKDMETHANE
PART I
GENERAL IMFORMATICN
1.1 Identification CAS No.: 000074873
NIOSHNo.: PA63000
(G16)
1.2 Synonyms
Methyl chloride (G22)
1.3 Chemical Formula and Molecular Weight
CH3C1 Mol. wt. 50.49 (G22)
1.4 Chemical and Physical Properties
1.4.1 Description: Colorless gas; compresses to a colorless 1
quid of ethereal odor and sweet taste
(G23)
1.4.2 Boiling Point; -24.2° C (G22)
1.4.3 Melting Point; -97.73° C (G22)
1.4.4 Absorption Spectrometry:
No information found in sources searched
1.4.5 Vapor Pressure: 5 atm at 22° C (G22)
1.4.6 Solubility: Soluble in water and alcohol;
Soluble in all proportions in ether, acetone,
benzene, chloroform and acetic acid
(G22)
1.4.7 OctanolAteter Partition Coefficient;
log P =1.08 (estimate) (G36)
OGTI
1.5 Production and Use
1.5.1 Production; 453.500 Million Ibs (1972)
366.449 Million Ibs (1975)
377.672 Million Ibs (1976) (G24)
1.5.2 Use: As a catalyst carrier in low-temperature polymerization
(butyl rubber); in manufacturing of tetramethyllead,
silicones; as a refrigerant; as an anesthetic in medi-
cine; as a fluid for thermometric and thermostatic equip-
ment; as a methylating agent in organic synthesis such as
methylcellulose; as an extractant and low-teirperature sol-
vent; as a propellant in high-pressure aerosols; as a herbi-
cide (G21,G23)
V-3
-------
Quantitative Distribution:
Percent
Silioones 40
Tetramethyllead 35
Butyl rubber 4
Methyl cellulose 4
Herbicides 4
Quaternary amines 4
Miscellaneous 9
"Too
(1)
1.6 Exposure Estimates
1.6.1 Release Rate: 18,1 Million Ibs (G28)
1.6.2 NOHS Occupational Exposure;
Rank: 1814
Estimated no. of persons exposed: 31,000*
*rough estimate
(G29)
1.7 Manufacturers
Allied Chemical Corp.
Continental Oil Co.
Diamond Shamrock Corp.
Dow Chemical, USA
Dow Corning Corp.
E.I. du Pont de Nemours and Co.
Ethyl Corp.
General Electric Co.
Stauffer Chemical Co.
Union Carbide Corp.
Vulcan Materials Co. (G25)
V-4
-------
Specific Reference for Part I
1. Chemical Profile, Methyl Chloride, Chemical Marketing Reporter, March 29, 1976
V-5
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CHLOROMETHANE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
No report on the bioaccumulation of chloromethane could be
found in the searched literature. The high vapor pressure
(5 atm. at 22° C) and significant water solubility (ca. 0.7%,
303 ml gas/100 g water, 20° C (G23) ) \ndicate that chloro-
methane has a low potential for bioaccumulation.
2.2 Contaminants and Environmental Degradation or Conversion
Products"
Since chloromethane is nearly odorless, acrolein has
sometimes been added to serve as a warning agent (G3). When
manufactured by direct chlorination (2% of current U.S.
production), chloromethane is also likely to be contaminated
with, in decreasing order of quantity, dichloro-, trichloro-,
and tetrachlororaethanes. Most chloromethane is made by hydro-
chlorination of methanoi. The most likely contaminants in
the product are water vapor and hydrogen chloride gas (7).
Though it is thermally stable up to 800° F (427° C),
when heated to decomposition it emits highly toxic fumes of
rydrogen chloride and other toxic gases (G5). Chloromethane
is stable when dry but in contact with moisture undergoes
slow decomposition to hydrochloric acid and methanoi (G4).
V-6
-------
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances
(G16) reports the lowest lethal concentrations of chloromethane
as follows:
Parameter Dosage Animal Route
LCLo 3,146 ppm/7H mouse inhalation
LCLo 20/000 ppm/2H guinea pig inhalation
The following effects have been reported in guinea pigs and
other unspecified animals after acute inhalation exposures: death in
a short time at 150,000-300,000 ppm; serious effects in 30-60 minutes
at 20,000-40,000 ppm; no serious effects for up to 60 minutes at 7,000
ppm; no effect for up to 8 hours at 500-100Q ppm (1). Narcosis occurs
at 40,OOU ppm in rabbits and at 108,600 ppm in cats (2).
Human poisonings resulting from the use of chloromethane as
a refrigerant have been reported fairly frequently in the past.
Over 200 cases have been reported prior to 1961, involving
some 20 deaths (3). An important factor in many poisoning
incidents is that the gas is colorless and almost odorless and
produces no perceptible irritation to the eyes, so that the
victim is often unaware of its presence even at toxic levels.
The concentrations required to produce toxic effects in
man have not been established precisely. Von Oettingen (2)
and Scharnweber et al. (4) state that most cases of intoxi-
cation by chloromethane have involved concentrations well above
500 ppm.
V-7
-------
Symptoms following acute exposures include drowsiness,
dizziness, misty vision, mental confusion, staggering gait,
and slurred speech. In more severe cases, symptoms include
ataxia, double vision, nausea, vomiting, general muscular
spasms, diarrhea, and sometimes convulsions with cyanosis and
unconsciousness (2,4). The primary cause of death appears to
be cerebral and pulmonary edema associated with circulatory
failure (2).
Pathological findings in fatal poisonings with chloro-
methane include congestion, edema, and hemorrhages in various
organs, particularly in the lungs; fatty changes in the liver;
and degeneration of the kidneys. There may be focal changes in
the central nervous system, spinal roots, and ganglia in
certain sections of the brain (2). Acute hemolysis has also
been reported in addition to damage to the kidney and liver (3).
2-4 Other Toxic Effects
Chloromethane acts as a central nervous system depressant
i
in humans. Light cases of intoxication are marked by a
characteristic latent period of one half to several hours
between exposure and the onset of symptoms. Recovery usually
occurs within 5-6 hours. In more severe cases damage to the
kidney and liver may occur, but neurological symptoms are
usually more prominent. Some central nervous system effects
ay be long-lasting and post-recovery symptoms such as headache,
insomnia, and nervousness may persist (2,4).
V-8
-------
Chloromethane also produces neurological disturbances in
several animal species at concentrations lower than those
required to produce narcosis (2). Concentrations of 15,000
and 40,000 ppm produced a primary increase in the heart rate
and a rise in arterial and venous blood pressure in dogs (2).
The Threshold Limit Value (TLV) for chloromethane has
been set by the ACGIH at 100 ppm (approximately 210 mg/m ) (Gil).
No long-term toxicological studies have been found in the
literature searched.
2.5 Carcinogenicity
No data on the carcinogenicity of chloromethane were
found in the searched literature.
2.6 Mutagenici hy
Chloromethane has been reported to be mutagenic in the
Salmonella typhimurium tester strain TA 1535 (5). No signi-
ficant difference between the number of revertant colonies
with or without added rat liver homogenate was observed,
indicating that metabolic activation is not required to pro-
mote mutagenesis. In another report, chloromethane was
found to be mutagenic in Sj. typhimurium strain TA 100
(base-pair substitutions with overlap to frameshift mutations)(6).
2.7 Teratogenicity
No information on the teratogenicity of this compound was
found in the searched literature.
2.8 Metabolic Information
Chloromethane is broken down in the body into methanol and
hydrochloric acid. The neutralization of the acid forms chlorides,
-------
which have no toxicological importance. The speed and extent
of the preliminary breakdown of chloromethane in the body are
not known. However, the excretion of chloromethane is very
slow and occurs nainly through the lungs (G3). Redford-Ellis
and Gowenlock (8) report that death from chloromethane intoxi-
cation may be the result of the accumulation of methylglyoxal
in the brain. Methylglyoxal is normally converted to lactic
acid, but this process is impaired by the presence of monohalo-
methanes (8) . Davis e_t al. (7) and Flury (cited in ref. 2)
have suggested that the toxic effects of chloromethane may be
attributable to its hydrolysis to methanol and subsequent
oxidation to formaldehyde.
2.9 Ecological Effects
There is a considerable amount of information (9,10,11)
that indicates that chloromethane is a natural environmental
constituent. It has been suggested (9) that a major source of
chloromethane may be microbial fermentation (12) and smoldering
and combustion of vegetation. It has been estimated (9) that
1% of the chlorine content of vegetable matter is converted to
chloromethane. Palmer (13) has estimated the total amount of
chloromethane produced by combustion in the United States as
2x10 metric tons per year, considerably larger than the
estimated rate of release of the synthesized product. Forty
percent of the total was estimated to be produced in burning
Buildings and by burning polyvinyl chloride in waste, with
,. \e rest stemming from agricultural burning and forest fires (13)
V-10
-------
Chloromethane is also present in cigarette smoke (about 0.6 mg
per cigarette (14,15)).
The oceans are probably a major source of Chloromethane(<>,
11). The presence of Chloromethane in drinking water has been
reported, possibly formed during the process of chlorination
(6,7) . Chloromethane is also detected as a result of the use
of bromoethane as a fumigant on stored wheat (7). Davis et
al. (7) suggest the probability that the amount of Chloromethane
formed may be related to the chlorine content of the food.
Chloromethane is widely distributed in the atmosphere,
typically at concentrations of the order of one part per
billion (9,10,11). Although it is removed from the troposphere
by various processes, small quantities diffuse upward into the
stratosphere and are believed to play a role in the catalytic
destruction of ozone (16,17). However, the importance of
anthropogenic Chloromethane in stratospheric ozone depletion is
believed to be small relative to that of other synthetic
halocarbons (16,17).
The Aquatic Toxicity Rating (96 hr TLm, species unspeci-
fied) of Chloromethane is stated to be over 1000 ppm (G16).
V-ll
-------
REFERENCES
1. National Academy of Sciences, Committee on Safe Drinking Water,
Subcommittee on Organic Contaminants. Drinking water and health,
Washington, B.C. (1977) .
2. Von Oettingen, W.F. Halogenated Hydrocarbons of Industrial
and Toxicological Importance. Elsevier Publishing Co., New
York (1964).
3. Mackie, I.J. Methyl chloride intoxication. Med. J. Australia
1:203-205 (1961).
4. Scharnweber, H.C., Spears, G.N., and Cowles, S.R. Chronic
methyl chloride intoxication in six industrial workers.
J. Occup. Med. 16:112-113 (1974).
5. Andrews, A.W., Zawistowski, E.S., and Valentine, C.R.
A comparison of the mutagenic properties of vinyl chloride
and methyl chloride. Mutation Res. 40(3):273-275 (1976).
6. Tardiff, R.G., Carlson, G.P. , and Simmons, V. Halogenated
organics in tap water: a toxicological evaluation.
Proceedings of the Conference on the Environmental Impact
of Water Chlorination, Oak Ridge, Tenn. (1975).
7. Davis, L.N., Strange, J.R., Hoecker, J.E., Howard, P.H.,
Santodonato, J. Investigation of selected potential environ-
mental contaminants: monohalomethanes. U.S.
E.P.A., Contract no. 68-01-4315.
8. Redford-Ellis, M. and Gowenlock, A.H. Reaction of chloro-
methane with human blood. Acta Pharmacol. Toxicol. 30(1-2):
49-58 (1971).
9. Lovelock, J.E. Natural halocarbons in the air and in the
sea. Nature 256(5514):193-194 (1975).
10. Grimsrud, E.P. and Rasmussen, R.A. Survey and analysis of
halocarbons in the atmosphere by gas chromatography-mass
spectrometry. Atmos. Environ. 9(11):1014-1017 (1975).
11. Singh, H.B., Salas, L.J., and Cabanagh, L.A. Distribution,
sources and sinks of atmospheric halogenated compounds.
J. Air Pollut. Control Assoc. 27(4):332-336 (1977).
12. Cowan, M.I., Gain, A.R., Hutchinson, S.A., MacCartney, M.E.,
Mackintosh, J.M., and Moss, A.M. Production of volatile
metabolites by species of Fomes. Trans. Brit. Mycol. Soc.
60(92) :247-35] (1973).
V-12
-------
13. Palmer, T.Y. Combustion sources of atmospheric chlorine. '-
Nature 263:44-46 (1976).
14. Chopra, N.M. and Sherman, L.R. Systematic studies on the
breakdown of p-p'-DDT in tobacco smokes. Presence of
methyl chloride, dichloromethane, and chloroform in
tobacco smokes. Anal. Chem. 44(6):1036-1038 (1972).
15. Johnson, W.R., Hale, R.W., Nedlock, J.W., Grubbs, H.F.,
and Powell, D.H. The distribution of products between
mainstream and sidestream smoke. Tobacco Science 17:
141-144 (1973).
16. National Academy of Sciences, Committee on Impacts of Strato-
spheric Change. Halocarbons: environmental effects of chloro-
fluoromethane release. Washington, D.C. (1976).
17. National Academy of Sciences, Panel on Atmospheric Chemistry
Halocarbons: effects on stratospheric ozone. Washington, D.C.
(1976) .
V-13
-------
-------
CRESOLS
TABLE OF CONTENTS
Page
Overview VI-1
Part I - General Information
Cresol (mixed isomers) VI-3
m-Cresol VI-6
o-Cresol VI-8
p_-Cresol VI-10
Summary of Characteristics VI-12
Part II - Biological Properties
2.1 Bioaccumulation VI-13
2.2 Contaminants and Environmental VI-13
Degradation or Conversion
Products
2.3 Acute Toxicity VI-14
2.4 Other Toxic Effects VI-15
2.5 Carcinogenicity VI-16
2.6 Mutagenicity VI-17
2.7 Teratogenicity VI-17
2.8 Metabolic Information VI-17
2.9 Ecological Effects VI-18
2.10 Current Testing VI-18
References VI-19
Vl-i
-------
-------
CRESOLS
AN OVERVIEW
There are three isomers of cresol: o-cresol, m-cresol,
and p_-cresol. All three isomers as well as mixtures are art-
icles of commerce. Cresols are solid or liquid at room tem-
perature (melting points 11-35°C). They are slightly soluble
in water and soluble in organic solvents.
The composition of the commercial products depends on the
method of production and upon the degree of refining. Cresols
are sold in a wide variety of grades, varying in composition,
color, and boiling range. Technical grade cresols commonly con-
tain xylenols and phenol. A less refined product called creo-
sote oil contains 10-20% by volume of tar from the coking process
Total annual production of cresols in the United States is pro-
bably in excess of 100 million pounds.
Cresols are used for a wide variety of purposes: disin-
fectants, solvents, in ore flotation, and as intermediates in
the production of phosphate esters and phenolic resins. They
are also present, in a number of consumer products, including dis-
infectants, metal cleaners, and motor oil additives.
The number of persons occupationally exposed to cresols is
estimated to be two million. Environmental release of the mixed
isomers and of the p_- and o-isomers are estimated at 30 million
pounds and 16 million pounds, respectively.
Cresols have a broad spectrum of toxicity to micro-organisms
and are used as disinfectants and fungicides. There is little
VT-1
-------
other infprmation on their potential toxicity to wildlife.
Cresols are relatively easily metabolized by mammals and micro-
organisms and are unlikely to undergo significant bioaccumulation,
Cresols are moderately toxic to mammals by ingestion and
dermal exposure, and are corrosive to skin and other tissues.
Little information is available on effects of chronic exposure.
In one experiment all three isomers of cresol were reported to
promote the carcinogenicity of dimethylbenzanthracene on mouse
skin. m-Cresol caused developmental abnormalities in toad em-
bryos. Otherwise/ no significant information is available on the
potential carcinogenicity, mutagenicity, or teratogenicity of cre-
sols.
VI-2
-------
CRESOLS
PART I
GENERAL INFORMATION
I. Cresol (mixed isomers)
1.1 Identification CAS No. 001319773
NIOSH No. G059500
1.2 Synonyms and Trade Names
Cresylic acid; methyl phenol; hydroxytoluene;
tricresol; cresylol
(G23,G21,
G16)
1.3 Chemical Formula and Molecular Weight
OH
C7HgO Mol. Wt. 108.15
(G23)
1.4 Chemical and Physical Properties
1.4.1 Description: A mixture of isomers in which
m-isomer predominates, obtained
f~rom coal tar or petroleum;
colorless, yellow or pinkish
liquid; phenolic odor; combustible;
becomes darker with age and on
exposure to light.
(G21,G23)
1.4.2 Boiling Point: 191 - 203° C (G21)
1.4.3 Melting Point: 11 - 35° C (G21)
1.4.4 Absorption Spectrometry;
No information found in sources
searched
1.4.5 Vapor Pressure: No information found in sources
searched
1.4.6 Solubility; Soluble in alcohol, glycol,
dilute alkalis, ether, chloro-
form;
Slightly soluble in water
(G21,G25)
1.4.7 Octanol/Water Partition Coefficient;
Log P . = 2.70 (estimate)
oct
VI -3
-------
1.5 Production ana Use
1.5.1 Production:
60 Million Ibs (1968)
80 Million Ibs (1973)
(G25)
1.5.2 Use:
As a disinfectant; intermediate in manufactur-
ing of phenolic resins/ tricresyl phosphate/
salicylaldehyde, coumarin, and herbicides; as
an ore flotation agent; as a textile scouring
agent; as an organic intermediate; as a sur-
factant
(GiJl)
Quantitative Distribution of Uses:
Phosphate esters
Magnet wire
Antioxidants
Resins
Exports
Cleaning and disinfectant
compounds
Ore flotation
Miscellaneous
Percent
22
15
15
15
10
6
6
11
100
Consumer Product Information;
Cresol is present in:
automotive parts cleaner
metal cleaner, stripper, degreaser
disinfectant
motor oil additive
carbon remover
embalming supplies
1.6 Exposure Estimates
1.6.1 Release Rate:
30.4 Million Ibs
1.6.2 NOHS Occupational Exposure:
Rank: 105
Estimates no. of persons exposed:
(G25)
(G35)
(G28)
1,914,000
(G29)
VI-4
-------
1.7 Manufacturers
American Cyanamid Co.
Amoco Oil Co.
Crowley Tar Products Co., Inc.
Froese Chemicals,
Koppers Co., Inc.
Merichem Co., ' •
Mobil Oil Corp.
Northwest Petrochemical Corp/
Pitt-Consol Chemicals
Productol Chemical Co.
Sherwin-Williams Co.
United States Steel Corp.
(G25)
VI-5
-------
CKESOLS
II . nr-Cresol
1.1 Identification CAS No. : 000108394
NIOSH No. : 0061250
1.2 Synonyms and Trade Names
nt-Cresylic acid; m-tnethylphenol; 3-methylphenol; l-hydroxy-3-methyl-
benzene; m-kreso.'.; m-oxytoluene
(G16)
1.3 Chemical Ponnula and Molecular Weight
OK
b
(
*tol. wt. 108.15
1.4 Chemical and Physical Properties
1.4.1 Description;
Colorless to yellowish liquid; phenol-like
odor
1.4.2 Boiling Point; 202.2° C
1.4.3 Melting Point; 11.5° C
1.4.4 Absorption Spectronatry;
(G21)
(G22)
(G22)
= 214, 271,277
log £ = 3.79, 3.20, 3.27
1.4.5 Vapor Pressure; 1 irni at 52.0° C
(G22)
1.4.6 Solubility;
Slightly soluble in water;
Soluble in hot water, organic solvents;
Soluble in all proportions in alcohol, ether,
acetone, benzene and carbon tetrachloride
(G22)
1.4.7 Qctanol/Water Partition Coefficient;
log P = 2.37
VI-6
-------
1.5 Production and Use
1.5.1 Production;
No information found in sources searched
1.5.2 Use; In disinfectants and fumigants; in photographic
developers, explosives (G23)
1.6 Exposure Estimates
1.6.1 Release Rate;
Mo information found in sources searched
1.6.2 NOHS Occupational Exposure;
Rank: 2781
Estimated no. of persons exposed: 9,000*
*rough estimate (G29)
1.7 Manufacturers
Koppers Co., Inc. (G24)
VI-7
-------
CRESOLS
III. o-Cresol
1.1 Identification
CAS No.
NIOSH No.
000095487
GO63000
1.2 Synonyms and Trade Names
o-Cresylic acid; o-methyl phenol; 2-methyl phenol;
orthocresol; l-hydroxy-2-methylbenzene; o-hydroxy-
toluene; o-methylphenol; o-oxytoluene; 2-hydroxy-
toluene "~
1.3 Chemical Formula and Molecular Weight
OH
(G16)
C7H80
1.4 Chemical and Physical Properties
1.4.1 Description;
Mol. Wt. 108.15
(G22)
White crystals; phenol-like odor;
combustible; becomes dark with age
and exposure to air and light.
(G23,G21)
190.95 C
30.94° C
1.4.2 Boiling Point;
1.4.3 Melting Point;
1.4.4 Absorption Spectrometry;
A .._. as 219, 275 nm
(G22)
(G22)
log
1.4.5 Vapor Pressure;
1.4.6 Solubility;
£ - 3.71, 3.22
1 mm at 38.2° C
(G22)
(G22)
Soluble in water and ordinary
organic solvents;
Very soluble in alcohol and ether;
Soluble in all proportions in
acetone, benzene, carbon tetrachloride
(G22)
VI-8
-------
1.4.7 Octanol/Water Partition Coefficient;
Log P
oct
3.40
1.5 Production and Use
1.5.i Production:
49.700 Million Ibs
20.481 Million Ibs
22.187 Million Ibs
(1972)
(1975)
(1976)
1.5.2 Use:
Disinfectant; solvent
1.6 Exposure Estimates
1.6.1 Release Rate: 15.b Million Ibs
(G15)
(G28)
(G24)
(G24)
(G23)
(G28)
1.6.2 NOHS Occupational Exposure;
Rank: 1480
Estimates no. of persons exposed: 52,000*
* rough estimate
(G29)
1.7 Manufacturers
from coal tar:
Koppers Co . / Inc
Ferro Corp.
from petroleum:
Mericnem Co.
Ferro Corp.
Sherwin-Williams Co.
(G24)
VI-9
-------
CRESOLS
IV. g-Cresol
1.1 Identification CAS No.: 000106445
NIOSH No.: G064750
1.2 Synonyms and Trade Names
4-cresol; £-cresylic acid; l-hydroxy-4-methylbenzene; £-
hydroxytoluene; 4-hydroxytoluene; £-Jcresol; l-methyl-4-
hydroxybenzene; £-methylphenol; 4-methylphenol; p_-oxyto-
luene; para-cresol; paramethyl phenol
(G16)
1.3 Chemical Formula and Molecular Weiaht
C HO Mol. wt. 108.15
7 8
(G22)
1.4 Chemical and Physical Properties
1.4.1 Description; Crystalline mass; phenol-like
odor
(G21)
1.4.2 Boiling Point; 201.9° C (G22)
1.4.3 Melting Point; 34.8° C (G22)
1.4.4 Absorption Spectrometry ;
^cyclohexane
log £ = 3.23 (G22)
1.4.5 Vapor Pressure; 1 mm at 53.0° C (G22)
1.4.6 Solubility; Slightly soluble in water;
Soluble in hot water, organic solvents;
Soluble in all proportions in alcohol,
ether, acetone, benzene and carbon
tetrachloride
(G22)
1.4.7 Octanol/Water Partition Coefficient
poct = 2-35
VI- 10
-------
1.5 Prpduction and Use
1.5.1 Production;
No information found in sources searched
1.5.2 Use; As a chemical intermediate (G24)
1.6 Exposure Estimate
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOES Occupational Exposure
Rank: 2466
Estimated no. of persons exposed: 14,000*
*rough estimate
(G29)
1.7 Manufacturers
Sherwin-Williams Co.
(G24)
VI-11
-------
CPFSOLS
SUMMARY OF CHARACTERISTICS
Name
Cresol
(mixed isomers)
o-Cresol
m-Cresol
p_-Cresol
Solubility
s in ale, glycol,
dil. alk, eth,
chl.
ss in HJD
Log P
Estimated
Environmental
Release
oct (Million Ibs)
2.70
30.4
Production
(Million Ibs)
~60 (1968)
-80 (1973)
s in HJD and COS. 3.40
vs in ale and eth.
oo in ace, bz, CC1..
ss in H2O; s in hot 2 .37
H20, os;00 in ale,
eth, bz, ace, CC14
ss in H20; s in 2.35
hot H2O, os;oo in
ale, eth, bz, ace,
cci.
15.6
49.7 (1972)
20.481(1975)
22.187(1976)
Estimated no.
of persons
exposed
(occupational)
1,914,000
52,000
9,000
14,000
Use
Disinfectant; phenolic
resins; tricresyl phos-
phate; ore flotation;
textile scouring agent;
organic intermediate;
mfg. of salicylaldehyde,
coumarin, and herbicides;
surfactant
Disinfectant, solvent
In disinfectants, fumi-
gants, photographic
developers, explosives
cyclic intermediate
* No information found in sources searched.
VI-12
-------
CRESOLS
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
Log octanol/water partition coefficients are 3.40, 2.37, and
2.35 for the o-, m-, and p_-isomers, respectively (G15). The high
partition coefficient of the o-isomer is due to the steric effect
of the methyl group on the hydroxyl group. The high octanol/
water partition coefficients of the cresols indicate that bio-
accumulation in aquatic organisms is a possibility, but specific
data on such bioaccumulation are not available. By analogy with
phenol, which appears to be completely eliminated from the body
within 24 hours (G19), it is expected that cresols would not be
bioaccumulated in mammals. Cresols in waste waters near indust-
rial plants are reported to undergo rapid biodegradation (G14),
which indicates that cresols, like phenol, are relatively easily
metabolized.
2-2 Contaminants and Environmental Degradation or Conversion
Products
Cresols are sold in a wide variety of technical and special
grades, classified by color and distillation range (G25). The
composition of the various materials depends upon the starting
material and the method of production. A major source of cresols
is the tar-acid oil obtained as a by-product of coking of coal (G25)
Cresols (boiling above* 204°C), available as a mixture of o-,
m-, and p_-isomers from tar acids are called cresylic acid. A less.-
refined product called creosote oil contains 10-20% by volume of
the tar from the coking process; it is used as a wood preservative
(G25). Creosote oil may contain polynuclear aromatic hydrocarbons.
Xylenols and phenol are common impurities (or ingredients) of tech-
nical grade cresols (G25).
VI-13
-------
The high environmental stability of the cresols in soils
(owing to their antimicrobial properties) contributes to their
widespread use as wood perservatives. o-Cresol is degraded by
the hydroxyl radical and ozone in air and by organic peroxide
radicals in water; half life estimates are less than 1 day in
air and 10 days in water (G14) . The m- and p_-isomers are ex-
pected to behave similarly. Environmental degradation is likely
to be by air oxidation to give quinones and dihydroxybenzenes (G14)
Biodegradation products of cresols by sewage microorganisms
include carbon dioxide, methane, 3-methylcatechol, 2-hydroxy-6-
oxahepta-2,4-dienoic acid, oxalic acid, pyrocatechol,carboxylic
acid, and salicylic acid (G14). By analogy with phenol, cresols
may be methylated in the environment to form the corresponding
anisoles.
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances
(G16) reports the acute toxicity of cresols as follows:
Substance Parameter
Cresol
o-Cresol
m-Cresol
Dosaqe
Animal
LD50
LD50
LD50
LD50
L050
LDLo
LDLo
LDLo
LD50
LDLo
LDLo
LDLo
LDLo
LD50
LD50
LD50
LD50
LDLo
LDLo
LDLo
LD50
LDLo
LDLo
LDIo
LDLo
1454 mg/kg
861 mg/kg
121 mg/kg
1100 mg/kg
344 mg/kg
410 mg/kg
5 5 mg/kg
940 mg/kg
1380 mg/kg
450 mg/kg
180 mg/kg
360 mg/kg
200 mg/kg
242 mg/kg
620 mg/kg
350 mg/kg
828 mg/kg
450 mg/kg
180 mg/kg
1400 mg/kg
2050 mg/kg
500 mg/kg
280 mg/kg
100 mg/kg
250 mg/kg
rat
mouse
rat
rat
mouse
mouse
cat
rabbit
rabbit
rabbit
rabbit
guinea pig
frog
rat
rat
rat
mouse
mouse
cat
rabbit
rabbit
rabbit
rabbit
guinea pig
frog
Route
oral
oral
oral
skin
oral
subcutaneous
subcutaneous
oral
skin
subcutaneous
intravenous
intraperitoneal
subcutaneous
oral
skin
unknown
oral
subcutaneous
subcutaneous
oral
skin
subcutaneous
intravenous
intraperitoneal
subcutaneous
VT-3
-------
(continued)
Substance Parameter Dosage Animal Route
£-Cresol
LD50
LD50
LD50
LDLo
LD50
LDLo
LDLo
LD50
LDLo
LDLo
LDLo
LDLO
207 mg/kg
705 mg/kg
344 mg/kg
150 mg/kg
160 mg/kg
80 mg/kg
620 mg/kg
301 mg/kg
300 mg/kg
180 mg/kg
100 mg/kg
150 mg/kg
rat
rat
mouse
mouse
mouse
cat
rabbit
rabbit
rabbit
rabbit
guinea pig
frog
oral
skin
oral
subcutaneous
unknown
subcutaneous
oral
skin
subcutaneous
intravenous
intraperitoneal
subcutaneous
Cresols are rated as moderately toxic to humans (G4). Acute
exposures can cause muscular weakness, gastroenteric disturbances,
severe depression, collapse, and death (G38). Organs attacked by
cresols include the central nervous system, liver, kidneys, lungs,
pancreas, spleen, eyes, heart, and skin (G38). The type of exposure
to cresols determines, in part, the toxic effects. Cresols are highly
corrosive to any tissues they contact (G5) and are readily absorbed
by skin and mucous membranes. Systemic effects, including death,
occur after dermal exposure. Because their vapor pressure is low
at 25°C, cresols do not usually constitute an acute inhalation
hazard. No data are available on the toxicity of cresol vapors to
humans (G39).
In animals, cresol toxicity varies with the isomer, the species
and the route of exposure. Reported LDSOs vary from a low of 121
mg/kg in the rat (oral, o-cresol) to a high of 2050 mg/kg in the
rabbit (skin, m-cresol) (G16). Evidence for different biological
effects of the three isomers includes the observation that the ratios
between the LDSOs of the least toxic and most toxic isomers vary from
as low as 1.8 (cutaneous, rat) to as high as 6.8 (cutaneous, rabbit).
Furthermore, p_-cresol, but neither o- nor m-cresol, produced
permanent pigment loss in the hair of mice (1).
2.4 Other Toxic Effects
Chronic poisoning from absorption of cresols through the skin,
va-15
-------
mucous membranes or respiratory tract has not been well studied.
Campbell (2) presented incomplete studies showing that exposure
of mice to an atmosphere saturated with cresylic acid vapors for
1 hr/day on consecutive days caused irritation of the nose and
eyes, and death in some animals. Uzhdavini et al. (3) performed
poorly documented studies on the chronic effects of o-cresol in-
halation. In mice, they found evidence for: tail necrosis; slowed
weight gain; cellular degeneration of the CNS; respiratory tract
hyperemia, edema, proliferation of cellular elements, and hemor-
' rhagic patches; myocardial fiber degeneration; and protein deposits
• in liver and kidney cells. In rats, they reported alterations in
a conditioned reflex, and alterations in both peripheral blood and
bone marrow elements.
, The Threshold Limit Value established by the ACGIH for cresols
is 5 ppm (Gil).
*2.5 Carcinogenicity
' o, m, and p_-Cresol have been reported to promote the carcino-
•<• genicity of dimethylbenzanthracene (DMBA) in skin tests with mice
(4). They were slightly less active as promoters than phenol in
this experiment (see table below).
No. mice Avg. no. % survivors
survivors/ papillomas with
Promoter* original no. per survivor papilloma
Benzene Control 12/12 0 0
20% phenol 22/27 1.50 64
20% o-cresol 17/27 1.35 59
' 20% m-cresol 14/29 0.93 50
20% p_-cresol 20/28 0.55 35
* Initiator: 0.3% DMBA in acetone. Promoter in benzene.
Data at 12 weeks.
No carcinogenicity tests conducted with cresols alone have been
found in the searched literature.
VI-16
-------
2.6 Mutagenicity
In onion root tips, m- and p_-cresol produced cytological
abnormalities including stickiness, erosion, pycnosis, C-mito-
sis, polyploidy, and chromosome fragmentation (5). o-Cresol
did not appear as active (5). These chromosomal effects do
not necessarily imply that the cresols will have genetic ac-
tivity in mammals. No other mutagenicity studies-were found
in the searched literature.
2.7 Teratogenicity
No systematic studies of the teratogenic potential of the
cresols have been found. The only information available is
on the effect of m-cresol on embryos of a toad (Xenopus laevis)
at the neural tube stage of development (6). Concentrations of
20 to 80 ppm, m-cresol caused two developmental abnormalities:
edema and tail flexion.
2.3 Metabolic Information
Very little is known about the metabolic fate of cresols
in mammals. One study showed that the cresols are excreted in
rabbit urine primarily as oxygen conjugates: 60-72% as
ether glucuronides and 10-15% as ethereal sulphates (7).
Paper chromatography showed that o- and m-cresol are
hydroxylated and that p_-cresol forms p_-hydroxybenzoic acid (7) .
£-Cresol glucuronide was isolated from the urine of rabbits
closed by stomach tube with p_-cresol, whereas o- and m-cresol
were metabolized to 2,5-dihydroxytoluene (7). No studies
have been traced of the biological effect of these and other
possible metabolites of the cresols.
VI-17
-------
2.9 Ecological Effects
The 96-hour LC50 of o-cresol to channel catfish (Ictalurus
punctatus) is reported to be 67 mg/1 (8). In tests with
perch and sunfish, lethal concentrations (not LCSOs) were
determined in 1 hour exposures. In perch (Perca fluviatilis) ,
lethal concentrations for o-, m- and p_-cresols were in the
range 10-20 ppm (9). The Aquatic Toxicity Rating (96-hour
TLm, species unspecified) for cresols is listed as 10-1 ppm
(G16). Although o-cresol is less toxic to juvenile Atlantic
salmon (Salmo salar) than p_-cresol, the salmon avoided
o-cresol more efficiently (10).
Cresols have a broad spectrum of toxicity to microorganisms
They are used as disinfectants and as fungicides to protect
materials such as wood. They are also reported to be active
against mycoplasnas (11), viruses (12) , and plant galls (13).
2.10 Current Testing
A criteria document on cresols is planned for completion
in 1977 by NIOSH.
VI-1S
-------
REFERENCES
1. Shelley, W. B. p_-Cresol: cause of ink-induced hair depitment-
ation in mice. Brit. J. Dermatol. 90:169-174 (1974).
2. Campbell, J. Petroleum cresylic acids - a study of their toxi-
city and the toxicity of cresylic disinfectants. Soap Sanit.
Chem. 17:103-111 (1941).
3. Uzhdavini, E.R., Astafyeva, I.K., Mamayeva, A.A. and Bakhtizina,.
G.Z. Inhalation toxicity of o-cresol. Tr. Ufim. Nauchno-Issied
Inst. Gig. Profzabol. 7:115-119 (1972). (Russian)
4. Bontwell, R.K., and Bosch, O.K. The tumor-promoting action of
phenol and related compounds for mouse skin. Cancer Res.
19:413-424 (1959).
5. Sharma, A.K. and Ghosh, S. Chemical basis of the action of
cresols and nitrophenols on chromosomes. The Nucleus 8:183-
190 (1965).
6. Johnson, D.A. The effects of meta-cresol on the embryonic
development of the African Clawed Toad, Xenopus laevis.
J. Ala. Acad. Sci. 44:177 (1973).
7. Bray, H.G., Thorpe, W.V., and White, K. Metabolism of
derivatives of toluene. 4. Sresols. Biochem. J. 46:275-
278 (1950).
8. Clemens, H.P., and Sneed, K.E. Lethal dose of several com-
mercial chemicals for fingerling channel catfish. U.S. Fish.
Wildlife Serv. Spec. Sci. Rep. Fisheries 316 (1959).
9. Jones, J.R.E. Fish -and River Pollution. Butterworths, London
(1964). Pp 118-153.
10. Zitko, V., and Carson, W.G. Avoidance of organic solvents
and substituted phenols by juvenile Atlantic salmon. Fish-
eries Res. Board Can. MS. Rep. 1327 (1974).
11. Kihara, K., Sasaki, T., and Arima, S. Efeect of antiseptics
and detergents on Mycoplasma. Igaku T.o Seibutsugaku, 83:5-8
(1971).
12. Sellers, R. F. The inactivation of foot-and-mouth disease
virus by chemicals and disinfectants. Vet. Rec., 83:504-506
(1963).
13. Schroth, M.N. and Hildebrand, D.C. A chemotherapeutic treatment
for selectively eradicating crown gall and olive knot neoplasms.
Phytopath. 58:848-854 (1954).
VI-19
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HEXACHLORO-1,3-BUTADIENE
TABLE OF CONTENTS
Page
Overview VII-1
Part I - General Information VII-3
Specific References VII-5
Part II - Biological Properties
2.1 Bioaccumulation VII-6
2.2 Contaminants and Environmental VII-9
Degradation or Conversion Products
2.3 Acute Toxicity VII-10
2.4 Other Toxic Effects VII-12
2.5 Carcinogenicity VII-15
2.6 Mutagenicity . VII-15
2.7 Teratogenicity . j VII-15
2.8 Metabolic Information VII-15
2.9 Ecological Effects VII-15
2.10 Current Testing VII-17
References VII-19
Vll-i
-------
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HEXACHLORO-1,3-BUTADIENE
AN OVERVIEW
Hexachloro-l,3-butadiene (HCBD) is a clear colorless liquid
with a mild odor. It is insoluble in water but soluble in alcohol
and ether. It is an unreactive compound, stable to acids and alkalis
and extremely resistant to hydrolysis.
HCBD is not known to have been produced commercially in the Uni-
ted States since 1970, but is imported into the U.S. for industrial
solvent use, mainly from West Germany. HCBD is a waste product in the
manufacture of chlorinated solvents such as perchloroethylene, tri~
chloroethylene, and carbon tetrachloride. It occurs in tarry wastes
with hexachlorobenzene and other chlorinated by-products.
Some of the uses of HCBD are as a solvent for elastomers, as an
agent for the recovery of chlorine from gas streams in chlorine plants,
as a heat transfer liquid and as a chemical intermediate in the manu-
facture of rubber compounds.
HCBD has been reported to bioaccumulate in fish and other aquatic
organisms. The release of HCBD into the environment has not been
quantified, but there is evidence that it may be widely distributed
in the aquatic environment. No incidents of ecological damage caused
by HCBD have been reported. However, it is toxic to fish at low con-
centrations. Its use as a pesticide in overseas countries provides
further indication of its biological activity.
HCBD is moderately toxic to mammals: reported LD50 values in
several species are in the range 65-350 mg/kg. A number of studies
VJJ-I
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of subacute and chronic toxicity of HCBD have been published, primarily
in the Russian literature. HCBD causes pathological changes in the
kidney, liver, central nervous system, and lungs of the offspring.
Adverse effects on reproduction in rats have been reported in one stu-
dy.
HCBD is mutagenic in the Salmonella reversion test with microsoin-
al activation. No adequate carcinogenicity tests and no teratogenicity
or metabolic studies have been traced. Studies of chronic oral toxi-
city, carcinogenicity, and effects on reproduction are in progress.
VII-2
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HEXACHLORD-l , 3-BUTADIENE
PART I
GENERAL IMFOBMATION
1.1 Identification CAS No.: 000087683
NKDSHNo.; BJ07000
1.2 Synonyms and Trade Names
HCBD; C— 46;
(G16)
1.3 Chemical Font81^ and Mole<7n1flr Weight
C12C » C - C • CC12 C4C16 Mai. wt. 260.76
Cl Cl
1.4 Chemical and Physical Properties
1.4.1 Description; Clear, colorless liquid with mild odor;
nonflammable (G21)
1.4.2 Boiling Point; 215° C (G22)
1.4.3 Melting Point; -21° C (G22)
1.4.4 Absorption Spectrcmetry;
1.4.5 Vapor Pressure;
=253™
log £ =3.7 (G22)
0.15 mm at 20* C (1)
1.4.6 Solubility; Insoluble in water;
Soluble in alcohol and ether
(G22,G21)
1.4.7 Octanol/Water partition Coefficient;
No information found in sources searched (G36)
1.5 Production and Use
1.5.1 Production; Hexachlorobutadiene has not been produced
in the U. S. since 1970 because of low
domestic demand. Imported hexachlorobutadiene
is available in the U.S. - see 1.7 Suppliers
VII-3 (2)
-------
1.5 Production and Use (Continued)
1.5.2 Use; As a solvent for elastomers; as a heat transfer
liquid; in transformer and hydraulic fluid; in
wash liquor for removing C4 and higher hydrocarbons;
for recovery of chlorine-containing gas; as a chemi-
cal intermediate in the manufacture of rubber
compounds (G21, 2)
1.6 Exposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NCHS Occupational Exposure;
No information found in sources searched
1.7 Suppliers;
Davos Chemical Corp.
Kay-Fries Chemicals, Inc.
Rhodia, Inc.
(G37)
VII-4
-------
Specific References for Part I
1. Pearson, C. R. and McConnell, G., Chlorinated C, and C2 hydrocarbons in
the marine environment. Proc. R. Soc. London, Ser. B, - 189 (1096): 325-332
(1975) .
2. Survey of Industrial Processing Data, EPA, June 1975.
VII-5
-------
HEXaCHLORO-1 , 3-BUTADIENE
PART II
BIOLOGICAL
2 . 1 Bioaccumulation
Hexachloro-1, 3 -butadiene (HCBD) is a water -insoluble, stable compound.
Several reports on its propensity to bioaccuinulate were found. In one
report on aquatic fauna from the IJsselmeer, IJssel River, and the Ketelmeer
(all in The Netherlands and fed by industrial waters of the River Rhine) ,
HCBD levels in fish and other aquatic animals were found to be about
1,000 times higher than the concentration in the waters of the Ketelmeer
(a lake) (1) . Thus, HCBD levels in fish (perch, pike, tench, canton bream,
white bream, and roach) ranged from 0.13 ppm to 1.86 ppm, while the level of
HCBD in the water was 0.13 ppb. Similar elevated levels of HCBD (0.03 to
2.41 ppm) were noted in molluscs (Lymnaca peregra and Sphaerium spp.) ,
oligochaete worms (mainly Limnodrilus spp.) and detritus (1) . However, the
data indicated that bioaccumulation via food chains to higher trophic levels
did not occur.
In another study, chemical pollutants known to be present in the River
Rhine (HCBD; hexachiorobenzene; 1,2,3,4- and 1,2,3,5-tetrachlorobenzene;
1,3,5-trichlorobenzene; o^dichlorobenzene; and lindane) were fed as a mix-
ture to albino rats (2) . HCBD was stored at low levels. Of the 7 compounds
fed, HCBD accumulated least as shown by analyses of abdominal and renal
fat (2) .
HCBD has been found in fish of the lower Mississippi River basin at
levels that ranged from 0.01 to 1.2 ppm in one study (3) and from a
VII-6
-------
trace to 4.65 ppm in another (4). The concentration of HCBD in the water
was not determined.
A Russian investigator stated that HCBD has cumulative properties (5),
while another Russian author stated that cumulative properties are rather
weak (6).
Tables 1 and 2 summarize the results of laboratory bioaccumulation
tests with fish and mussels exposed to about 1.5 ppb HCBD (7). Bio-
accumulation factors were 500 - 700 in the flesh of fish (dabs and
plaice) and 7,000 - 10,000 in their livers. In mussels, the factors
were 900 - 2,000 in the whole animals. To check food-chain accumulation,
HCBD-contaminated mussels were fed to plaice for 88 days but no
accumulation occurred (Table 1).
In another experiment, removal of contaminated fish to water free of
HCBD resulted in almost complete loss of HCBD in 30 - 40 days (7).
TABLE 1
ACCUMULATION OF HEXACHLOFOBUIADIENE BY DABS AND PLAICE (7)
Species
dab
plaice
plaice
tissue
analysed
flesh
liver
flesh
liver
flesh
liver
period of
exposure
days
27-39
27-39
21-106
21-106
19-88*
19-88*
mean exposure
concentration,
parts/106
0.0016
0.0016
0.0017
0.0017
1.8**
1.8**
mean
concentration
in tissues,
parts/106
1.1 (6)
20.0 (6)
0.78 (10)
12.1 (9)
0.04 (15)
0.66 (15)
accumulation
factor
x 700
x 10000
x 500
x 7000
« 1
Numbers in parentheses are number of specimens analysed.
*Fed to fish in food
**These concentrations are mean values for mussels which
were fed to the plaice after having been previously
exposed to HCBD in sea water.
VII-7
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TABLE 2
ACCTMULATION OF HEXACHLORDBUTADHNE BY MUSSELS (7)
mean
tissue
analysed
whole
whole
foot
gill
gonad
digestive
gland
period of
exposure,
days
38
50
21-106
21-106
21-106
21-106
mean exposure concentration
concentrations, in tissues,
parts/106 parts/106
0.0013
0.0016
0.0017
0.0017
0.0017
0.0017
2.55
1.37
0.82
1.73
3.92
5.52
(10)
(5)
(10)
(10)
(10)
(10)
accumulation
factor
x 2000
x 900
x 500
x 1000
x 2000
x 3000
Numbers in parentheses are the numbers of specimens
analysed.
The laboratory accumulation factors in the aquatic organisms were
similar to those found in these organisms taken from industrial waters
(Liverpool Bay, England) (7).
Table 3 shows the concentrations of HCBD found in algae (Qedogonium
cardiacum) exposed to water containing 16,9 ppb HCBD in a continuous-flow
experiment (25).
TABLE 3
days
exposure
1
3
7
ACCUMULATION OF HCBD BY ALGAE (25)
HCBD in
algae (ppb)
966
2547
2701
accumulation
factor
x 57
x 150
x 160
VII-8
-------
Adsorption of HCBD to sediments was shown in another continuous-flow
experiment in which sediments were exposed to water containing 3.6 ppb HCBD.
The concentration of HCBD in sediments was 725 ppb after 1 day of
exposure, 938 ppb after 4 days exposure, and 632 after 4 days in clean
water (25).
In summary, HCBD does bioaccumulate, particularly in fish located in
HCBD-contaminated waters. However, two reports indicated that HCBD did
not bioaccumulate to higher trophic levels in aquatic organisms via the
food chain; also, HCBD was eliminated in 30-40 days from fish placed in
HCBD-free water.
2.2 Contaminants and Environmental Degradation or Conversion Products
Owing to lew demand, HCBD has not been produced in the U.S. since
1970, and only 200,000-500,000 Ib/yr are imported for domestic needs (8).
However, about 11 million Ib/yr are generated annually in distillation
residues as a by-product of the production of perchloroethylene, tricholoro-
ethylene, and carbon tetrachloride. About 98% of the by-product is
disposed of in land fills or by incineration; the remaining HCBD is lost
to the environment via air and water, about 1% to each (8). A major
concern is that HCBD will contaminate the environment and ultimately the
food supply (4).
HCBD is reactive toward OH radical and ozone with half-lives less than
1 day; the half-life toward peroxy radical is 1000 days (G14). In
laboratory tests, the half-life of HCBD vapor exposed to outdoor light was
quite short, about 1 week. The major product of degiadation of the
compound exposed to light simulating that in the troposphere was identified
V.II-9
-------
as HC1 (95%) (7). However, traces of HCBD have been found in ambient air
(G14).
Breakdown of HCBD in water appears to be very slow. Owing to its
structure and low vapor pressure, HCBD is adsorbed on sediments and is
transferred to the air slowly (7).
A Midwest Research Institute report (8) states that HCBD is a
"potentially hazardous environmental pollutant that is resistant to
chemical degradation." HCBD is stable to acids and alkalis and extremely
resistant to hydrolysis. The lack of reactivity of the molecule is
evident from its high thermal stability, with a half-life at
380° C of 53 hours ( 9). Oxidation of HCBD requires exposure to oxygen
betareen 110-210° C (10). In Europe, the compound has been found in fruit
juices, wine, and run-off waters (G14), which is indicative of its per-
sistence.
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances
(G16 ) reports the acute toxicity of HCBD as follows:
Route
oral
oral
inhalation
intraperitoneal
Parameter
I£>50
LD50
LDLo
LDLO
Dosage
90 mgAg
110 mgAg
235 ppm/4H
32 mgAg
Animal
rat
mouse
mouse
mouse
VII-10
-------
The results of toxicity tests with HCBD conducted by Hazelton
Laboratories, Washington, D.C. for the Diamond Shamrock Corporation
have been reported in a secondary source (8) as follows:
The acute oral LD50 of HCBD for male albino rats is 178 jj I/kg
of body weight. At a dosage level of 100 ul/kg none of a group of five
animals succumbed. At a level of 316 /il/kg, all of a group of five
animals succumbed within 2 days.
The acute dermal LD50 of HCBD for albino rabbits of either sex
is 1,780 jUl/kg of body weight. After an exposure period of 24-hr, none
of a group of four rabbits succumbed at a dosage level of 1000 u lAg-
At a dosage level of 3,160 ^1/kg, all of a group of five rabbits suc-
cumbed within a period of 5 days. The exposed skins of all animals
showed a mild to moderate degree of erythema. This completely subsided
by the second or third day and thereafter snowed no gross signs of
dermal irritation.
A single application of HCBD to the eyes of a group of three
albino rabbits of either sex produced a mild degree of irritation which
completely subsided within 24 hours. There was no evidence of systemic
tcciicity from mucous membrane absorption.
Reference 8 also gives details of acute inhalation toxicity tests
concluded by Hazel'aDn Laboratories. Mice, rats, and guinea pigs exposed
to an aerosol of HCBD at approximately 6,800 ppm (73 g/m ) died after
periods ranging from 165-357 minutes.
VII-11
-------
Dosage
87 mgAg
350 mg/kg
90 mgAg
Animal
mouse
rat
guinea pig
Route
oral
oral
oral
Murzakaev, a Russian investigator (11), determined the acute oral
IDSOs of HCBD to be as follows:
Parameter
LD50
I£>50
ID50
Gradiski et al. (12) have reported the ID50 by oral and intra-
peritoneal routes for female and male mice and rats as follows:
Route of Administration ID50, mgAg
Mice Rats
Female Male Female Male
Intraperitoneal 76+5 105+15 175+25 216+6
Oral 65+5 80+5 270+20 250+30
HCBD has a mild irritant action on the skin and ocular mucous
membranes of rabbits. It produces marked skin reaction on guinea pigs (12).
2.4 Other Toxic Effects
The subacute inhalation toxicity of HCBD has been reported by Gage (15)
as follows in rats (4 male and 4 female):
Dosage Exposure Time Effects
250 ppm 2 x 4 hr Eye and nose irritation, respiratory
exposures difficulty, females affected more than
males, apparent recovery after exposure;
autopsy (histol.), degeneration of middle
renal proximal tubules and of adrenal cortex
100 ppm 12 x 6 hr Eye and nose irritation, respiratory
exposures difficulty, poor condition, weight loss,
slight anemia in females, urine tests
normal, 2 females died; autopsy, kidneys
pale and enlarged, degeneration of renal
cortical tubules with epithelial regeneratioi
VH-12
-------
Subacute inhalation toxicity of HCBD (Continued):
Dosage
25 ppm
Exposure Time
15 x 6 hr
exposures
Effects
10 ppm
5 ppm
15 x 6 hr
exposures
15 x 6 hr
exposures
Poor condition, diminished weight gain
in females; respiratory difficulty,
blood and urine tests normal; autopsy,
kidneys pale and enlarged, (histol.)
damage to renal proximal tubules
Retarded weight gain in females; autopsy,
organs normal
No toxic signs; autopsy, organs normal
The results of a preliminary behavioral study on mice suggest that
hexachlorobutadiene has effects on the central nervous system. Morpho-
logical, hematological and biochemical tests revealed hepatic and renal
disorders in laboratory animals (mice, rats, guinea pigs, and rabbits) (12).
The remainder of information in this section is compiled from abstracts
of papers appearing in Russian journals.
Rats and guinea pigs fed 0.004, 0.04, 2 and 7 mgAg HCBD showed
a decrease in the sulfhydryl (SH) groups in the blood serum after 3
months at the 2 mgAg level. Rats fed 7 mgAg showed a decrease in the
SH level in the gray matter of the brain and a functional change in CMS
activity (19). Female rats fed 7.0 mgAg for 6 months showed disrupted
ability to form conditioned reflex pathways, decreased SH group content
in the blood and brain, and morphological changes in the liver, kidneys,
and cardiac muscle (6).
In inhalation, oral, and topical treatments, HCBD was found to be a
poly tropic poison in rats, mice, guinea pigs and cats. The following
VII-13
-------
effects were noted:
Leucocytosis and lymphocytosis along with a decreased erythrocytic
osmosis resistance
Displacement of the pH towards acidosis along with decreased
Vitamin B, and C levels in the internal organs
Increased residual serum nitrogen and decreased total blood protein
levels along with enhanced internal organ transarainase, decreased
blood peroxidase and catalase activities
Inrnunological depression including decreased antibody formation
potentials along with reduced neutrophil and reticulendothelial
phagocytic capacities (5)
Oral treatment of rabbits in subacute (10 mgAg daily for 10 days)
or chronic (1 mgAg daily for 90 days) exposures is stated to have caused
"metabolic acidosis" (13, 14).
Chronic poisoning due to HCBD may cause protein denaturation and
necrotic nephrosis followed by auto-sensitization and the development of
autoallergic glomerulonephritis as an end result. HCBD at 8.4 mgAg caused
dystrophic changes in kidneys and at 10 mgAg caused necrosis (16).
HCBD administered orally to puppies at 0.05 mgAg daily for 45
days (from 1.5 to 3 months postnatal) increased the amounts of HC1
and chloride secreted by the stomach and caused irritation of the gastric
mucosa. Respiration, body temperature and growth rate were not affected (17)
The effects of HCBD on reproduction in albino rats have been reported
by Poteryaeva (20). Subcutaneous administration to female rats at a
dosage of 20 mgAg led to lowered vitality, reduced weight gain and loss
VII-14
-------
of motor examination in their offspring. Pathological changes in the lungs,
liver, kidneys, and gastrointestinal tract were also reported. All the
offspring of the rats which had received HCBD died within three months
of birth. Offspring of rats given a higher dose level (70-150 tog/kg
either orally or subcutaneously) died within two months of birth (20).
2.5 Carcinogenicity
This compound has been tested orally in guinea pigs and rats for
7 months. No tumors were reported but liver and kidney damage was
observed (19).
2.6 Mutagenicity
Hexachlorobutadiene is reported to be mutagenic in the Salmonella typhiinu-
rium reversion test in strain TA100, with rat liver uvicrosome activation (26).
2.7 Teratogenicity
No reports of teratogenicity tests in mammals have been found in the
searched literature. In a reproduction study in Japanese quail, no
morphological abnormalities were found in chicks hatched from eggs laid
by females exposed to HCBD at 30 ppm in the diet (21).
2.8 Metabolic Information
No information found in searched literature.
2.9 Ecological Effects
In the United States, environmental contamination with HCBD originates
primarily from its generation as a by-product in the manufacture of other
chemicals, mainly perchloroethylene (see Section 2.2). Much of this
by-product is buried in landfills, which constitute a potential pollution
source. A recent survey disclosed that eggs and vegetables produced near
VI1-15
-------
perchloroethylene plants are not likely to be contaminated with HCBD (3).
However, HCBD residues (0.01-1.2 ppm) were found in freshwater fish from
the lower Mississippi River (3,4). In an English survey, levels of
HCBD in fish and aquatic organisms were generally non-detectable, although
some were in the 2-5 ppb range (7). The average and maximum concentrations
of HCBD in water from the Liverpool Bay area were 0.004 and 0.03 ppb,
respectively (7). In marine sediments from the same bay, HCBD concentra-
tions were in the range 0.02-8.0 ppm (7). Residues of HCBD in fish, molluscs,
and other organisms in polluted waters in the Netherlands were in the
range 0.13-2.41 ppm (see Section 2.1).
HCBD is toxic to insects and fungi and has been used as a soil
fumigant in some European countries. It is used in the USSR as an
insecticide, primarily to combat grape phylloxera (s) . These uses may be a
source of food contamination. Indeed, HCBD has been found in fruit
juices and wine in Europe (G14).
Although no incidents of ecological damage from HCBD have been re-
ported, the following information is pertinent.
96-hr LC50 values for HCBD were reported as 0.09 ppm in goldfish,
0.13 ppm in a crustacean (Asellus aquatlcus) and 0.21 in a mollusc
(Lymnaea stagnalis). Acute and semichronic intoxication with HCBD in
goldfish produced body-weight loss, abnormal behavior, and incoordination.
Relative liver weight was increased by exposure to 9.6 ppb, and activities
of liver phenylalanine hydroxylase and glucose 6-phosphatase decreased.
A no-toxic-effect level was reported to be 3 ppb in semichronic exposures (12)
VTI-16
-------
The 96-hr LC50 of HCBD was 0.45 mg/1 for dabs (marine fish) and the
48-hr LC50 of HCBD was 0.87 mg/1 for barnacle nauplii (7).
In a reproduction study in Japanese quail fed HCBD at levels up to
30 ppm for 90 days, no effects were observed on body weight, demeanor,
food oonsumption, egg production, percent fertility and hatchability of
eggs, survival of hatched chicks, or eggshell thickness. In addition,
there were RO gross or histopathologic changes in the organs or tissues of
the birds that could be related to treatment (21).
2.10 Current Testing
The following studies are recently completed or in progress.
(A) Chronic oral toxicity of hexachlorabutadiene in rats. By
Toxicology Research Laboratory, Health and Environmental
Research, Dow Chemical Company, Midland, Michigan 48640.
The studies involve determination of the toxicological effects
from long-term ingestion of graded doses of HCBD in the diet
of Sprague-Dawley rats. Pathology is being completed and a
report is being drafted, according to Tax-Tips (23). Principal
investigator - Dr. R. J. Kociba or Dr. B.A. Schwetz.
(B) Carcinogenesis study of hexachlorobutadiene. By New York
University Medical Center, New York, N.Y. 10016. (Investigators-
Dr. B. Van Duuren et al., supported by the National Science
Foundation). This compound is being tested as an initiator,
promoter and complete carcinogen using two-stage skin tests
in female ICR/HA mice. Long-term tests began in September and
October, 1976, and are expected to continue for the life span
of the mice (24).
VII-17
-------
(C) One-generation reproduction study of rats maintained on diets
containing hexachlorobutadiene. By Tbxicology Research Laboratory,
Health and Environmental Research, Dow Chemical Company, Midland,
Michigan, 48640. The purpose of this study is to determine the
effects of diets containing various amounts of HCBD on reproduc-
tion. The project is completed and a report is being prepared
*
for publication, according to Tox-Tips (23). Principal
investigator - Dr. B. A. Schwetz.
(D) A carcinogenicity study in A-strain .nice by i.p. administration
is in progress at the Veterinary Sciences Division, Litton
Bionetics, Inc., Kensington, Md. 20795 (G13). Principal
investigators - Dr. M. Shimkin and G. Stoner.
(E) A carcinogenicity study in rats (Sprague-Dawley) by administration
in the diet is in progress at Toxicology Research Laboratories,
Health and Environmental Research, Dow Chemical Co. Midland,
Michigan 48640 (G13). Principal investigator - Dr. C. G.
Humiston.
This report appeared after the October 1977 TSCA/ITC
report to the EPA Administrator; Schwetz, B.A., Smith,
F.A., Humistan, C.G., Quast, J.F. and Kocba, R.J. Re-
sults of a reproduction study in rats fed diets contain-
ing hexachlorobutadiene. Toxicol. Appl. Pharmacol. 42(2):
387-398 (1977) .
VII-18
-------
REFERENCES
1. Goldbach, R., Van Genderen, H., and Leeuwahn, P. Hexachloro-
butadiene residues in aquatic fauna from surface water fed by
the River Rhine, Sci. Tot. Environ. 6:31-40 (1976).
2. Jacobs, A., Elangetti, M., Helmund, E., and Koelle, W.
Accumulation of organic compounds identified as harmful
substances in Rhine water, in the fatty tissues of rats.
Kernforschungszentrum Karlsruhe 1969:1-7, Chem. Abst,
82:039285 (1974).
3. Yip, G. Survey for HCBD in fish, eggs, milk and vegetables.
J.Assoc. Off. Anal. Chem. 59(3):559-561 (1976).
4. Yurawecz, M.P., Dreifuss, P.A. and Kamps, L.R. Determination
of hexachloro~l,3-butadiene in spinach, eggs, fish and milk
by electron capture gas-liquid chromatography, J. Assoc.
Off. Anal. Chem. 59 (3):522-558 (1976).
5. Poteryaeva,G. Sanitary and toxicological characteristics
of hexachlorobutadiene. Vrach. Delo. 4:130-133 (1971).
6. Murzakaev, F.G. Action exerted by low hexachlorobutadiene
doses on the activity of the central nervous sytem and morpho-
logical changes in the organs of animals poisoned there-
with. Gig. Tr. Prof. Zabol. ll(3):23-28 (1967).
7. Pearson, C.R., and McConnell, G. Chlorinated C, and C2 hydro-
carbons in the marine environment. Proc.Roy.Soc.London Ser.
B 189(1096):305-322 (1975).
8. Midwest Research Institute, Survey of industrial processing
data. Task I-Hexachlorobenzene and hexachlorobutadiene
pollution from chlorocarbon processing. NTIS report PB-
243641 (1975).
9. Grant, D. The pyrolysis of chlorocarbons. J. Appl. Chem.
Biotechnol. 24:49-53 (1974).
10. Ageev, N.G. and Poluektov, V.A. Oxidation of hexachloro-
butadiene. J. Appl. Chem. USSR. 44:2778-2783 (1971).
11. Murzakaev, F.G. Some data on the toxicity of a new insecti-
cide-hexachlorobutadiene and its semi-products. Farmakol.
Toksikol. 29(6):742-744 (1966).
12. Gradiski, D., Duprat, P., Magaduar, J.L. and Fayelin, E.
Experimental toxicological study of hexachlorobutadiene.
Eur. J. Toxicol. Environ. Hyg. 8(3):180-187 (1975).
VII-19
-------
13. Popovich, M.I. Acid-base equilibrium and mineral metabolism
under the effect of hexachlorobutadiene in subacute and
chronic experiments. Issled. Obi. Farm. Khim. 122-123
(1975).
14. Popovich, M.I. Acid-base equilibrium and mineral metabolism
following acute hexachlorobutadiene poisoning. Issled. Obi.
Farm. Khim. 120-122 (1975).
15. Gage, J.C. Substitute inhalation toxicity of 109 industrial
chemicals. Brit. J. Ind. Med. 27(1):1-18 (1970).
16. Shroit, I.G., Vasilos, A.F., and Gul'ko A.G. Kidney
lesions under experimental hexachlorobutadiene poisoning.
Aktual.Vop, Goig. Epidemiol. 73-75 (1972).
17. Kravitskaya, P.S. and Boranova, T.I. Secretory function of
the stomach in pups from 1.5 to 3 months of age under the
effect of hexachlorobutadiene. Ek p. Issled. Khim. Biol.
207-211 (1974).
18. Boranova, T.I. Nitrogen-releasing function of the stomach in
ontogenesis under the effect of hexachlorobutadiene.
Eksp. Issled. Khim. Biol. 198-202 (1974).
19. Murzakaev, F.G. Data for substantiating maximal permissible
concentrations of hexachlorobutadiene and polychlorobutane
in water reservoirs. Gig. Sanit. 9-14 (1962) .
20. Poteryaeva, G. Effect of hexachlorobutadiene on the off-
spring of albino rats. Hyg. Sanit. 31:331-335. CA 65:
1281 (1966).
21. Schwetz, B.A., Morris, J.M., Kociba, R.J., Keller, P.A.,
Corneir, R.F. and Gehring, P.J. Reproduction study in
Japanese quail fed hexachlorobutadiene for 90 days.
Toxicol. Appl. Pharmacol. 30 (2) :255~265 (1974).
22. Leeuwangh, P., Bult, H., and Schneiders, L. Toxicity of
hexachlorobutadiene in aquatic organisms. Proceedings of a
Swedish-Netherlands Symposium on Sublethal Effects of Toxic
Chemicals in Aquatic Animals. 167-176 (1975).
23. Tox Tips, National Library of Medicine, Maryland, June
1976.
24. i'ox Tips, National Library of Medicine, Maryland, March,
1977.
25. Laseter, J.L., Clelmer, K.B., Laska, A,L., Kolmquist, D.G.,
Condie, D.B., Brown, J.W., and Evans, R.L. An Ecological
Study of Hexachlorobutadiene (HCBD). EPA 560/6-76-010 (1976),
VII-20
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26. Tardiff, R.G., Carlson, G.P., and Simnons, V. Halogenated organics
in tap water: a toxicological evaluation. Proceedings of the Conference
on the Environmental Impact of Water Chlorination, Oak Ridge, Tenn.(1975)
VII-21
-------
-------
NITROBENZENE
TABLE OF CONTENTS
Overview
Part I - General Information
Part II - Biological Properties
2.1 Bioaccumulation
2.2 Contaminants and Environmental
Degradation or Conversion
Products
2.3 Toxicity
2.4 Carcinogenicity
2.5 Mutagenicity
2.6 Teratogenicity
2.7 Metabolism
2.8 Ecological Effects
References
Page
VIII-1
VIII-3
VIII-5
VIII-5
VIII-6
VIII-8
VIII-8
VIII-8
VIII-9
VIII-10
VIII-20
VHI-i
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NITROBENZENE
AN OVERVIEW
r?;i trchenzena is a pale yellow liquid which is very soluble
.n alcohol, ether and benzene and slightly soluble in water.
U.S. production of nitrobenzene in 1976 was about 400 million
>ounds. Although its predominant use (97 percent of production) is
.n closed systems in aniline manufacture, nitrobenzene is also an
.ndustrial solvent and dye intermediate. General population expo-
;ure can arise from environmental release, and from dispersive uses
.n soaps; woodcleaners; and metal polishes. It is estimated that
.9,000 workers are occupationally exposed to nitrobenzene. Its re-
,ease to the environment has been estimated to be about 20 million
•ounds annually.
Evidence indicates that nitrobenzene does not bioaccumulate ap-
ireciafaly in aquatic systems. Acute effects have been demonstrated
.n fish. Nitrobenzene inhibits oxygen utilization and hydrogen sulfide
iroduction in sewage microorganisms, inhibits growth in yeast, and is
:oxic to various soil bacteria and microorganisms.
There are four major reaction sites to nitrobenzene: in the blood,
.n the central nervous system, in peripheral metabolism, and from skin
sxposure. Mammalian toxicity effects include heart, liver, kidney,
ind CNS damage; hemolytic anemia; methemoglobinemia, sulfhemoglobinemia,
litroxyhemoglobineinia; and changes in WBC and RBC. nitrobenzene
Is metabolized in humans to p_-ami no phenol and p_-nitrophenol
VIII-1
-------
No adequate information is available on the carcinogenicity
and mutagenicity of nitrobenzene; but teratogenic effects of
nitrobenzene have been reported in the Russian literature.
VIII-2
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NITROBENZENE
PART I
GENERAL INFORMATION
1.1 Identification CAS No..- 000098953
NIOSH No.: DA64750
1.2 Synonyms and Trade Names
C.I. solvent black 5; essence of mirbane; essence of myrbane; ncLrbane
oil; nigrosine spirit soluble B; nitrobenzol; nitrobenzol, liquid;
oil of mirbane; oil of myrbane
1.3 Chemical Formula and Molecular Weight
(G16)
M9l. Wt. 123.11
1.4 Chemical and Physical Properties
1.4.1 Description;
Greenish-yellow crystals or yellow, oily
liquid; combustible; odor of volatile oil
of almond
1.4.2 Boiling Point: 210.8° C
1.4.3 Melting Point; 5.7° C
1.4.4 Absorption Spectrometry;
=260™
(G22)
log €
1.4.5 Vapor Pressure;
1.4.6 Solubility;
= 3.91
1 mm at 44.4° C
Slightly soluble in water;
Very soluble in alcohol, ether,
acetone, benzene
1.4.7 Octanol/Vfater Partition Coefficient;
oct
(G22)
(G22)
(G36)
VIII-3
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1.5 Production and Use
1.5.1 Production; 290 Million Ihs U965) CG25)
560 Million Ibs a970] (G25)
414.288 Million Ibs (1975) (G24)
409.023 Million Its (1976) (G24)
1.5.2 Use; In manufacture of aniline; as a solvent for cellulose
ethers; in modifying esterification of cellulose ace-
tate; as an ingredient of metal polishes and soaps; in
manufacture of benzidine, quinoline, azobenzene, etc.;
for refining lubricating oils
(G21,G23)
Quantitative Distribution_of Uses;
Percent
Aniline 97
Miscellaneous 3_
100 (G25)
Consumer Product Information;
Nitrobenzene is present in:
Cleaners for wood paneling, furniture, woodwork,
and wood floors
Veterinary liniment
(G35)
1.6 Exposure Estimates
1.6.1 Release Rate; 19.3 Million Ibs (G28)
1.6.2 NCHS Occupational Exposure;
Rank: 2184
Estimated no. of persons exposed: 19,000*
* rough estimate (G29)
1.7 Manufacturers
Allied Chemical Corp.
E.I. du Pont de Nemours and Co., Inc.
First Chemical Corp.
Mobay Chemical Company
Monsanto Company
Rubicon Chemicals, Inc.
(G24)
VIIT-4
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FITK3BEN2ENE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccurnulation
Evidence to date indicates that nitrobenzene does not bioaccumulate ap-
preciably in aquatic systems. Thus, labeled nitrobenzene has been tested by
adding it to the water phase of an aquatic system which included fish, mosquito
larvae, Daphnia, snails, algae, and plankton (39). Only in fish (Gambusia) was
nitrobenzene bionagnified and then only 10-fold. Nitrobenzene was found in the
other organisms only at low levels.
2.2 Contaminants and Environnvsntal Degradation or Conversion Products
SRC reports the following contaminants in technical grade nitrobenzene:
nitrophenol, dinitrobenzene, and sulfuric acid (G14).
With synthetically prepared sewage effluent, complete biological degradation
of dissolved nitrobenzene is obtained (41, as reported in 32). Biological de-
composition of nitrobenzenes by Azotobacter agilis has been reported in a model
waste water system and in laboratory cultures, but the reduction products could
not be detected (33). Growing cultures, washed-cell suspensions and cell-free
extracts of Nocardia erythropolis and Pseudomonas fluorescens have also been found
to reduce the nitro group to amino, perhaps through the nitroso and hydroxylamino
intermediates (5).
Nitrobenzene is relatively unreactive to light (32).
VI.TI-5
-------
2.3 Toxicity
The NIOSH Reistry of Toxic Effects of Chemical Substances (G16) reports
west reported
Parameter
LDLO
IJ3LO
LDLO
LDLo
LDLo
LDLo
LDLo
LDLO
LDLO
lethal doses of nitrobenzene
Dosage
800 mgAg
400 mgAg
480 mgAg
750 mgAg
150 mgAg
2000 mgAg
700 mgAg
600 mgAg
1000 mgAg
as follows:
Animal
rat
mouse
mouse
dog
dog
cat
rabbit
rabbit
mammal
TDLO
200
(unspecified)
human
Route
subcutaneous
skin
subcutaneous
oral
intravenous
oral
oral
skin
oral
oral
There are four major physiological reactions to nitrobenzene:
1. In the blood: The hemoglobin is converted to methemoglobin and thereby
is eliminated from the oxygen transport cycle. 2. In the central nervoiis
syrtem: Nitrobenzene causes headache, vomiting, cramps and, in large
enough doses, coma. 3. In peripheral metabolism: Metabolic processes
VIII-6
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degenerate rapidly due to excessive consumption of body substances and high
body temperatures. Liver damage and jaundice may result. 4. On the skin:
Irritation and sensitization will occur with eczema (G17).
Mild intoxication (3,0-15% methemoglobin) may produce no symptoms,
or a mild headache, a sense of exhilaration, cyanosis of the lips, tongue,
or nail beds. Moderate intoxication (25-50% methemoglobin) causes severe
headache, dizziness, weakness and definite cyanosis. Higher intoxication
(over 50% methemoglobin) produces severe headache and generalized weakness,
nausea, vomiting, drowsiness, shortness of breath on exertion and severe
cyanosis. Methemoglobin levels above 65-70% may result in coma. Hie
lethal level of methemoglobin is 85-90% (G5).
Dorigan and Hushon have summarized the reported toxicological effects
in humans and animals resulting from nitrobenzene exposure (32). Table I
is taken directly from their review.
The anemiagenic action of nitrobenzene is reflected in enlarged
spleens and livers, and jaundice (1), (2,37, as reported in 32).
Menstrual disturbances occurred after chronic exposure to nitro-
benzene (2, as reported in 32).
Chronic inhalation of small doses by mice resulted in weight loss,
anemia, respiration insufficiency and significant changes in oxygen
consumption and cerebral enzyme activity (38, as reported in 32).
Chronic nitrobenzene intoxication impairs copper metabolism and
certain iron-containing enzyme systems (43, as reported in 32).
Nitrobenzene vapor is readily adsorbed through the lungs. A vapor
concentration of 5 mg/m results in an average adsorption rate of up to
18 mg via the lungs and 7 mg cutaneously after six hours of exposure (36).
The lung retention rate during six hours of exposure is about 80% (24) .
VITl-7
-------
The major source of potential hazard is through cutaneous absorption
of nitrobenzene liquid (36). The absorption rate of liquid through
the skin can reach about 2 mg/cm /hr (40, as reported in 36).
The Department of Transportation has classified nitrobenzene as a
Class B Poison (34).
®
The Threshold Limit Value (TLV) for nitrobenzene has been set by
the ACGIH at 1 ppm (5 mg/m3) (Gil).
2.4 Carcinogenicity
No information found in the searched literature.
2.5 Mutagenicity
A secondary source (G28) reported a Russian experiment to
induce sex-linked recessive lethal mutations in Drosophila
Lnpgaster when administered as a vapor for 8-10 days. The
incidence was 4% of chromosomes analyzed comparer to 0.14% of
chromosomes from untreated controls. According to the
secondary source, the data presented in the original Russian
paper were insufficient for evaluation.
2.6 Teratogenicity
Dorigan and Hushon (32) cite a number of Russian studies on the
teratogenic potential of nitrobenzene.
Changes in the tissues of the chorion and placenta were reported in
pregnant women who worked in the production of a rubber catalyst that uses
nitrobenzene (6). Nitrobenzene administered to pregnant rats was reported
to cause dead and deformed embryos and changes in respiratory tissues
(26, ?7). Subcutaneous administration (125 mg/kg) of nitrobenzene to
rats during the pre-imp Iantation and placentation periods was reported
to cause delay of embryogenesis and the appearance of abnormalities in
fetuses, respectively (28). When injected into rats during the period of
VI !1-8
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placentation, glycogen content was reportei to increase and polysaccharide
composition to change in embryonic and placental tissues (26).
2.7 Metabolism
After intubation (0.25 ml) in rabbits, 54% of the compound was
absorbed by the tissues by the second day; in four to five days, 70%
was excreted and after eight days only 8% of the dose remained in the
rabbit's tissues, mainly as metabolic products. The remainder of the dose
was slowly eliminated in urine and exhalation (15).
In another study with rabbits, a labeled dose of nitrobenzene was ad-
ministered by s ocnach tube and the metabolites were measured during the next
four to five days. 58% of the dose was excreted in the urine as aromatics.
The predominant urine metabolites were £-aminophenol (31% of dose) and nj-
and p-nitrophenol (both 9% of the dose). Another 9% of the dose was ex-
creted in the feces, two thirds of which was pj-aminophenol. TWO percent
of the dose was expired from the lungs as C02/ aniline and unchanged nitro-
benzene. 15%-20% of the radioactivity accounted for was found in the
tissues as unspecified metabolic products (15).
Following the ingestion of approximately 50 ml of nitrobenzene by a
19-year old female in an attempted suicide, pj-nitrophenol and pj-atninophenol
were observed in the urine for the next 22 days. A total of 712 mg of £-
aminophenol and 1,780 mg of g-nitrophenol were measured in the urine (37, as
reported in 32).
A woman exposed to unspecified atmospheric concentrations of solvent
vapor (99.7% nitrobenzene, 0.27% benzene) for about six weeks had 1,056 milli-
moles/ml of pj-nitrophenol and 416 millimoles/ml of pj-aminophenol in her urine.
The metabolites gradually disappeared from the urine during two weeks of
hospitalization (1).
VTII-9
-------
Metabolic studies on men exposed to nitrobenzene vapor under experimented
conditions have been reported by Piotrowski (36). It was found that about half
as much vapor was absorbed through the skin as through the lungs and that p_-nitro-
phenol was excreted in the urine in increasing amounts on successive days of
exposure and became fairly steady after the third day. In humans, pj-nitrophenol
excreted daily was, on the average, equivalent to 16% of the daily uptake of
nitrobenzene, while the efficiency of conversion of nitrobenzene into pj-nitrophenol
in rats was about 23%. When g-nitrcphenol, itself, was given, excretion was very
rapid, but when nitrobenzene was given, pj-nitrophenol was excreted slowly. Thus,
the bioaccumulation observed does not depend on thJ behavior of the metabolite
but is due to the slow rate (kinetics) of metabolism of nitrobenzene. p_-Aminophenol
was not detected in urine under the experimental conditions.
2.8 Ecological Effects
Lethal and other acute effects in fish are mentioned in one Toxline abstract;
however the concentrations and types of fish are not reported (14). The
aquatic toxicity rating (96-hr Tlzn, species unspecified) is 100-10 ppm
(G16), which is described as slightly toxic.
Effects on aquatic microorganisms have been reported only at relatively
high levels. Nitrobenzene decreased the oxygen uptake of benzene-acclimated
sludge by 50% when added at 630 mg/1 (45, as reported in 32). Hydrogen
sulfide production and growth were retarded in sulfate reducing bacteria
when nitrobenzene was present at 2-20 ppm (46, as reported in 32). Spores
of the yeast Actinomyces sphaeroides showed a decrease in viability of
6%-80% following treatment of 0.001-0.004 M nitrobenzene (35, as reported
in 32).
Nitrobenzene loss in water effluents from production facilities has
been reported (0.09% in one plant, 2% in another) (42,44, as reported in 32).
vin-io
-------
Nitrobenzene escapes to the atmosphere during industrial production
(47, as reported in 32), although this level is considered to be low (32).
The ground level concentration 500 meters downwind from the largest production
facility was estimated at 1.56 rag/m (32),
VIII-11
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NITROBENZENE
Table I
Reported Toxicological Effects
Dose
Orqanism
human
Route
inhalation
Concentration
inhalation
(poor ventilation)
inhalation
inhalation
inhalation
0.2-0.5 mq/1
(40-100 ppm)
0.129 mg/m3
"larqe" amounts
(poor ventilation)
Exposure time
8 hours/day for
17 months
factorv worker
(paint firm)
8 tours/day for
1.5 months
factory worker
(paint firm)
8 hours/day for
4.5 months
ca. 6 hours
Response Reference
cyanosis, headache fatigue 1
methemoglobinemia
cyanosis, headache, fatigue
methemoqlobtnemia, liver damage
hypotension
above plus: liver and spleen enlarqed 1
and tender, hyperalciesia in extremeties
slight effects, e.q., headache, 2
fatigue
threshold level for electroencepha- 3
lograph disturbance
hospitalized: 4
day 1 - fatigue, headache, asthma
2 - vertigo, coma, cyanosis
1 - labored breathing, urine with
almond odor, methemoglobinemia
7 - svmtorns gone
recovery after one month
The contents of this table are quoted directly from Doriyan, J. and Hushon, J. Air Pollution
Assessment ot nitrobenzene, MITRE, MTR-7228 (1976).
VIII-12
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Oraanism
Route
Dose
Concentration
Exposure rT1ime
Response
Reference
human
inhalation
inhalation
acute
inhalation
6-30
inhalation
inhalation
inhalation
inhalation
acute
nitrobenzene
factorv worker
6 hours
factory worker
(rubber
accelerator).
factory worker
(glass,
porcelain)
industrial
exposure
factory worker
(filled con-
tainers with
nitrobenzene)
burning throat, nausea, vomiting
gastrointestinal disturbances, cold
skin, livid face, cvanosis
intermittent symptoms:
cyanosis, pallor and jaundice,
pharyngeal congestion, headache,
changes in blood cell composition
(increased polynuclears and
eosinophiis)
retained 80 percent of vapor in lungs
urinary excretion of p-nitrophenol
(maximum in 2 hours, still detected
after 100 hours)
pregnant women:
thickening of tissue in blood vessels,
decreased placental absorption,
necrosis in placental tissue
changes in bone marrow, increased
lymphoid cell production, impairment
of copper metabolism and certain
iron-containing enzymes
disturbance of notor ijtpulses
14 days: cyanosis, headache, backache
stomachache, vomiting
ca. 21 days: drank beer and fell uncon-
scious, cvanosis, dilated pupils,
retarded respiration, weak pulse
1 year: intelligence dimmed
2 years: emaciated, atrophied muscles
3 years: memory failed
6 years: loss of perception of time
and space (Karsakoff's svridrome)
VIH-13
-------
Organism
human
rabbit
Route
cutaneous
absorption
cutaneous
absorption
cutaneous
absorption
oral
oral
oral
subcutaneous
injection
subcutaneous
injection
cutaneous
absorption
intraperi-
toneal
injection
Dose
Concentration
dye used in
diaper stamps
shoe dye
0.5% by weight
in paper
Exposure Time
333 ml
0.4 ml
0.8 mgAg
10-14 mgAg
0.7 gn\/kg
0.5 gmAg
ca. 7 hours
(handled carbon
paper)
from human milk
one dose
one dose
daily
one
one
Response Reference
babies: cyanosis, rapid pulse, 2
shallow respiration, vomiting, con-
vulsions, recovery in 24 hours
unconsciousness after consuiption of 9
alcoholic beverages, death
dermatitis 10
nurselings became cyanotic, recovery 11
in 24 hours (mothers ate almond cake ar-
tificially flavored with nitrobenzene)
maximum dose with recovery reported 2
(following severe symptoms)
mininun lethal dose reported 9
maximum dose not causing death 12
minimum effective dose: slow and
lasting methemoglobinemia
52 hours: lethal
reduced blood pressure and myocardial 13
glyoogen level
VIII-14
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Organism
rabbit
Route
intravenous
oral
Dose
Concentra tion
0.1 gm
9 gm
inhalation
subcutaneous
injection
0.2 gmAg
Exposure Time
daily or every 5
days
4 doses, one
every 15 minutes
oral
oral
oral
oral
oral
oral
oral
guinea inhalation
pig
4.8 gm
700 mgAg
600 mg
300 mg
50 mgAg
>1 mgAg
0.1 mgAg
saturated air
(0.04 volume %)
one
one
one
one
one
one
one
2-5 hours
2-3 hours
every other day
for 6 months
Response Reference
simultaneous doses of 2-20 ml 14
ethanol increased severity of
poisoning
convulsions, death 2,9
lethal instantly 2,9
lethal dose G23
dizziness, loss of reflexes, methemo- <*
globinemia, congestion of brain
tissue. 12 hours - death
fatigue for one week 15
tissue degeneration, especially 1C
heart, liver, kidney
lowered hemoglobin, erythrocytes and 17
lymphocytes: increased leucocytes
threshold toxic dose 17
death following tremors, paralysis 9
of hind legs
death 9
hemolytic anemia, loss of weight 18
decreased motor activity, fluxes in
urinary excretion of 17-oxo-cortico-
steroids
VIII-15
-------
Organ! an
guinea
pig
rat
Route
oral
oral
Dose
Concentration
ca. 3 gm
ca. 1.2 gm
Exposure Time
one
one
Response Reference
0.5 hours: tremors, faint heart- 9
beats, labored respiration
2 hours: death
immediately motionless, then 9
complete recovery
oral
oral
oral
inhalation
inhalation
inhalation
inhalation
oral
intraperi-
toneal
injection
50 mg/kg
>1 mg/kg
0.1 mg/kg
5 mg/m3
ca. 0.03 mg/m3
0.06-0.1 mg/m3
0.008 mg/m3
0.6 gm/kg
0.8 gm/kg
< 1 year
one
one
8 hours
daily, up to
98 days
70-82 days
73 days
one
one
tissue degeneration, especially
heart, liver, kidney
lowered hemoglobin, erythrocytes,
lymphocytes; increased leucocytes
threshold toxic dose
metabolites excreted in 3 days
increased ability to form sulfhemo-
globin in preference to methemoglobin
cerebellar disturbances, inflamed
internal organs
no effect
^50
lethal
17
17
17
1
19
20
3
21
22
VIII-16
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Organism
rat
mouse
Route
subcutaneous
injection
subcutaneous
injection
subcutaneous
injection
subcutaneous
injection
cutaneous
absorption
intraperi-
toneal
injection
intraperi-
toneal
Dose
Concentration
640 mgAg
300
200
or
100 mgAg
125 mgAg
subcutaneous 100-200 mgAg
injection
480 gmAg
1.23 gmAg
1 gmAg
Exposure Time
one
one
one
daily for 10 days
one
one
one
one
Response Reference
blood catalase activitv decreased 23
continuously over % hours
LD 14 -methemoglobinemia G14
anemia, sulfhemoglobinemia
metbemoglobinemia, sulfhemoglo- 25
binemia, anemia
delayed embryoctenesis, abnormal 26
fetal development and embryo death, 27
chanaes in polysaccharide composi- 2fl
tion of placenta
sulfhemoglobin (most reoular and 29
persistent form of hemoglobin) nitroxy-
hemoglobin, increased methenoglobin
30 min. - prostrate, motionless 2
24 hours - death
ACt min. - 67% dead 30
10-15 min. - incoordination, comatose, 30
shallow respiration
several hours - regained coordination
immediately before death - lost coordina-
tion again, respiratory arrest
Afi hours - death
VIII-17
-------
nose
Organism
mouse
cat
tog
Route
intraperi-
toneal
injection
intraperi-
toneal
injection
inhalation
inhalation
oral
inhalation
intravenous
injection
Concentration
20 mgAg
12.3 mgAg
saturated air
(volume %:
0.04)
-
2.4 gm
"thick vapor"
0.15-0.25 gnv/kg
Exposure Time
one
one
2-5 hours
2-3 hours
one
1 1/2 hours
one
Response
oral
28.8 gm plus
6 gm
2 doses, 0.5
hours apart
oral
24 gm
one
Reference
24
30
lethal dose
10 minutes: 4.2% nethemoglogin
formed
death following tremors, paralysis
of hind legs
death
death in 12 to 24 hours 2,9
complete anesthesia and sleep 9
minimum lethal dose, lowered blood 2
pressure, pulse rate increased then
decreased, respiration stimulated
until paralyzed
immediate - agitation, then notion- 9
less
1 hour - convulsions, then motionless
4.5 hours - tremors, hind legs para-
lyzed
18 hours - death
few hours - "stupid" (sic) 9
12 hours - deep coma, slow respiration,
lowered skin temperature,
stomach strongly alkaline
VTII-18
-------
Dose
Organism
dog
chicken
pigeon
Route
oral
oral
oral
oral
oral
oral
inhalation
Concentration Expsoure Time
2.4 gm one
0.75-1.0 gm/kq one
0.5-0.7 gmAg one
daily
1.2 gm one
2.4 gm one
1 hour
frog
2-3 hours
inhalation
oral, sub-
cutaneous
injection or
inhalation
saturated air
(volume %: 0.04)
Response Reference
1 hour - vomiting, then sleepy, 9
continuing for 6 hours
6 hours - appears normal
15-R1 hours - rigid muscles
104 hours - death
minumum lethal dose 2
salivation, unrest, dizziness, tremors, Q
increased pulse rate, sometimes con-
vulsions
formed methemoglobin continuously 31
at "certain" concentration
unsteady gait, recovery 9
immediately unconscious 9
no effects 9
death
general depression 2,9
paralysis of all movement, abolition
of all reflexes, death
VIII-19
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2. Von Oettingen, W.F. The aromatic amino and nitro compounds,
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171 (1971).
7. Yordanova, F., Perfanov, K., Uzunov, P. and Slivkova, L.
Hematological changes caused by chronic nitrobenzene exposure.
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9. Chandler, W.L. Physiological action of nitrobenzene vapor on
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10. Calnan, C.D. and Connor B.L. Carbon paper dermatitis due to
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11. Dollinger, A. Peroral poisoning with nitrobenzene or aniline
in the newborn. Monatsschr. Kinderheilk 97:91-93 (1949).
12. Yamada, Y. Studies on experimental chronic poisoning with
nitrobenzene. Kobe J. Med. Sci. 4(4):227-239 (1958).
1?. Labunskii, V.V. Effect in experiments of aromatic nitro,
chloro, and amino compounds on the cardiovascular system.
(Russian) Farmakol. Tokskol. (Kiev) 7:156-159 (1972).
VIII-20
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14. Matsumara, H. and Yoshida, T. Nitrobenzene poisoning. Kyushu
J. Med. Sci. 10:259-264 (1959).
15. Parke, D.B. Studies in detoxification. 68. The metabolism
of (14-C) nitrobenzene in the rabbit and guinea pig. Biochem.
62(2) :339-346 (1956).
16. Papageorgiou, G. and Argoudelia, D. Cation dependent quenching
of the fluorescence of chlorophyll A in vivo by nitroaromatic
compounds. Arch. Biochem. Biophys. 156(1):134-142 (1973).
17. Kazakova, M.I. Sanitary-hygienic evaluation of nitrobenzene
in water reservoirs. Gig. Sanit. 21(3):7-10 (1956).
18. Nakotchenko, V.N. and Akhemetov, Z.B. Adrenal cortex function
in chronic nitrobenzene poisoning of guinea pigs and the
effect of hydrocortisone on the course of poisoning. (Russian)
Farmakol. Tokskol. (Moscow) 35 (2) :247-249 (1972).
19. Andreeshcheva, N. Features and criteria of the toxic action
of some nitro and amino benzenes. Gig. Sanit. 35(4):44-47
(1970) .
20. Khanin/ A.G. Pathohistological changes in the central
nervous system and viscera of experimental animals after
chronic continuous inhalation of toxic substances. Tr. Tsentr.
Inst. Usoversh. Vrachei 135:97-106 (1969)
21. Smith, H.F., Jr., Weil, C.S., West, J.S. and Carpenter, C.P.
An exploration of joint toxic action: Twenty-seven indus-
trial chemicals intubated in rats in all possible pairs.
Toxicol. Appl. Pharmacol. 14(2):340-347 (1969).
22. Magos, L. and Sziza, M. Effect of p_-nitrobenzaldehyde
on methemoglobin formation. Naturwissenschaften 45:522
1958.
23. Goldstein, I. and Popovici, C. Action on nitrobenzene on blood
catalase activity in acute experimental intoxication.
Igiena 8:215-221 (1959).
24. Salmowa, J., Piotrowski, J. and Neuhorn, U. Evaluation of
exposure to nitrobenzene. Absorption of nitrobenzene vapor
through lungs and excretion of p_-nitrophenol in urine. Br.
J. Ind. Med. 20(l):41-49 (1963).
25. Zvezdai, V.I. Comparative diagnostic value of various patho-
logical derivatives of hemoglobin in conditions of acute
and subacute poisoning by aniline, nitrobenzene, and their
chloride derivatives. (Russian) Farmakol. Tokskol. (Kiev)
7:159-162 (1972).
VIII-21
-------
26. Kazanina, S.S. Histochemical study of mucopolysaccharides
in the placenta of rats poisoned with nitrobenzene. Gistokhim.
Norm. Patol. Morfol. 68-69 (1967).
27. Kazanina, S.S. The effect of nitrobenzene on the develop-
ment of the fetus and placenta in the rat. Nauch. Tr.
Novosibirsk. Med. Inst. 48:42-44 (1968).
28. Kazanina, S.S. Morphology and histochemistry of hemochorial
placentas of white rats during poisoning of the maternal
organism by nitrobenzene. Byull. Eksp. Biol. Med. 65(6):
93-96 (1968).
29. Vasilenko, N.M. and Zvezdai, V.I. Comparative evaluation
of blood changes in acute and subacute poisoning with aro-
matic nitro- and amino-compounds. Farmakol. Tokskol.
(Moscow) 35(1):108-110 (1972).
30. Smith, R.P. Alkaitis, A.A. and Shafer, P.R. Chemically
induced methemoglobinemias in the mouse. Biochem. Pharmacol.
16(2):317-328 (1967).
31. Hashimoto, T. Changes of methemoglobin with daily adminis-
tration of aniline and nitrobenzene. Kokumin Eisei. 27:239-245
(1958).
32. Dorigan, J. and Hushon, J. Air pollution assessment of nitro-
benzene, MITRE, MTR-7228 (1976).
33. Bringmann, G. and Keuhn, R. Biological decomposition of
nitrotoluenes and nitrobenzenes by Azotobacter agilis.
Gesundh. Ing. 92 (9) : 273-276 (1971).
34. U.S. Department of Transportation, Code of Federal Regula-
tions; .1-9 part 172.101, Washington, D.C. (1976).
35. Romanova, N.B. and Rapoport, I.A. Mutagenic model of a study
of nitro-compounds as protective agents from ultraviolet
radiation. Teor. Khim. Mutageneza, Mater. Veses. Soreshch.,
4th ed. (1971).
36. Piotrowski, J. Further investigations on the evaluation
of exposure to nitrobenzene. Br. J. Ind. Med. 24(l):60-65
(1967) .
37. Hyslak, Z., Piotrowski, J.K. and Ilusialowicz, E. Acute
nitrobenzene poisoning. Arch. Toxicol. 28 (3) : 208-312 (1971).
VIII-22
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38. Pisharn, V. Experimental nitrobenzene intoxication. Igiena
(Bucharest) 11:497-505 (1962).
39. Lu, P. and Metcalf, R. Environmental fate and biodegradability
of benzene derivatives as studied in a model aquatic ecosystem.
Env. Health Pers. 10:269-284 (1975).
40. Pinching, A.J., Doeving, K.B. Selective degeneration in
the rat olfactory bulb following exposure to different odors.
Brain Research 82 (2):195-204 (1974).
41. Barnhart, E.L. and Campbell/ G.R. The effect of chlorination
on selected organic chemicals. U.S. Environmental Protection
Agency PB-211-160, NTIS, Springfield, Virginia (1972).
42. Boswer, B.B., Plant Environmentalist for American Cyanamid.
Personal Communication with Mitre Corp. November 1975.
43. Yordanova, F., Perfanoc, K. , Uzunov, P., and Slivkova, L.
Hematological changes caused by chronic nitrobenzene exposure.
Sco. Sci. Med. Annu. Sci Pup. 9(2):69-77 (1971).
44. Ott, R.C., Environmental Coordinator, E.I. duPont de Nemours
and Co., Personal Communication with Mitre Corp. December 1975.
45. Malaney, C.W. and McKinney, R.C. Oxidative abilities of
benzene-acclimated activated sludge. Water and Sewage Works
(August): 302-309, (1966).
46. Allen, L.A. The effect of nitro-compounds and some other
substances on production of hydrogen sulphide and sulphate-
reducing bacteria in sewage. Proc. Soc. Appl. Bact. (2):26-38
(1949) .
47. Sittig, M. Pollution control in the organic chemical industry.
Noyes Data Corporation, Park Ridge, New Jersey, c. 1974.
VIII-23
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TOLUENE
TABLE OF CONTENTS
Page
Overview IX-1
Part I - General Information IX-3
Specific References IX-7
Part II - Biological Properties
2.1 Bioaccumulation IX-8
2.2 Contaminants and Environmental IX-8
Degradation or Conversion
Products
2.3 Acute Toxicity IX-9
2.4 Other Toxic Effects IX-11
2.5 Carcinogenicity IX-12
2.6 Mutagenicity IX-13
2.7 Teratogenicity IX-14
2.8 Metabolic Information IX-14
2.9 Ecological Effects IX-15
2.10 Current Testing IX-17
References IX-20
IX-i
-------
-------
TOLUENE
AN OVERVIEW
Toluene is a clear, colorless, refractive, noncorrosive liquid
with a sweet pungent odor similar to that of benzene. Toluene is
quite stable in air, slightly soluble in water and miscible with al-
cohol, ether and benzene.
Toluene is produced in the U.S. primarily from petroleum; smaller
quantities are produced from coal. Annual production is in excess of
5 billion pounds.
Toluene is widely used as a solvent, as a gasoline additive and
has many other household and industrial uses; e.g., as an intermediate
in the manufacture of trinitrotoluene (TNT), benzaldehyde and benzoic
acid.
Toluene has an unusually high occupational exposure, estimated to
involve more than 4 million workers. This ranks it as sixth in the
NOHS survey of 7000 agents in the workplace. Release to the general
environment occurs from evaporation of gasoline, in emissions from
production facilities and from coke ovens. Toluene is currently being
substituted for benzene in many uses and has an annual release rate
exceeding 1 billion pounds. Both the occupational and general popu-
lation exposures are large.
In man, toluene is metabolized primarily to benzoic acid, the
major portipn of which is conjugated with glycine in the liver and
excreted almost entirely in the form of hippuric acid. No evidence
IX-1
-------
of bioaccumulation of toluene has been found. Effects of toluene
on fish, algae/ bacteria, and other organisms have been reported
only at levels far higher than those likely to occur in the environ-
ment.
Toluene is primarily a central nervous system depressant in both
humans and animals. Evidence for hematopoietic or myelotoxic dys-
function is inconclusive. Carcinogenicity tests with toluene by skin
applications have given positive or negative results of borderline
significance. No information on the teratogenicity of toluene has been
reported. Mutagenicity studies in humans exposed to toluene have been
reported in Russian literature.
IX-2
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TOLUEYIE
PART I
GENERAL INFORMATION
1.1 Identification CAS No.: 000108883
NIOSHNo.: XS52500
(G16)
1.2 Synonyms and Trade Names
Methylbenzene; toluol; phenyimethane; methacide
(G23)
1.3 Chemical Formula and Molecular Weight
C7Hfl Mol. wt. 92.15
(G22,G23)
1.4 Chemical and Physical Properties
1.4.1 Description; Colorless liquid with benzene-like odor
(G23)
1.4.2 Boiling point; 110.6° C (G22)
1.4.3 Melting point; -95° C (G22)
1.4.4 Absorption Spectrometry:
\^M= 201, 260 nm;
mcLA,
log € = 3.97, 2.48 (G22)
1.4.5 Vapor Pressure; 40 mm at 31.8° C (G22)
1.4.6 Solubility; Soluble in water 534.3 ppm;
Soluble in acetone, ligroin, carbon disulfide;
Soluble in all proportions in alcohol, benzene,
ether
(G22)(1)
1.4.7 Octanol/Water Partition Coefficient;
log PQCt =2.69 (G36)
1.5 Production and Use
1.5.1 Production; 5,917.200 Million Ibs (1972)
5,040.519 Million Ibs (1975)
7,138.997 Million Ibs (1976) (G24)
IX-3
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1.5 Production and Use (Continued)
1.5.2 Use: In aviation gasoline and high-octane blending stock; in
manufacture of benzene, phenol and caprolactam; as a
solvent for paints and coatings, gums, resins, most
oils, rubber, vinyl organosols; as a diluent and
thinner in nitrocellulose lacquers; as an adhesive
solvent in plastic toys and model airplanes; in
manufacture of chemicals (benzoic acid, benzyl and
benzoyl derivatives); in manufacture of saccharin,
medicines, dyes, perfumes, explosives (TNT); as a
source of toluene diisccyanates (polyurethane resins);
in toluene sulfonates (detergents); as a fluid in
scintillation counters
(G21)
Quantitative Distribution of uses:
~"Percent
Benzene 51
Solvents 10
Explosives 9
Isocyanates 5
Phenol 1
Gasoline pool and miscellaneous 24
100
Consumer Product Information:
No. of Toluene
products in category 10f)
No. of toluene Total no. of products
Category containing products in category
Household aerosols 1014 2£.99%
Paints, varnishes, shellac, 272 2.47%
rust preventatives, etc.
Adhesives and adhesive pro- 61 11.55%
ducts including glue
Paint and varnish thinners 20 62.50%
Flame-retardant chemicals 13 2.20%
Cleaning agents and compounds 5 0.28%
Solvent-based cleaning and 3 1.38%
sanitizing agents
Paint and varnish remover 2 18.18%
Photographic chemicals 1 1.25%
Caustics, lyes and drain 1 0.44%
cleaners
Other chemicals 1 1.55%
The 1,393 products surveyed contained an average of 12.2% toluene.
(G27)
DC-4
-------
Toluene is present in:
adhesives - model and china cement, construction adhesive
paint and varnish removers
stain removers and dry cleaners
nail polishes
inks- permanent markers
fuel system antifreeze
paints and paint thinner
asphalt remover
metal cleaner
anthelmintic - veterinary (G35)
1.6 Exposure Estimate
1.6.1 Release Rate: 1,074.2 Million Ibs (G28)
1.6.2 NOHS Occupational Exposure;
Rank: 6
Estimated no. of persons exposed: 4,811,000 (G29)
1.7 Manufacturers
From petroleum:
American Petrofina Co. of Texas
Ashland Oil Co.
Atlantic Richfield Co.
BP Oil Corp.
Champlin Petroleum Co.
Charter Oil Co.
Coastal States Marketing, Inc.
Conitonwealth Petrochemicals Co.
Cosden Oil and Chemical Co.
Crown Central Petroleum Corp.
Exxon Corp
Gulf Oil Corp.
Marathon Oil Co.
Mobil Oil Corp.
Monsanto Co.
Phillips Petroleum Co.
Shell Chemical Co.
Southwestern Oil and Refining Co.
Standard Oil Co. of Calif.
Sun Oil Co. of Pa.
Suntide Refining Co.
Tenneco, Inc.
Texaco, Inc.
Union Oil Co. of Calif.
IX-5
-------
From Coal:
Amco Steel Corp.
Bethlehem Steel Corp.
CF and I Steel Corp.
Indiana Gas and Chemical Corp.
Interlake, Inc.
Jones and Laughlin Steel Corp.
Mead Corp.
Republic Steel Corp.
United States Steel Corp.
By-Product Toluene:
Dow Chemical USA
Foster Grant Co., Inc.
Monsanto Co.
Union Carbide Corp.
(G25)
IX-6
-------
SPECIFIC REFERENCE FOR PART I
1. Button, C. and Calder, J.A. Solubility of alkylbenzenes in distilled
water and seawater at 25.0° C. J. Chem. Eng. Data 20(3):320-322 (1975)
EC-7
-------
TOLUENE
PART II
BIOLOGICAL PROPERTIES
2.1 Bioaccumulation
No report on the bic>accurnuiation of toluene could be found in the
searched literature. Mammals are reported to metabolize about 8u%
of absorbed toluene and exhale about 20% (1^. Toluene is oxidized to
benzoic acid which is conjugated with glycine and excreted as the water-
soluble hippuric acid. In an 18-hour experiment with humans, 68% of
absorbed toluene was excreted as hippuric acid following exposure to 1UO
and 200 ppm toluene (2). Toluene has a high octanol/water partition co-
efficient (log P = 2.6y) , but its rapid metabolism would probably pre-
OCt
elude bioaccumulation (3). Compounds with potential for significant bio-
accumulation in organisms are reported to be those having water solubilities
less than 50 ppm (4); toluene has a solubility of 534.8 ppm in distilled
water (5).
2.2 Contaminants and Environmental Degradation or Conversion Products
Benzene is a comon contaminant of toluene. Highly purified toluene
(reagent grade and nitration grade) contains less than 0.01% benzene as
contaminant. Industrial grade and cruder-grade toluene (90-i20°C boiling
range) contain significant quantities of benzene (as much as 25%) and
probably other hydrocarbons as well (G19). Myelotoxic effects attributed
IX-8
-------
to toluene on the basis of early studies are judged by more recent investi-
gators to probably result from concurrent exposure to benzene present as
a contaminant (G19). The possibility that bone marrow and other effects
are attributable to contaminating benzene remains open.
In the atmosphere, toluene may be subject to photochemical degradation (6)
Toluene exhibited moderate reactivity in studies conducted in smog
chambers (6). However, its long-term stability under true atmospheric
conditions remains unknown.
Some microorganisms can metabolize toluene (see Section 2.8).
2.3 Acute Toxicity
The NIOSH Registry of Toxic Effects of Chemical Substances (G16) reports
the acute toxicity of toluene as follows:
Reference
7
8
al 9
10
on 12
13
Information on the purity of the toluene used in the above-listed
tests has been reported only where it contained 0.01% benzene. For a
Parameter
U350
LCLo
IDLo
IDLo
I£>50
LC50
ID50
Dosage
5000 mgAg
4000 ppn/4H
800 mgAg
5000 mgAg
1640 mgAg
5300 ppm
14 gAg
Animal
rat
rat
rat
rat
rat
mouse
rabbit
Route
oral
inhaL
intraj
subcui
intra]
inhaL
skin
DC-9
-------
60% benzene and 40% toluene mixture the inhalation LC50 in mice was reported
as 7200 ppm (12).
Toluene is a primary skin irritant. Contact of toluene with pulmonary
tissue causes chemical pneumonitis, pulmonary edema and hemorrhage. It
damages the cornea on contact. It is irritating to the mucous membranes
of the respiratory tract. The degree of irritation depends on the concen-
tration and the duration of the exposure (14).
Central nervous system depression, headache, giddiness, fainting,
weakness, paresthesia, disturbance of coordinati->n and equilibrium,
and loss of consciousness are the symptoms of acute systemic toluene in-
toxication (14).
The effects observed (14) in human subjects exposed to toluene for an
eight-hour period are summarized below:
Toluene in Air
ppm Signs and Symptoms
50 drowsiness, headache
100 fatigue, sleepiness
200 insomnia, incoordination, paresthesia,
nausea, confusion, weakness
600 dizziness, staggering, lack of self
control
800 severe nervousness, muscular fatigue
and insomnia, which lasted for several
days
Animal and human responses to the vapor inhalation of "50 thinner," a
comiercial solvent containing 32% toluene, 65% heptane, and 3% other hydro-
carbons have been reported recently by Carpenter et al. (15) as follows:
IX-10
-------
Animal Response
rats IC50(4 hours) was 33 rag/liter (8300 ppm).
Tolerated 5.2 ing/liter (1300 ppn) for 4
hours without any signs of discomfort.
dogs (beagles) Tolerated 2.4 mg/liter (600 ppm) for 6
hours without any sign of discomfort (no
ill effect level).
cats At 30 mg/liter (7600 ppm) for 6 hours
developed signs of central nervous system
effects but survived.
human During 15-minute inhalation periods the
only irritative response was a mild sen-
sation of dryness of the eyes in one of
the five subjects inhaling 0.83 mg/liter
(210 ppm) or 1.7 mg/liter (430 ppm). The
same subject felt "light-headed" at 2.0
mg/liter level in both 15 and 30 minute
inhalation periods. The concentration of
1.7 mg/liter (430 ppm) was suggested as
the hygienic standard.
2.4 Other Toxic Effects
Continued or repeated skin contact with toluene will cause dermatitis
due to dehydration and removal of the natural fats from the skin (14). The
inhalation of toluene vapors may cause loss of appetite, nausea and vomiting
and evidence of central nervous system effects (headache, fatigue, nervous-
ness and insomnia). Pain in the chest, nosebleed, liver enlargement and
intolerance to alcohol have been reported in man following repeated exposure
to toluene (14).
The myelotoxic effect of toluene has been the subject of persistent
controversy. Much of this controversy is attributable to the experimental
use of toluene derived from coal tar which was contaminated to varying
degrees with benzene (1, G19).
IX-11
-------
Studies in experimental animals show rather convincingly
that toluene is not myelotoxic. In rabbits, subcutaneous
injections of pure toluene did not result in depression of
bone marrow function or changes in peripheral blood at doses
of 300 mg/kg/day for six weeks or 700 mg/kg/day for nine
weeks (16). No significant bone marrow toxicity or adverse
effect on other organs was reported in a study of workers
exposed to ambient toluene concentrations of 200-800 ppm (1).
It has been reported that leukemia patients tolerated daily
doses of 10 g toluene in olive oil for three weeks without
complaints or clinical evidence of side effects (G19). Based
on a large number of blood examinations of many persons
exposed to toluene, no effect on the blood comparable to that
of benzene has been observed except where the toluene was
found to contain some benzene (G2).
The Threshold Limit Value (TLV) recommended by the ACGIH
(1976) is 375 mg/m (100 ppm) for skin exposure (Gil).
2.5 Care inogenic ity
Skin application studies have given inconclusive results,
In one study (17), toluene was applied three times
weekly to the skin of the intrascapular region for the life-
time of the mice. No evidence of the carcinogenicity
of the compound was revealed.
Toluene (16-20^1) was applied topically to the skin of
30 mice, twice weekly for 72 weeks. Tumors occurred in two
mice and were diagnosed histologically as a skin carcinoma
and a skin papilloma (18, as reported in G18).
TX-12
-------
Two other studies (G18) of the potential carcinogenic!ty of toluene
gave negative results. However, they are of less significance due to the
limited number of animals used, the short duration of the experiments, or
both. In one study toluene was administered by subcutaneous injection, at
a dose rate of 1 ing/kg body weight in olive oil, daily for up to 51 days
(G18). In another study toluene was administered to an unspecified
number of rats by stonach tube at doses of 118, 354, 590 mg/kg/day in
olive oil (emulsified with 5-10% aqueous solution of acacia). Observa-
tions of the test animals for 193 days revealed no tumors (19).
2.6 Mutagenicity
Walker (1) has cited two Russian studies on the mutagenicity of
toluene. Rats given toluene (1 mg/kg body weight) subcutaneously, daily
for twelve days showed evidence of bone marrow chranosome damage (20).
Subcutaneous administration of 0.8 g/kg to rats for 12 days was reported to
have stimulated neutrcpoiesis and induced metaphase aberrations and chrono-
sonal breaks in the laminar cells of bone marrow (21).
Chromosome studies were carried out on peripheral blood lymphocytes
of 34 workers of a rotogravure plant and 34 controls matched for sex and
age. Ten of the workers were exposed to benzene before 1953 and then to
toluene and 24 have been exposed only to toluene after 1953. The frequencies
of chromosome changes in the benzene group were higher than in the toluene
group and the differences were statistically significant. The group of
subjects exposed to toluene showed a higher rate of unstable chromosome
IX-13
-------
changes and of calculated breaks compared to the controls, but the difference
was not statistically significant (22).
Mutagenic effects of benzene, toluene and a mixture of benzene and toluene
(1:2) by inhalation (4 hrs. daily for 4 months) have been recently
reported (23) in an abstract of a Russian article as follows:
Percentage of metaphases
Test Dosage with damaged chromosomes Additional
Material mg/m in bone marrow effects
Benzene 300 27.42 Leukocytopenia
Toluene 610 21.56 Leukosis
Benzene & 300 + 600 41.21 Leukosis
Toluene
Controls 4.02
One month after the experiment the frequency of chromosome damage
was still high, whereas the morphological composition of blood had almost
completely returned to normal.
2.7 Teratogenicity
No information found in the searched literature.
2.8 Metabolic Information
The metabolism of toluene involves oxidation and conjugation prior to
excretion. The following sequence represents the major pathway for the oxi-
dation of toluene in mammalian systems (24).
Toluene —^ —> Benzyl ^ ^ Benzoic ^. *. Hippuric
alcohol acid acid
In man and rabbits, toluene is oxidized in 80% yield to benzoic acid,
the major portion of which is conjugated with glycine in the liver and
IX-14
-------
excreted in the form of hippuric acid. The in vivo metabolism of toluene
by rats has been shown to produce o- and g-cresol. Rabbit liver micro-
somes also oxidize toluene to small amounts of these phenols (24).
•itti iidc.- i,)hi.al oxidation of toluene has been reported by several inves-
tigators. Pseudomonas aeruginosa oxidizes toluene through benzyl alcohol,
benzaldehyde, benzoic acid and catechol (25). Glaus and Walker (26)
isolated strains of two bacteria (Pseudomonas and Achromobacter) which
appeared to metabolize toluene via 3-methyl-catechol, according to the
following sequence:
Toluene —*, _^. 3-methylcatechol—> —^. Unidentified —> —^ acetic acid and
yellow ether- pyruvic acid
soluble acidic
substance
Initial reactions in the oxidation of toluene by Pseudomonas putida were
reported (27) to form 2,3-dihydroxy-2,3-dihydrotoluene as an intermediate
preceding formation of 3-methylcatechol. The non-enzymatic product of
this intermediate is o-cresol.
Proposed reactions for the in vivo metabolism of toluene in mammalian
systems and initial reactions in the oxidation of toluene by Pseudomonas
putida as reported in the literature (24, 27) are shown in Figures
1 and 2, respectively.
2.9 Ecological Effects
Total annual emissions of toluene to the environment have been estimated
to be about 450,000 metric tons (G28) with 99.3% of this amount going to
the atmosphere and 0.7% to waste water. Toluene concentrations in grab and
composite samples of industrial water effluents have been found to range
from 0.04 to 0.28 ppm (23). Influent water from the tv\o Ohio
IX-15
-------
municipal wastewater treatment plants contained from 3 to 150 ppb toluene
in 13 of 15 samples and 1 to 10 ppb toluene in 4 of 11 samples in
which toluene was detected (29). Toluene is volatile and is
readily transferred from water surfaces to the atmosphere (30). In
Los Angeles, Eoluene concentration in air was 37 ppb on the average and
129 ppb maximum (31); in Toronto, the average concentration in the summer
of 1970 was 30 ppb and 188 ppb maximum (32). The presence of toluene in
the atmosphere is said to be attributable primarily to auto emissions (31).
Effects of toluene exposure on humans and animals (rats, mice, guinea
pigs, dogs, and rabbits), mostly by inhalation, are summarized in Sections
2.3 and 2.4. Toxic effects have been reported only at levels greatly in
excess of those encountered in the ambient atmosphere.
In a continuous flow bioassay study, IDSOs- for goldfish (Carassius)
were determined to be 42 ppm and 23 ppm for 24 and 96 hours, respectively.
Fish were exposed to toluene emitted from outboard motor exhausts in this
experiment (33). Toxicity of toluene to the fathead minnow, bluegill,
goldfish, guppy, and orange-spotted sunfish has been reported. LC50 values
all exceeded 24 ppm in exposures of 24- to 96-hours duration (34, 35).
The Aquatic Toxicity Rating (96 hr. Tim, species unspecified) of
toluene is 100-10 ppm (G16).
Tests of four pseudomonads (motile marine bacteria) at toluene con-
centrations of 0.1 and 0.5% showed strong negative chemotactic responses
(movement away from high concentrations of the chemical) (36). Toluene
at a concentration of 0.6% inhibited the normal positive chemotactic
response of marine bacteria to glucose in seawater (37).
K-16
-------
Studies of the effect of toluene on the growth of the unicellular green
alga Chlorella vulgaris showed an LC50 of 245 ppm. Toxicity thresholds
of 10 mg/1 for the algae Skeletonema costatum, Amphidinum carterae and
C3..u-.ro3phaera carterae, and 10 mg/1 for Dunaliella tertiolecta have been
reported (38).
Toluene is a contact poison in terrestrial plants at very high concen-
trations (greater than 5,000 ppm). At ambient atmospheric levels, however,
toluene has not been shown to have any adverse effects (39).
The transport and fate of toluene within organisms is not well known.
A variety of pure cultures of microorganisms have been shown to have enzy-
matic systems capable of metabolizing toluene (24, 26, 40).
2.10 Current Testing
Toluene has been designated by the Chemical Industry Institute of
Toxicology (CIIT) for investigation of toxic and carcinogenic effects
following chronic inhalation exposure in at least one mammalian species.
A summary report is available on a 90-day inhalation study in albino rats.
The study, conducted by Industrial Biotest Laboratories for CIIT, involved
commercial toluene containing 100 ppm benzene.
The study was conducted with 4 groups of 30 animals exposed to either
30, 100, 300 or 1000 ppm. An additional group of 30 rats served as an
untreated control. Observations were made of mortality, reactions displayed,
food consumption, body weight, hematologic and clinical chemistry. The only
mortalities recorded throughout the investigation occurred during blood
collection.
Effects in male rats were limited to red deposits and/or red discharge
IX-17
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around the nose, and red deposits around the eyes. The only effect noted in
female rats was alopecia around the ears. No significant differences between
control and test animals were reported in body weight, hematologic or
clinical chemistry, urinalyses, or the frequency of histopathologic changes.
IX-18
-------
1. Proposed reactions for the in vivo metabolism of toluene (24).
CH,
H
0
H
CH,
OH
0-Cresol
CH,
CH2OH
COCH
C-NH-CH2-COOH
Hippunc acid
CH,
•H
CH,
OH
p-Cresol
Figure 2. Initial reactions in the. oxidation of toluene by Pseudononas putida (M)
Toluene
CH.
H
r--»o
H
Hypothetical
Oioxetane
CH.
CH.
OH
OH
H
•CH
•OH
as-2,3- Dihydroxy- 3-Methylcotecnol
2,3- dihydrotoluene
jnon-enzymotic
CH,
OH
ortho- Cresol
JX-1S
-------
REFERENCES
1. Walker, P. Air pollution assessment of toluene. MTR-7215. Mitre Cor-
poration, McLean, Virginia (1976).
2. Ogata, M., Tonokuni, K., and Takatsuka, Y. Urinary excretion of hippuric
acid and nr or p-xylene as a test of exposure. Brit. J. Ind. [-fed.
27:43-50 (19707-
3. Teisinger, J. and Srbova, J. Elimination of benzoic acid with the urine
and its relation to the maximum tolerable toluene concentration in the
air. Arch. Mai. Prob. 16:216-220 (1955) .
4. Me+TMif, R.L. and Sanborn, J.R. Pesticides and environmental quality in
Illinois. 111. Hat. Hist. Survey Bull. 31(9) :394-399 (1975).
5. Sutton, C., and Calder, J.A. Solubility of aUcylbenzenes in distilled
water and seawater at 25 °C. J.Chem. Engin. Lata 20(3) : 320-322 (1975) .
6. Laity, J.L. , Burstain, I.G., and Apel, B.R. Photochemical smog and atmos-
pheric reactions of solvents, in Solvents: Theory and Practice. Adv. in Chem.
Series, No. 124, Amer. Chem. See., Washington, D.C., p. 95-112 (1973).
7. Gerarde, H.W. Toxicological studies on hydrocarbons. III. The biochemorph-
ology of the phenylalkanes and phenylalkenes. Arch. Ind. Health 19:403
418 (1959) .
8. Smytli, H. et al . Range-finding toxicity data: List VII* Amer. Ind. Hyg.
Assoc. J. 30:470-476 (1969).
9. Keplinger, M.L., Lanier, G.F. and Deichmann, W.B. Effects of environmental
temperature on the acute toxicity of a number of compounds in rats. Toxicol.
Appl. Pharmacol. 1:156-161 (1959) .
10. Cameron, G. et al. The toxicity of some methyl derivatives of benzene with
special reference' to pseudccumene and heavy coal tar naphtha. J. Pathol.
Bacteriol. 46:95-107 (1938) .
11. Ikeda, M. and Ohtsuji, H. Phenobarbital-induced protection against
toxicity of toluene and benzene in the rat. Toxicol. Appl. Pharmacol.
20:30-43 (1971).
12. Svirbely, J. and Dunn, R. The acute toxicity of vapors of certain solvents
containing appreciable amounts of benzene and toluene. J. Ind. Hyg. Toxicol.
25:366-373 (1943).
13. Union Carbide Data Sheet, Toluene, July 23, 1970.
14. 'lerarde, H.W. Toxicology and Biochemistry of Aromatic Hydrocarbons. Elsevier
Publishing Co., N.Y. p. 142-150 (1960).
DC-20
-------
15. Carpenter, Q.P., Geary, D.L., Jr., Myers, R.C., Nachreisner, D.J.,
Sullivan, L.J. and King, J.M. Petroleum hydrocarbon studies. X.
Animal and human response to vapors of "50 thinner." Tbxicol. Appl.
Pharmacol. 36:427-442 (1976).
16. Gerarde, H.W. Toxicological studies on hydrocarbons. II. A comparative
study of the effects of benzene and certain mono-n-alkylbenzenes on hena-
poiesis and bone marrow metabolism in rats. Arch. Ind. Health
13:468-474 (1956).
17. Poel, W.E. Skin as a test site for the bioassay of carcinogens and
carcinogen precursors. Nat. Cane. Inst. Monogr. 10:611-631 (1963).
18. Lijinsky, W. and Garcia, H. Skin carcinogenesis tests of hydrogenated
derivatives of anthracene and other polynuclear hydrocarbons.
Z. Krebsforsch. Klin. Onkol. 77(3):226-230 (1972). CA.160866e.
19. Wolf, M.A., Rowe, V.K., McCollister, D.D., Hollingsworth, R.L. and
Qyen, F. Toxicological studies of certain .alkvlated benzenes and
benzene. Arch. Ind. Health 14:387-398 (1956)".
20. Lyapkalo, A.A. Genetic activity of benzene and toluene. Gig. Tr. Prof.
Zabol. 3 (1973).
21. Dobrokhotov, V.B. Mutagenic action of benzene and toluene under
experimental conditions. Gig. Sanit. 10:36-39 (1972).
22. Forni, A., Pacifico, E. and Limonta, A. Chromosome studies in workers
exposed to benzene or toluene or both. Arch. Environ. Health
22 (3): 373-378 (1971).
23. Dobrokhotov, V.B. and Enikeev, M.I. Mutagenic effect of benzene, toluene
and a mixture of these hydrocarbons in a chronic experiment. Gig. Sanit.
1:32-34 (1977).
24. Gibson, D.T. Microbial oxidation of aromatic hydrocarbons. CRC Crit.
Rev. Microbiol. l(2):199-223 (1971).
25. Kitagawa, M. Studies on the oxidation mechanisms of methyl groups.
J. Biochem, (Tokyo) 43:533 (1956).
26. Claus, D., and Walker, N. The decomposition of toluene by soil bacteria.
J. Gen. Microbiol. 36:107-122 (1964).
27. Gibson, D.T., Hensley, M., Yoshioka, H. and Mabry, T.J. Formation of
(+) - Cis-2,3-dihydroxy-l-methyl-cyclohexa-4,6-diene from toluene by
Pseudomonas putida. Biochem. 9:1626 (1970).
28. Unpublished data, Region IV, EPA.
IX-21
-------
29. Municipal Environment Research Laboratory. Survey of two municipal waste-
water treatment plants. Wastewater Research Division USEPA, Cincinnati,
Ohio. p. 18 (1977).
30. Mackay, D., and Wblkoff, A.W. Rate of evaporation of low solubility
contaminants from water bodies to the atmosphere. Environ. Sci.
Technol. 7:611-614 (1973).
31. U.S. Department of Health, Education and Welfare. Atmospheric levels
of hydrocarbons and their related products. Pages 3-1 to 3-15 in Air
Quality Criteria for Hydrocarbons (1970).
32. Pilar, S. and Graydon, W.F. Benzene and toluene distribution in Toronto
atmosphere. Environ. Sci. Technol. 7(7):628-631 (1973).
33. Brenniman, G., Hartung, R., and Weber, W.J. A continuous flow bioassay
method to evaluate the effects of outboard motor exhausts and selected
aromatic toxicants on fish. Water Res. 10(2):165-169 (1976).
34. Shelford, V.E. An experimental study of the effects of gas waste upon
fishes with special reference to stream pollution. Bull. 111. Lab. Nat.
Hist. 11:381-412 (1917).
35. Pickering, Q.H. and Henderson, C. Acute toxicity of some important
petrochemicals to fish. J. Water Pollut. Control Res. 38:1419-1429
(1966).
36. Young, L.Y. and Mitchell, R. Negative chemotaxis of marine bacteria
to toxic chemicals. Appl. Microbiol. 25(6):972-975 (1973).
37. Mitchell, R., Fogel,S. and Chet, I. Bacterial chemoreception: an
important ecological phenomenon inhibited by hydrocarbons. Water Res.
6(10):1137-1140 (1972).
38. Kauss, P.B. and Hutchison, T.C. The effects of water-soluble petroleum
components on the growth of Chorella vulgaris beijerinck. Environ.
Pollut. 9(3):157-174 (1975).
39. Currier, H.B. Herbicidal properties of benzene and certain methyl
derivatives. Hilgardia 20(19):383-406 (1951).
40. Gibson, D.T., Roch, J.R., and Kallio, R.E. Oxidative degradation of
aromatic hydrocarbons by microorganisms. I. Enzymatic formation of
catechol from benzene. Biochemistry 7(7):2653-2662 (1966).
IX-22
-------
XYLENES
TABLE OF CONTENTS
Page
Overview X-l
Part I - General Information
Xylenes, mixed X-3
m-Xylene X-6
o-Xylene X-8
p_-Xylene X-10
Summary of Characteristics X-12
Specific References X-13
Part II - Biological Properties
2.1 Bioaccumulation X-14
2.2 Contaminants and Environmental X-14
Degradation or Conversion
Products
2.3 Acute Toxicity X-15
2.4 Other Toxic Effects X-18
2.5 Carcinogenicity X-23
2.6 Mutagenicity X-23
2.7 Teratogenicity X-23
2.8 Metabolic Information X-24
2.9 Ecological Effects X-27
2.10 Current Testing X-27
References X-28
X-i
-------
-------
XYLENES
AN OVERVIEW
There are three isomers of xylene: o-xylene, m-xylene, and
£-xylene. All three isomers/ as well as mixtures, are articles
of commerce. In this dossier/ "xylene" refers to a mixture of the
three isomers/ unless otherwise stated, o-, and m-Xylene are color-
less liquids; p_-xylene is a crystalline solid melting at 13°C. Xy-
lenes are insoluble in water but miscible with alcohol, ether and
many organic solvents.
Commercial xylene which is predominantly the m-isomer is pro-
duced both from petroleum and from coal tar. o- and £-Xylene, ethyl-
benzene, and small quantities of other aromatic hydrocarbons are also
present in the commercial product. In the aggregate, approximately
10 billion pounds of xylene are produced annually.
Xylene is used by industry as a raw material for the production
of several chemicals, and as a solvent, having replaced the more tox-
ic benzene for a number of solvent uses. In the NOHS survey of oc-
cupational exposure, xylene (mixed isomers) was ranked 13th out of
approximately 7000 agents: more than 4 million workers are believed
to be exposed to it. Its presence in a wide variety of consumer
products results in general population exposures as well. Approxi-
mately 900 million pounds are released to the environment each year.
Xylenes ,are expected to bioaccumulate appreciably, as a result
of their partitioning into organic solvents, and storage in fish and
X-l
-------
shellfish has been reported. No reports of ecological damage have
been attributed to xylenes. However, low levels cause tainting in
fish and shellfish. Xylene isomers are oxidized to o-, m- and p_-
toluic acids, which are excreted as water-soluble conjugates. Xy-
lenols also form as minor metabolites. Bacteria oxidize xylenes to
dihydrodiols, catechols, and xylenols.
Toxic effects in humans following acute and/or chronic exposure
to xylene include narcosis, liver, kidney and heart damage. When
contaminated with benzene, commercial xylene has been reported to be
myelotoxic. Animal data on the carcinogenicity of xylenes are not
adequate for an evaluation, and xylenes have been tentatively se-
lected for carcinogenicity testing by NCI. Mutagenicity tests have
not been reported for any of the xylenes. According to Russian stu-
dies, xylenes are embryotoxic.
X-2
-------
PART I
GENERAL INFORMftlTCN
I. Xylenes, mixed
1.1 Identification CAS No,: 001330207
NIOBHNb.: ZE21000
1.2 Synonyms and Trade Names
Dimethylbenzene; xylol (G16)
1.3 Technical Product Composition
20% o-xylene 20% ethylbenzene
40% m-xylene small quantities of toluene
20% p-xylene and CQ aromatics
y (1)
(G21,G23)
1.4 Chemical and Physical Properties
1.4.1 Description; Clear, mobile, flammable liquid
1.4.2 Boiling Point: 137 - 140° C (G23)
1.4.3 Melting Point:
No information found in sources searched
1.4.4 Absorption Spectrometry;
No information found in sources searched
1.4.5 Vapor Pressure;
No information found in sources searched
1.4.6 Solubility; Insoluble in water;
Soluble in alcohol, ether and other
organic liquids
(G21,G23)
1.4.7 Octanol/Water Partition Coefficient:
log P =3.13 (estimate) (G36)
X-3
-------
1.5 Production and Use
1.5.1 Production:
5,336 Million Ibs (1972)
5,666 Million Ibs (1973)
5,821 Million Ibs (1974)
4,608 Million Ibs (1975)
(2)
1.5.2 Use:
In aviation gasoline: in protective coatings; as a
solvent for alkyl resins, lacquers, enamels, rubber
cements? in synthesis of organic chemicals
(G21)
Quantitative Distribution of Uses:
Pj-Xylene
oj-Xylene
Other isomers for cb'mical use
Gasoline, benzene, solvent, and
USQS
Percent
39
18
6
37
100
Consumer Product Information:
No. of mixed xylene pro-
No, of mixed xylene ducts in category
Category
cleaning agents and com-
pounds
paints, varnishes, shellac,
rust preventatives , etc.
flame retardant chemicals
aerosols
solvent-based cleaning and
sanitizing agents
caustics, lyes and drain
cleaner
agricultural chemicals
adhesives & adhesive pro-
due4- s including glue
caulking & spackle
paint & varnish thinners
containing pro-
ducts
477
15
579
7
1
4
6
3
total no. of products
in category
0.05%
4.3%
2.5%
15.4%
3.2%
0.9%
1.4%
0.8%
9.2%
9.4%
-xlOO
The 1,095 products surveyed contained an average cf 9.5% mixed xylene.
(G27)
X-4
-------
Xylene is present in:
Fuel system cleaner
Automatic choke and carburetor cleaner
Bullet and chisel paint markers - permanent
Pigmented ink
Permanent ink
Water repellent wood preservative
Penetrating solvent
Nail enamels
Liquid transmission additive
Spray paint
On and below grade adhesive
Marine paint
Edge dye for shoe soles
Laundry tub and appliance finish
Spot remover
Miticide (G35)
1.6 Exposure Estimates
1.6.1 Release Rate; 904.6 Million Ibs (G28)
1.6.2 NDHS Occupational Exposure:
Rank: 13
Estimated no. of persons exposed: 4,304,000
(G29)
1.7 Manufacturers
American Oil Co.
American Petrofina Co. of Texas
Ashland Oil, Inc.
Atlantic Richfield Co.
Crown Central Petroleum Corp.
ConmDnwealth Petrochemicals, Inc.
Cosden Oil and Chemical Corp.
Cities Service Oil Co.
Exxon Chemical Co.
Gulf Oil Corp., Gulf Oil Chemicals Co.
Champlin Petroleum Co.
Hercor Chemical Corp.
Amerada Hess Corp.
Marathon Oil Co., Texas Refining Div.
Monsanto Co.
Phillips Puerto Rico Core, Inc.
Shell Oil Co., Shell Chemical Co. Div.
Standard Oil Co. of California, Chevron Chemical Co.
Charter International Oil Co.
Styrochem Corp.
Sun Oil Co.
Tenneco Oil Co.
Union Carbide Corp.
Union Oil Co. of California
(G24)
X-5
-------
XYLENES
II . m-Xylene
1.1 Identification CAS No.: 000108383
NIOSH No.: ZE22750
1.2 Synonyms and Trade Names
1,3-Dimethylbenzene; m-xylol (G16)
1.3 Chemical Formula and Molecular Weight
CH_
CQHnr> Mol. Wt. 106.17
o 1U
(G22)
1.4 Chemical and Physical Properties
1.4.1 Description: Clear, colorless liquid (G21)
1.4.2 Boiling Point: 139.1° C (G22)
1.4.3 Melting Point; -47.87° C (G22)
1.4.4 Absorption Spectrornetry :
X lohexane = 269, 274 nm;
log ^ = 2.3, 2.3 (G22)
1.4.5 Vapor Pressure; 10 itm at 28.3° C (G22)
1.4.6 Solubility ; Insoluble in water;
Soluble in all proportions in alcohol, ether,
acetone, benzene, petroleum ether and other
organic solvents (G22)
1.4.7 Octanol /Water Partition Coefficient;
log P . - 3.20 (G36)
oct
X-6
-------
1.5 Production and Use
1.5.1 Production; 1,710 Million Ibs (G15)
1.5.2 Use; As a solvent/ as an intermediate for dyes and organic
synthesis, especially isophthalic acid; in insecticides;
in aviation fuel
(G21)
1.6 Exposure Estimates
1.6.1 Release .Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
Rank: 4284
Estimated no. of persons exposed: 2,000*
*rough estimate (G29)
1.7 Manufacturer
Atlantic Richfield Co. (G25)
X-7
-------
XYLEHES
III. o-Xylene
1.1 Identification CAS No.: 000094576
NIOSH No.: ZE24500
1.2 Synonyms and Trade Names
1,2-Dimethylbenzene (G16)
1.3 Chemical Formula and Molecular Weioht
IIQ Mol. wt. 106.17
(G22)
1.4 Chemical and Physical Properties
1.4.1 Description; Clear, colorless liquid (G21)
1.4.2 Boiling Point: 144.4° C (G22)
1.4.3 Melting Point; -25.18° C (G22)
1.4.4 Absorption Spectrometry;
X = 265, 271 nm;
log 6 = 2.3, 2.2 (G22)
1.4.5 Vapor Pressure; 10 ttm at 32.1° C (G22)
1.4.6 Solubility; Insoluble in water/-
Soluble in all proportions in alcohol, ether,
acetone, benzene, carbon tetrachloride, and
petroleum ether
(G22)
1.4.7 Octanol /Water Partition Coefficient;
log P - 2.77 (G36)
X-8
-------
1.5 Production and Use
1.5.1 Production; 702.923 Million Ihs (1975)
853.813 Million IDS U976N (G24)
1.5.2 Use! Current produc±ion is used almost entirely for the
roa-.iufao-.-uva of phthalic anhydride which is employed
in the production of alkyd resins, certain unsatu-
rated polyester resins and plasticizers for poly-
vinyl chloride resins; also in vitamin and pharma-
ceutical synthesis; in dyes; in insecticides; in
motor fuels
(G21,3)
1.6 Exposure Estimates
1.6.1 Release Rate;
No information found in sources searched
1.6.2 NOHS Occupational Exposure;
Rank: 3710
Estimated no. of persons exposed: 3,000*
*rough estimate (G29)
1.7 Manufacturers
Atlantic Richfield Co.
Chevron Chemical Co.
Cities Service Co.
Commonwealth Petrochemicals Co.
Cosden Oil and Chemical Co.
Crown Central Petroleum Corp.
Exxon Corp.
Monsanto Co.
Phillips Petroleum Co.
Shell Chemical Co.
Southwestern Oil and Refining Co.
Sun Oil Co.
Tenneco, Inc.
(G25)
X-9
-------
XYLENES
IV. g-Xylene
1.1 Identification CAS No.: 000106423
NIOSH No.: ZE26250
1.2 Synonyms and Trade Names
1,4-Dimethylbenzene, pj-xylol (G16)
1.3 Chemical Formula ani Molecular Weight
OL
Mol. wt. 106.17
(G22)
1.4 Chemical and Physical Properties
1.4.1 Description; Moncclinic prismatic crystals at low tempera-
tures; colorless liquid
(G21,G22)
1.4.2 Boiling Point; 138.35° C (G22)
1.4.3 Melting Point; 13.26° C (G22)
1.4.4 Absorption Spectrccnetry;
alcohol
0_e
, 275 nm;
log £ = 2.7, 2.7 (G22)
1.4.5 Vapor Pressure; 10 mm at 27.3° C (G22)
1.4.6 Solubility : Insoluble in water;
Soluble in all proportions in alcohol, ether,
acetone, benzene, petroleum ether and other
organic solvents
1.4.7 Octanol/Water Partition Coefficient;
log P_. =3.15 (G36)
oct
X-10
-------
1.5 Production and Use
1.5.1 Production: 2,483.521 Million Ibs (1975)
— 2,911.451 Million Ibs (1976) (G24)
1.5.2 Use; In synthesis of terephthalic acid for polyester
resins and fibers ("Dacron", "Mylar". "Terylene")?
in vitamin and pharmaceutical synthesis? in insecti-
cides
(G21)
1.6 Exposure Estimates
1.6.1 Release Rate; 39.9 Million Ibs (G28)
1.6.2 NDHS Occupational Exposure;
Rank: 3743
Estimated no. of persons exposed: 3,000*
*rough estimate (G29)
1.7 Manufacturers
Amoco Chemicals Corp.
Atlantic Richfield Co.
Charter Oil Co.
Chevron Chemical Co.
Cities Service Co.
Exxon Corp.
Harcor Chemical Corp.
Phillips Petroleum Co.
Shell Chemical Co.
Sun Oil Co.
Tenneco, Inc.
(G25)
X-ll
-------
SUMMARY OF CWI
XYLENES
Name
Solubility
Log P
oct
Estimated
Environmental
Release
(Million Ibs)
Production
(Million Ibs)
Xylenes, mixed i in H_O; s in ale,
eth, and other os
m-Xylene
o-Xylene
g-Xylene
i in H20;OO in ale,
eth, ace, bz, peth,
and other os
i in H-OfOO in ale,
eth, ace, bz, petli
andOCl,
i in H2O;Oo in ale,
eth, ace, bz, peth
and other os
Estimated no.
of persons
exposed
(Occupational)
3.13 904.6
5,336
5,666
5,821
4,608
(1972)
(1973)
(1974)
(1975)
4,304,000
3.20
2.77
3.15
39.9
1,710
702.923
853.813
2,483.521
2,911.451
(1975) ~2,000
(1975)
(1976)
(1975)
3,000
3,000
Use
Synthesis of organic chemi-
cals; aviation gasoline;
protective coatings; sol-
vent for alkyd resins,
lacquers, enamels, rubber
cements
Solvent; intermediate for
dyes and organic synthesis
especially isophthalic
acid; insecticides; avia-
tion fuel
Mfg. of phthalic anhy-
dride; vitamin and pharma-
ceutical synthesis; dyes;
insecticides; motor fuels
Synthesis of terephthalic
acid for polyester resins
and fibers: vitamin and
pharmaceutical synthesis,
insecticides
* No information found in sources searched.
X-12
-------
SPECIFIC REFERENCES FOR PART I
1. Activities of the Chemical Selection Working Group, January-March 1977.
Report to the Chemical Selection Subgroup of the Clearinghouse on En-
vironmental Carcinogens, National Cancer Institute (18 April, 1977).
2. Summary of data for chemical selection - mixed xylenes. Stanford
Research Institute, Menla Park, California (1977).
3. Chemical and Engineering News (November 7, 1977).
X-13
-------
XYLENES
PART II
BIOLOGICAL PROPERTIES
2.1
Because of their high partition coefficients (log P ^ 3 )
all isoroers of xylene are expected to show a strong partitioning into the
n-octanol phase of the n-octanol/water system. The retention of xylenes
in organisms, however, is probably dependent on their metabolic fate,
since the methyl groups of xylenes would tend to be readily oxidized,
especially in mammalian systems. Evidence exists that eels may not have
as much oxidizing capability', since xylenes do show some storage in
eel tissues (2) . While quantification was apparently performed, exact
figures were not available at the time of this writing. All three isomers
of xylene were stored at lower levels than either benzene or toluene
in the eels' flesh. Fish from a polluted river in Japan were found to
contain 0.02 ppm unspecified xylene in the flesh. Concentrations of both
toluene and benzene in the same fish were roughly ten times as high.
Concentrations in the water were not reported (3) . Xylenes are also
reported as being stored at unspecified levels in scallops from polluted
waters (4) .
In manuals, xylene was identified in rat brain tissue at unspecified
concentrations and considered to be endogenous (5) .
2,2 Contaminants and Environmental Degradation or Conversion Products
Ccmnercial xylene is produced from petroleum and from coal tar. It
has the following composition (G19) .
X-14
-------
Constituent Petroleum Product Coal Tar Product
o-Xylene 20% 10-15%
m-Xylene 44% 45-70%
p-Xylene 20% 23%
Ethylbenzene 15% 6-10%
Camercial xylene may also contain small amounts of toluene, trimethyl-
benzene, phenol, thiophene, pyridine and nonaronatic hydrocarbons. Xylene
has frequently been contaminated with benzene (G19).
Xylenes have been reported in air (0.016 - 0.061 ppm for nv-isomer;
less for other isomers) (G14). The reactivity of xylenes to oxidation is
low with estimated half-lives of 2200 years to peroxy radical and 100 years to
ozone; the half-life for reaction with hydroxyl radical was reported to be
3 days (G14).
Products of microbial degradation (as in soil) are reported to be X-
hydroxy-p-toluic acid, g-methylbenzyl alcohol, benzyl alcohol, m- and o-toluic
acids and 4-raethylcatechol (G14).
2.3 Acute Toxicity
Two publications, Criteria for a Recommended Standard for Occupational
Exposure to Xylene by NIOSH (G19) and Toxicity and Metabolism of Industrial
Solvents (Gl), have served as the major secondary sources for the toxicity
data and references cited in this and the following section (2.3 and 2.4).
Through the 1940s several papers appeared concerning occupational
disease in the printing industry resulting from exposure to xylene. The
relevance of these papers is questionable, however, as the term "xylene"
is not precisely defined. "Xylene" as used in the intaglio printing
industry might refer to pure xylene, pure toluene, a mixture of these, or
a mixture containing benzene and paraffin hydrocarbons.
X-15
-------
The NIOEfl Registry of Toxic Effects of Chemical Substances (G16) reports
Substance
Xylene
(mixed)
m-Xylene
:icity of xylene and individual isoners
Parameter
TCLo
UD50*
LDLo
LD50
LCIo
IDLo
IDLo
IDLo
IDLo
IDLo
Ldo
LD50
IDLo
LDLo
LETO
Dosage
200 ppm
4300 mgAg
2000 mgAg
5000 mgAg
8000 ppm/4H
2000 mg/kg
5000 mgAg
5000 mgAg
1500 mg/kg
2500 mgAg
6920 ppm
5000 mgAg
2000 mgAg
5000 mgAg
3460 ppm
Animal
human
rat
rat
rat
rat
rat
rat
rat
rat
rat
mouse
rat
rat
rat
mouse
as follows:
Route
inhalation
oral
intraperitoneal
oral
inhalation
intraperitoneal
subcutaneous
oral
intraperitoneal
subcutaneous
inhalation
oral
intraperitoneal
subcutaneous
inhalation
o-Xylene
£-Xylene
* In this study by Wblf et al. (30) the material used was
pure xylene (19% o-, 52% m-, and 24% £-). This is the
only study in which purity and/or composition are reported.
According to the NIOSH Criteria Document, the only well-documented toxic ef-
fects of xylene in humans are its irritating and narcotizing properties (Gi$).
Liquid xylene is a skin irritant, causing erythema, dryness and
defatting, and with prolonged contact, blistering. It is also an irritant
to mucous membranes, including the conjunctiva and respiratory tract (Gl, G19) .
Nelson et al. (31) found that xylene was more irritating than toluene to the
eyes and mucous membranes during a 3 to 5 minute exposure. Narcotic inhalation
doses reported by Browning (Gl) in a review of literature prior to 1935 are:
2100 to 3500 ppm for the m- and pj-isomers and 3500 to 10,000 ppm for o-xylene.
Narcosis occurred only with concentrations higher than 1150 ppm. Xylene was
reported in an article (32) cited by Browning (Gl) to be slower in exerting
an initial narcotic effect than either toluene or benzene at 15,000 ppm.
X-16
-------
Narcotic effects in rats were noted at concentrations of 15-20 mg/1
(3450-4600 ppm) for o-xylene, 10-15 mg/1 (2300-3450 ppn) for m-xylene,
and 10 mg/1 (2300 ppn) for pj-xylene (33, as reported in G19) .
Carpenter et al. (34) investigated animal and human responses to
vapors of mixed xylenes. The composition of the xylene used, as determined
by gas chromatography, is shown in Table 1. It should be noted that no
benzene was present in the sample.
Composition of Mixed Xylenes
Components Volume Percentage
Nonaromatics 0 . 07
Toluene 0.14
Ethylbenzene 19.27
£-Xylene 7.84
m-Xylene 65.01
o^-Xylene 7.63
CQ + aromatics 0.04
9 100.00 Total
In this study, one of seven human volunteers exposed to 1.0 mg/1
(230 ppn) and 1 of 6 exposed to 2.0 mg/1 (460 ppm) experienced slight
light-headedness without loss of equilibrium or coordination at the end
of the 15-minute exposure period. In a 15-minute inhalation period, the
only conmon sign of discomfort at 2.0 mg/1 (460 ppn) was eye irritation, and
some transitory olfactory fatigue (with recovery in 10 minutes) in four of
six human test panel members. The authors concluded that the odor threshold
is on the order of 0.0045 mg/1 (1 ppm) and that 1.0 mg/1 (230 ppm) of mixed
xylenes should not be objectionable to most people, based on the following
human sensory thresholds for nixed xylenes:
* From Carpenter et al. (38) .
X-17
-------
TABLE 2
Human Sensory Thresholds
Measured concentration mg/1
Measured concentration ppm
Number of volunteers
Number detecting odor
Number olfactory fatigue
Number throat irritation
Number eye irritation
Number with tears
Number reporting dizziness
for Mixed
0.46
110
6
6
3
1
0
0
0
Xylenes
1.0
230
7
7
3
0
1
1
1
2.0
460
6
6
3
1
4
1
1
3.0
690
6
6
0
2
4
2
4
The results obtained with animals in this same study are summarized
below:
Rats inhaled 46 mg/1 (11,000 ppm) of mixed xylenes. The LT50 was 92
minutes. The DC50 in a 4-hour inhalation period wai 29 mg/1 (6700 ppm).
Cats displayed central nervous system effects within 2 hours at 41 mg/1
(9500 ppm).
Rats and beagles that inhaled 3.5 mg/1 (810 ppm) , 2.0 mg/1 (460 ppm),
and 0.77 mg/1 (180 ppm) for 6 hours a day, 5 days a week for 13 weeks did
not show differences (body weight change, urine and blood analysis) which
were statistically significant from control groups.
Higher levels were not run because rats had poor coordination and dogs
had lacrimation at 5-6 mg/1 during a preliminary 4-hour exposure.
2.4 Other Toxic Effects
Rats and rabbits receiving 609 ppm and 1150 ppm xylene respectively, 8 hours
a day, 6 days a week, for periods of 40-130 days showed some somnolence, and in
the terminal phase dyspnea, disequilibrium and in some cases paralysis of the
hind legs. At the higher concentrations, there was conjunctival irritation, anorexia
and loss of weight at the end of the first week. Narcosis was more complete and
prolonged. Ataxia, developing into paralysis of the hind legs with chattering
of thf- teeth and redness of the mucous membranes, and hypothermia were also ob-
served. At the similar dose, lesions in the kidneys, in the form of congestion,
inflammation and cellular desquamation with some sign of commencing necrosis were
X-18
-------
observed in the animals (rats and rabbits) studied by Fabre et al. (35, as reported
in Gl). Liver necrosis and diffuse nephritis after xylene was injected intra-
peritoneally to rats, and moderate cloudy swelling of kidneys following exposure
by inhalation have been reported (Gl, G19).
Xylene is a central nervous system depressant. At high concentrations,
brief exposures can affect attention, judgment, or perception (G19). Liver and
kidney damage have been reported in a human after the inhalation of xylene and
liver damage after the accidental ingestion of a small amount of a xylene-toluene
thinner. In summary, effects of xylene have been reported on the liver (38), (37,39,
as reported in G19); the kidney (38), (40, as reported in G19); the cardiovascular
system (41, 42, as reported in G19); and the gastrointestinal tract (43, as re-
pjrfcad in G19) after inhalation of xylene vapor. According to the NIOSH Criteria
Document, effects on these organs and systems should be investigated to confirm
or deny any involvement of xylene (G19).
The Ihreshold Limit Value (TLV) recommended by the ACGIH (1976) is 100 ppm
(Gil).
In the past, xylene has been considered myelotoxic because leukopenia,
relative lymphocytosis and aplastic anemia were observed in occupational ex-
posures, and transitory leukopenia, leukocytosis and hyperplasia of the bone
marrow were reported in experimental animals. But in the NIOSH Criteria Docu-
ment (G19), it is concluded that xylene is not myelotoxic when uncontaminated
with substances such as benzene. This conclusion is based on the recent animal
studies (34,36) in which exposure to pure xylene did not produce significant
nematologic changes in rats, dogs, guinea pigs, or monkeys, while benzene has
been reported to induce aplasia in other animal studies.
The major toxicity data summarized in the NIOSH Criteria Document (G19)
have been compiled in Table 3.
X-19
-------
IWiLE
TOKICITY DATA ON XYLENES
Substance Animal
Route
xylene
Xylene
human
human
inhalation
inhalation
Dosage
200 ppm
10,000 ppm
(estimated
after the
incident)
m-xylene
guinea pig inhalation
300 ppm
p-xylene
pregnant
rats
inhalation
115 ppm
xylene
chinchilla
rabbits
inhalation 12 ppm
Exposure
T inie
3-5 min.
Effects
Irritation of eyes,
nose, throat
18.5 hrs. 3 painters in confined
tank became unconscious,
1 died. Autopsy revealed
severe lung congestion,
focal intra-alveolar
hemorrhage, pulmonary edema
petechial hemorrhage in the
brain and evidence of anoxic
neuronal damage. Survivors
suffered confusion, impaired
renal function and hepatic
impairment for about 1 month.
4 hrs/day Slight degeneration of the
6 weeks liver; inflammation of the
6 da/week lungs. At initial 450 ppm
concentration one of the
three animals died, others
were prostrate.
24 hrs/day Significantly greater pre-
20 days implantation mortality
(32.1%) than controls (11.3%);
significantly greater post-
implantation mortality
(38.9% vs 4.8%). No teratogenic
effects.
4 hrs/day Increases in hemoglobin,
for 10=12 erythrocytes, leukocytes,
months common proteins, gamma
globulin, increased activity
X-20 Of blood acetyl cholinesterase.
Reference
44
38
45
11
46
-------
TABLE 3 - continued
Substance Animal
Route
Dosage
Exposure
Time Effects
Roferenq
xylene (con't)
xylene
rat
inha-lation
1600 ppm
xylene
rat
inhalation
980 ppm
xylene
xylene
rat
rat
inhalation
subcutaneous
xylene
rabbits
inhalation
620 ppm
1-2 cc/kg
1:1 with
olive oil
1150 ppm
X-21
Decreases in weight,
imiiiunobiological activity,
weakening of adrenal cortex
functions, disturbance of
intermediary metabolism.
18-20 hrs Of original 4 rats, 1 died
per day after two days, 1 after four
2-4 days days. Death was caused by
narcosis which prevented
ingestion of food and water
leading to anhydremia and
death. White cell count
reduced 27% in one rat.
7 days Effects similar to above
without narcosis. Bone
marrow and spleen were hyper-
plastic and kidneys showed
acute congestion with moderate
cloudy swelling.
7 days 30% reduction in white cells
in 1 of 6 rats. No other
toxic effects.
10 days Slight reduction in activity
and in the red cell count.
Bone marrow became hyper-
plastic with mild necrosis of
the liver and diffuse nephritis.
8 hrs/day Decreases in red and white cells',
6 da/wk hyperplastic bone marrow, no
40-55 aplasia vascular congestion in
days the liver, heart, kidneys, adren-
als, lungs, and spleen.
17
17
17
-------
TABLE 3 - continued
Substance Animal Route
Dosage
Exposure
Time
Effects
Reicjrence
xylenc (con't)
rabbits
and rats
inhalation
690 ppm
xylene
rabbit
rabbit
subcutaneous
subcutaneous
o-xylene
rats, inhalation
guinea pigs,
monkeys,
dogs
rats, inhalation
guinea pigs
monkeys,
dogs
300 mg/kg
per day
700 mg/kg
per day
7 "7 0 ppm
G5S> m-xylene rats
19.3% ethyl benzene
14.5% other xylenes
inhalation
73 ppm
305 ppm
460 ppm
175 ppm
8 hrs/day
6 da/wk
110-130
days
6 weeks
9 weeks
8 hrs/day
5 da/wk
6 weeks
Same as in the 1150 ppm section
except that there were no
significant changes in the
blood at this level.Renal
lesions (glomerulonephritis)
were observed at both dosage
levels, (authors suggested that
such effects in man would be
indicated by an increase in
blood urea and the appearance
of albumin and blood in the
urine and thus caution should
be exercised in the use of
xylenes)
Using radiographic techniques,
it was determined that xylene
does not affect DNA synthesis
in the bone marrow. Earlier
reports of aplastic anemia were
prc'jably due to benzene impurities
Microscopic examination of heart,
lung, brain, kidney, spinal cord
and spleen were negative. No
significant changes in body
weight or leukocyte counts.
47
36
90 days same as above
continuous
6 hrs/day No gross or microsopic lesions
5 da/wk found. Blood counts and blood
13 weeks analyses were normal.
34
X-22
-------
2.5 Carcinogenicity
Carcinogenicity testing of the xylenes by mouse skin painting has been
reported (G18). In two studies (7, 8) of short duration (6-9 months) no
malignant tunors were reported. These studies are not considered adequate
for an evaluation of Carcinogenicity because of the short duration, and the
lack of data on dose levels and survival. In another mouse skin painting
study, the activity of mixed xylenes could not be evaluated because of con-
current treatment with a single application of urethane followed by repeated
applications of croton oil (10).
2.6 Mutagenicity
No reports on mutagenicity testing were found in the searched literature.
2.7 Teratogenicity
A Russian study (11) cited in the NIOSH Criteria Document (G19) examined the
embryotoxic and teratogenic effects of pj-xylene vapor. Rats were exposed to
p_-xylene at 115 ppm for 20 days, 24 hours per day. Treated rats experienced
significantly greater pre-implantation mortality (32.1%) than controls (11.33%).
Post-implantation mortality was also higher (38.9% vs. 4.8%). No teratogenic
effects were observed. The conclusion was drawn by the author that g-xylene
is much more toxic for the maternal organism than for the developing
embryos.
A conclusion that fat solvents, including xylene, may have a teratogenic
effect in man has been reported in a paper (12) cited in the NIOSH document.
However, NIOSH makes clear that the data are not adequate to support the
conclusions drawn by the authors of the article. The article reports that
9 spinal malformations (sacrococcygeal agenesis, or caudal regression
syndrome) were observed among more than 1,500,000 infants born in
Czechoslovakia from 1959-1966. Five of the 9 mothers involved had been
X-23
-------
exposed to fat solvents (xylene in 1 case) during their pregnancy. Experi-
ments with chick embryos exposed to xylene atmosphere (a rectangular window
was opened in the egg shell then covered with a glass square on a paraffin
frame) for 60, 120, 180 or 240 minutes resulted in a significant increase
in the incidence of malformations and in the mortality rate in the embryos
exposed at the earliest stage of development
Abstracts of two Russian articles (11, 13) state that xylenes
exerted a "significant embryotoxic effect" (dose up to 400 mq/kq/day) and
a "minor embryotoxic influence" (dose unspecified). No mention of fetal
abnormalities was made in either abstract.
Xylenes have been, found to cross the placenta in humans (14).
2.8 Metabolism
In vivo, xylene isomers are oxidized to <>-, m-, and p_-toluic acids,
of which the n>- and p_-isomers conjugate with glycine and are excreted in
the urine as the correspond ing toluylglycines, i.e., as m- and pj-methylhippuric
acid. c~Toluic acid, however, is thought to be excreted as the ether
glucuronide (15). In addition, hydroxylation also takes place in the
various xylene isomers to produce xylenols which are then excreted as
alucuronides in substantial amounts and as ester sulfates in small amounts
(16) . Unchanged xylenes are not detected in the urine but their elimination
via the lungs is a primary excretory route (6).
In rabbits, the three xylene isomers gave 60, 81, and 88% of o-, m-,
£-toluic acid, respectively. The resulting o-toluic acid was excreted mainly
in the unconjugated form or as an ester glucuronide (30% of the dose), but
a small amount (0.3% by isolation) is conjugated. There is evidence of
hydroxylation of all three isomers; 6 and 4% of the doses of oj- and m-xylene,
respectively, are excreted as ethereal sulphate and 10-15% of o-xylene is
probably excreted as an ether glucuronide (18).
X-24
-------
Small amounts of phenolic metabolites have been isolated in the urine
of rats, rabbits and guinea pigs given all three isomers orally (35).
Urinary excretion of m-, or pj-methylhippuric acid in the urine of
persons exposed to vapors of m- or pj-xylene has been determined by Ogata
et al. (19) in male volunteers.
Bacterial metabolism of £- and m-xylene has been reported by Gibson
et al. (20) Pseudomonas putida 39/t) oxidized pj-xylene to cis-3,6-dimethyl~3,
5-cyclohexadiene-l,2-diol (cis-p-xylene dihydrodiol). This metabolite
was stable enough to be isolated in crystalline form. In the case of m-xylene,
P. putida 39/D oxidized it to 3,5-dimethyl-3,5-cyclohexadiene-l,2 diol.
This product was very unstable and all attempts to isolate it led to the
formation of 2,4-dimethylphenol.
A metabolic study by Jamison et al. u-u was also cited in ref. 20.
In this study a strain (V-49) of Nocardia corallina, in addition to oxidizing
£-xylene to g-toluic acid and 2,3-dihydroxy-r toluic acid also produced
3,6-dimethyl pyrocatechol and <*,«' -diirethyl-cis^cis-rajconic acid. The
pathways proposed for the oxidation of g-xylene byN. corallina V-49
and by P. putida are shown in Figures 4 and 5, respectively.
Gibson et al. have reported that rat liver microsomes oxidize p-xvlene
to 3,6-dimethylphenol and p-toluic acid whereas m-xylene is oxidized pre-
dominantly tp 2,4-dimethylphenol and a trace of 2,6-dimethylphenol (20).
The absorption of liquid xylene through the skin in man was investigated
under experimental conditions (22). It was established that the rate of
absorption of liquid xylene was from 4.5 to 9.6 mg/cm2/hour.
X-25
-------
FIGURE 4. Proposed Pathway for the Oxidation
of pj-Xylene to <* , -OH
5,6-OIMETHYL-
PYROCATECHOU
i
CH,
•'- DIMETHYL- en. en-
MUCONlC AGIO
FIGURE 5. Pathway Proposed for the Oxidation
of p-Xylene by P. putida (21)
CH3
2.5 - OIMETHYLPHENOL
CMj
YL tNE
NONEN2YM4TIC
3IMY39CD-CL
CH,
OH
CH;
3.6 • DIME
CATECHOL
X-26
-------
2.9 Ecological Effects
Xylene has caused tainting in scallops (23) and fish (24). In fish
muscle, offensive flavors were detectable at concentrations of xylene as
low as 0.02 ppm, concentrations similar to those found in fish from a
polluted river (4).
The Aquatic Toxicity Ratings (96-hour TLm, species unspecified) for
xylene, o^xylene, and pj-xylene, are reported to be in the range of 100-10 ppm
(G16). The 96-hour LC50 for goldfish is 17 ppm (25). Rainbow trout detect
and avoid xylene at concentrations as low as 10 mg/1 (26).
At a concentration of 0.2%, xylene inhibited spore germination of
marine algae (Enteromorpha and Ectocarpus spp.) (27). However, at low con-
centrations in water, xylene stimulated growth of phytoplankton (28).
Xylene was not injurious to pollen of petunias when applied at con-
centrations similar to those of a pesticide solvent (29).
2.10 Current Testing
Xylenes have been tentatively selected by NCI for carcinogenicity
testing (G12) .
X-27
-------
REFERENCES
1. Fabre, R., Truhaut, R. , Laham, S. Toxicological research
on replacement solvents for benzene—IV. Study of xylenes.
Arch. Mai. Prof. 21:301-313 (1960).
2. Ogata, M. and M.iake, Y. Compound from floating petroleum
accumulating in fish. Water Res. 9:1075-1078 (1975).
3. Funauka, R. &t al. Offensive odor in fish from the Nagara
River, III. Aromatic hydrocarbons as one of the offensive-
odor substances. Eisei Kagaku 21:93-100 (Chem. Abst. 83:
173356N) (1975) .
4. Motohiro, T. and Iseya, Z. Effects of water polluted by
oil on aquatic animals. Bull. Fac. Fish Hokkaido Univ.
26:367-371 (1976).
5. Politzer, I. et al. Identification of some volatile en-
dogenous constituents in rat brain tissue and the effects
of lithium carbonate and chloral hydrate. Res. Commun.
Pathol. Pharmocol. 15:469-481 (1976).
6. Sedivec, V. and Flek, J. The absorption, metabolism, and
excretion of xylenes in man. Int- Arch. Occup. Environ.
Health 37(3) :205-217 (1976).
7. Kennaway, E.L. Brit. Med. J. 1:564-567 (1924).
3. Berenblum, I. The carcinogenic action of croton resin.
Cancer Res. 1:44-48 (1941).
9. Pound, A.W. Induced cell proliferation and the initiation
of skin tumor formation in mice by ultraviolet light. Path-
ology 2:269-275 (1970).
10. Pound, A.W. and Withers, K.R. The influence of some irritant
chemicals and scarification on tumor initiation by urethane
in mice. Brit. J. Cancer 17:460-470 (1963).
11. Krotov, I.A. and Chebotar', N.A. Study of the embryotoxic
and teratogenic action of certain industrial substances
formed during the production of dimethylterephthalate.
Gig. Tr. Prof. Zabol. 16:40-43 (1972).
12. Kucera, J. Exposure to fat solvents - a possible cause
of sacral agenesis in man. J. Pediat. 72:357-859 (1963).
13. Telina, 0. Akush Ginekol 7:63-64 (1974).
14. Dowty, B. et al. Transplacental migration and accumulation
in blood of volatile organic constituents. Pediat. Res. 10:696-
671 (1976).
j.5. Oqata, M., Tomukuni, K., Takatsuka, Y. Quantitative deter-
mination in urine of hippuric acid and m- or o-methylheppuric
acid, metabolites of toluene and m- or o-xylene. Brit J Ind
Med. 26:330-334 (1969).
X-28
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References - continued
16. Laham, S. Metabolism of industrial solvents. Ind. Med. Surg,
39:237-240 (1970).
17. Batchelor, J.J. The relative toxicity of benzol
and its higher homologues. Am. J. Hyg. 7:276-298
(1927).
18. Bray, H.G. , Humphris, B.C. and Thorpe, W.V. Metabolism
of derivatives of toluene —3. o, m- and p-xylenes.
Biochem. J. 45:241-244 (1949). " ~
19. Ogata, M., Tomokuni, K. and Takatsuka, Y. Urinary
excretion of hippuric acid and m- or p-methylhippuric
acid in the urine of persons exposed to vapors of
toluene and m- or p-xylene as a test of exposure.
Brit. J. Ind. Med. 27:43-50 (1970).
20• Gibson, D.T., Mahadevan, V. and Darey, J. Bacterial
metabolism of para- and meta-xylene: Oxidation of the
aromatic ring.37 Bacteriol. 119(3):930-936 (1974).
21. Jamison, V.W., Raymond, R.L. and Hudson, J.O. Micro-
bial hydrocarbon co-oxidation. III. Isolation and
characterization of
-------
26. Folmar, L.C. Overt avoidance reaction of rainbow trout
fry to nine herbicides. Bull. Environ. Contain. Toxicol.
15:509-514 (1976).
27. Skinner, C.E. Role of algae in the deterioration of
decorative and marine paints. FATIPEC Congr. II, 421-
427 (1972).
28. Dunston, W.M., Atkinson, L.P., and Matoli, J. Stimu-
lation and inhibition of phytoplankton growth by low
molecular weight hydrocarbons. Mar. Biol. 31:305-310
(1975).
29. Gentile, A.G., and Gallagher, K.J. Pollen germination
and tube elongation in petunia inhibited or reduced by
commercial formulations of pesticides in vitro.
J. Econ. Entomol. 60, 438-491 (1972).
30. Wolf, M.A., Rowe, V.K., McCollister, D.D., Hollings-
worth, R.L. and Oyen, F. Toxicological studies of cer-
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Health. 14:387-398 (1956).
31. Nelson, K.W., Ege, J.F., Jr., Ross, M., Woodman, L.E.
and Silverman, L. Sensory response to certain industrial
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32. Schumacher, H. and Grandjean, E. Comparative invest-
igations on the anesthetic effect and acute toxicity of
nine solvents. Arch Gewerbepathol Gewerbehyg 18:109-
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33. Lazarew, N.W. On the toxicity of various hydrocarbon
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(1929).
34. Carpenter, C.P., Kinkead, E.R., Gear, D.L., Jr., Sulli-
van, L.J. and King, J.M. Petroleum hydrocarbon toxicity
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mixed xylenes. Toxicol. Appl. Pharmacol. 33:543-558 (1975)
35. Fabre, R., Truhaut, R. and Laham, S. Toxicology—
study of the metabolism of xylenes or dimethylbenzenes
in the rat, the guinea pig, and the rabbit. C.R. Soc.
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36. Jenkins, L. J., Jr., Jones, R.A. and Siegel, J. Long-
term inhalation screening studies of benzene, toluene,
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Appl. Pharmacol. 16:818-823 (1970).
X-30
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37. Rosenthal-Deussen, E. Poisoning by a coating product
(Inertol). Arch. Gewerbepathol Gewerbehyg 2:92-98
(1931).
38. Morley, R- , Eccleston, D.W., Douglas, C.P., Greville,
W.E.J., Scott, D.J., and Anderson, J. Xylene poison-
ing—a report on one fatal case and two cases of recovery
after prolonged unconsciousness. Brit. Med. J. 3:442-443
(1970) .
39. Ghisland, E., Fabiani, A. Hepatic lesion caused by
accidental ingestion of nitrocellulose paint thinner.
Med. Lav. 48:577-579 (1957).
40. Joyner, R.E. and Pegues, W.L. A health hazard associated
with eposy resin-concrete dust. J. Occup. Med. 3:211-214
(1961).
41. Hirsch, S. On chronic xylene poisoning, especially the
effects of xylene on the heart and blood vessels. Dtsch.
Gessell. Innere Med. 44:483-497 (1932).
42. Sikora, H. and Gala, J. Effects of acute xylene poison-
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(1957).
43. Glass, W.I. Annotation: A case of suspected xylol
poisoning. N. Z. Med. J. 60:113 (1961).
44. Nelson, K.W., Ege, J.F., Jr., Ross, M. Woodman, L.E.,
Silverman, L. Sensory response to certain industrial
solvent vapors. Ind. Hyg. Toxicol. 25:282-285 (1943).
45. Smyth, A.F. and Smyth, H.F., Jr. Inhalation experiments
with certain lacquer solvents. J. Ind. Hyg. 10:261-271
(1928) .
46. Kashin, L.M., Kulinskaya, I.L., Mikhailovskaya, L.F.
Changes in animal organisms due to chronic effect of small
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47. Speck, B. and Moeschlin, S. The effect of toluene, xylene,
chlorampbenicol and thiouracil on bone marrow—Experimental
autoradiographic studies with 3H-thymidine. Schweiz Med.
Wochenschr.98:1684-1686 (1968).
X-31
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-------
APPENDIX A
GENERAL REFERENCES
Gl. Browning, E. Toxicity and Metabolism of Industrial Solvents.
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 Asso-
ciation/ Washington, D.C.
G6. Industrial Safety Data Sheets. National Safety Council,
Chicago, Illinois.
G7. Shepard, T.H. Catalog of Teratogenic Agents. Johns Hopkins
University Press, Baltimore (1973).
G8. Thienes, C.L. & Haley, T.J. Clinical Toxicology. Lea &
Febiger, Philadelphia (1972) .
G9. IARC Monographs on the Evaluation of Carcinogenic Risk of
Chemicals to Man. Lyon, France. WHO, International Agency
for Research on Cancer.
G10. Debruin, A. Biochemical Toxicology of Environmental Agents.
Elsevier/North-Holland, Inc., New York (1976).
Gil. Threshold Limit Values for Chemical Substances and Physical
Agents in the Workroom Environment with Intended Changes
for 1976. American Conference of Government Industrial
Hygienists.
G12. Chemicals Being Tested for Carcinogenicity by the Bioassay
Program, DCCP. National Cancer Institute (1977) .
G13. Information Bulletin on the Survey of Chemicals Being Tested
For Carcinogenicity, No. 6. WHO, Lyon, France (1976).
G14. Brown, S.L., et_ al_. Research Program on Hazard Priority
Ranking of Manufactured Chemicals, Phase II - Final Report
to National Science Foundation. Stanford Research Institute,
Menlo Park, California (1975) .
XI-1
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G15. Dorigan, J. , e_t al. Scoring of Organic Air Pollutants,
Chemistry, Production and Toxicity of Selected Synthetic
Organic Chemicals. MITRE, MTR-7248 (1976).
G16. NIOSH Registry of Toxic Effects of Chemical Substances (1976).
G17. Kirk-Othmer Encyclopedia of Chemical Technology. Edited
Standen,A(ed.),Interscience Publishers, New York (1963, 1972).
G18. Survey of Compounds Which Have Been Tested for Carcinogenic
Activity Through 1972-1973 Volume. DHEW Publication No.
NIH73-453, National Cancer Institute, Rockville, Maryland.
G19. Criteria for a Recommended Standard - Occupational Exposure
to .... / prepared oy NIOSH .
G20. Suspected Carcinogens - A subfile of the NIOSH Toxic Sub-
stance List (1975).
G21. The Condensed Chemical Dictionary, £ in 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. Synthetic Organic Chemicals, United States Production and
Sales. 1966-76. U.S. International Trade Commission, U.S.
Government Printing Office, Washington, D.C.
G25. Lowenheim, F.A. & Moran, M.K. Faith. Keyes, and Clark's
Industrial Chemicals, 4th ed. John wiley & Sons, New York
(1975) .
G26. Gosselin, Hedge, Smith & Gleason. Clinical Toxicology of
Commercial Products, 4th ed. The Williams and Wilkins Co.,
Baltimore (1976).
G27. Chemical Consumer Hazard Information System. Consumer Product
Safety Commission, Washington, D.C. (1977).
G28. U.S. Environmental Protection Agency, Office of Toxic Substances,
A study of industrial data on candidate chemicals for testing.
EPA, November 1976; August, 1977.
^29. National Occupational Hazards Survey (NOHS). National
Institute for Occupational Safety and Health, Cincinati
Ohio (1976).
G30. The Aldrich Catalog/Handbook of Organic and Biochemicals.
Aldrich Chemical Co., Inc. (1977-78) .
XI-2
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G31. McCutcheon's Functional Materials 1977 Annual. McCutcheon
Division, MC Publishing Co. (1977) .
G32. Hampel & Hawley. The Encyclopedia of Chemistry, 3rd ed.
Van Nostrand Reinhold Co., New York (1973).
G33. Casarett, L. J. & Doull, J. Toxicology, the Basic Science
of Poisons. Macmillan Publishing Co., Inc., New York (1975)
G34. EPA/Office of Research and Development, Chemical Production.
G35. CTCP/Rochester Computer Service. (See Reference No. G26.)
G36. Leo, A., Hansch, C. & Elkins, D. Partition coefficients
and their uses. Chem. Rev. 71:525-616 (1971).
G37. 1977-78 OPD Chemical Buyers Directory.
G38. Patty, F.A. Industrial Hygiene and Toxicology.. Vol. 2, 2nd ed.
Wiley Interscience, New York (1963) .
G39. Directory of Chemical Producers. Stanford Research Institute,
Menlo Park, California (1977).
XI-3
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APPENDIX B
KEY TO ABBREVIATIONS
TCLo - Lowest published toxic concentration
- the concentration of a substance in air which has
been reported to produce any toxic effect in animals
or humans over any given exposure time.
TDLo - Lowest published toxic dose
- the lowest dose of a substance introduced by any
route other than inhalation over any 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, other than
an LC50, in air that has been reported to have
caused death in humans or animals over any given
exposure time.
LDLo - Lowest published lethal dose
- tha lowest dose of a substance other than LD50
introduced by any route other than inhalation over
any given period of time that has been reported to
have caused death in humans or animals.
LC50 - Median lethal concentration
- the concentration of a test material that kills 50
per cent of an experimental animal population
within a given time period.
LD50 - Median lethal dose
- the dose of a test material, introduced by any route
other than inhalation, that kills 50 percent of an
experimental animal population within a given time
period.
LT50 - Median Lethal Response Time
-Statistical estimate of the time from dosage to the
death of 50 percent of the organisms in the population
subjected to a toxicant under specified conditions.
TLm - Median tolerance limit
- the concentration of a test material at which 50 per
cent of an experimental animal population are able
to 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.
XI-4
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TLv-TWA - Threshold limit value - time weighted average
- the time-weighted average concentration of a
substance for an 8-hour workday or 40-hour
workweek, to which nearly all workers may be
repeatedly exposed, day after day, without
adverse effect.
TLV^STEL- Threshold limit value - short term exposure limit-
- the maximal concentration of a substance to which
workers can be exposed for up to 15 minutes
without suffering acute or chronic toxic effects.
No more than four excursions per day are per-
mitted. There must be at least 60 minutes
between exposure periods. The daily TLV-TWA
must not be exceeded.
BOD - Biochemical oxygen demand
- a measure of the presence of organic materials
which will be oxidized biologically in bodies
of water.
NOHS Occupational Exposure:
- Rank
- an ordering of the approximately 7000 hazards
occurring in the workplace from most common to
least common
- Estimated number of persons exposed
- includes full- and part-time workers. For hazards
ranked 1 through 200, the figure projected to
national statistics by NIOSH is given; for the re-
maining hazards the number of people exposed given
in the survey was multiplied by a fixed number to
give a rough estimate of national exposure. The
fixed number used, —30—, is derived from the sta-
tistical sampling technique used in this survey.
i - insoluble
ss - slightly soluble
s - soluble
vs - very soluble
00 - soluble in all proportions
bz - benzene
chl - chloroform
XI-5
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eth - ether
peth - petroleum ether
ace - acetone
lig - ligroin
ale - alcohol
CC1, - carbon tetrachloride
dil. alk. - dilute alkalis
CS2 - carbon disulfide
os - organic solvents
oos - ordinary organic solvents
XI-6
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BIBLIOGRAPHIC DATA I.RebortNo. 2.
SHEET FPA 560-10-78-001
4. Title and Subtitle
Initial Report of the TSCA Interagency Testing Committee
and Information Dossiers on Substances Designated
7. Author(s)
9. Performing Organization Name and Address
Clement Associates, Inc.
1055 Thomas Jefferson St., N.W.
Washington, D.C. 20007
12. Sponsoring Organization Name and Address
National Science Foundation and
Environmental Protection Agency
Washington, D. C-
3. Recipient's Accession No.
PB~-275 36~7 "
5. Report Date i
October 1977
6.
8. Performing Organization Rep;.
No.
10. Project/Task/Work Unit No.
11. Contract/Grant No.
NSF-C-ENV 77-15417
13. Type of Report & Period
Covered
14.
15. Supplementary Notes
Project Officer - Carter Schuth, National Science Foundation
16. Abstracts
17. Key Words and Document Analysis. 17o. Descriptors
7b. Identifiers/Open-Ended Terms
Interagency Testing Committee Initial Report
Toxic Substance Control Act
7c. COSATI Field/Group
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