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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                       - 2 -
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
t
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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
                                  10

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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.
                                 12

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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.
                                 14

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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.
                                   15

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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.
                                   16

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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.
                                 17

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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).
                                 20

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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.
                                  24

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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.
                                25

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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

-------
    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

-------
Factor 6:  Bioaccumulation

    a.  Numerical Scores Assigned:

        3   High

        2   Appreciable

        1   Low (
-------
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

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    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

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   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

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                            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.

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                    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

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                                                 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

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                                                 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

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                         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

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to be mutagenic in several test systems.  Teratogenicity data on
epoxides are not available in the literature.
                                1-2

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                               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

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     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

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                                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

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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

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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

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                               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

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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

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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

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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

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                                                          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

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                      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

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                           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

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     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

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                           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

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     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

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                             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

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                             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

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                        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

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                      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

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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

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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

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                          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

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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

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                        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

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                        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

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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

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                        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

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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

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                        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

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                              REFERENCES
 1.  Metcalf, R.L., Booth, G.M., Schuth, C.K., Hansen, D.J., and Lu, P.
     Uptake and fate of di-2-ethylhexyl phthalate in aquatic organisms
     and in a model ecosystem.  Env. Kith. Persp. 3:27-34 (1973).

 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

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                                                  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

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               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

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             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

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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

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              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

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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

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               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

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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

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               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

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     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

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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

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     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 £.

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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

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     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

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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

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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

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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

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 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

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 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

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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

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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

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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

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2.10  Current Testing





      2-Dichlorbbenzene has been tentatively selected for testing by the



NCI.  Route and species are not specified (G12).
                                  111-34

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                                  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

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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

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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

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      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

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     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

-------
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

-------
              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

-------
                         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

-------
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

-------
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

-------

-------
                          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

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                             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

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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

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                          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

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                        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

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                        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

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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

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                          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

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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

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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

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                                    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

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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

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                            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

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     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

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                             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

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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

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                                                      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

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                         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

-------

-------
                    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

-------
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

-------
                         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

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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

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(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

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                      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

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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

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     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

-------
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

-------
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

-------
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,
     their toxicity and potential dangers, a review of the litera-
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 3.   Andreeshcheva, N.G.  Maximum permissible concentration of ni-
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 4.   Ravault,  P., Bourret, J.  and Roche, L.  Deux intoxications
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 5.   Cartwright, N.J. and Cain, R.B.  Bacterial degradation of
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 6.   Ferster,  L.N.  Morphological changes in the chorion and pla-
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 7.   Yordanova, F., Perfanov, K., Uzunov, P. and Slivkova, L.
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 8.   Zenk, H.   Occupational vestibular damages.  (German) Z. Aerztl.
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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
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1?.   Labunskii, V.V.  Effect in experiments of aromatic nitro,
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     (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
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16.  Papageorgiou, G. and Argoudelia, D.  Cation dependent quenching
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17.  Kazakova, M.I.  Sanitary-hygienic evaluation of nitrobenzene
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18.  Nakotchenko, V.N. and Akhemetov, Z.B.  Adrenal cortex function
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19.  Andreeshcheva, N.  Features and criteria of the toxic action
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20.  Khanin/ A.G.  Pathohistological changes in the central
     nervous system and viscera of experimental animals  after
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     Inst. Usoversh.  Vrachei 135:97-106  (1969)

21.  Smith, H.F., Jr., Weil, C.S., West, J.S. and Carpenter, C.P.
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22.  Magos, L. and Sziza, M.  Effect of p_-nitrobenzaldehyde
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23.  Goldstein, I. and Popovici, C.  Action on nitrobenzene on blood
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24.  Salmowa, J., Piotrowski,  J. and Neuhorn, U.  Evaluation of
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     J. Ind. Med. 20(l):41-49 (1963).


25.  Zvezdai, V.I.  Comparative diagnostic value of various patho-
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     chloride derivatives.  (Russian) Farmakol. Tokskol. (Kiev)
     7:159-162 (1972).
                            VIII-21

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26.  Kazanina, S.S.  Histochemical study of mucopolysaccharides
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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
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     93-96 (1968).

29.  Vasilenko, N.M. and Zvezdai, V.I.  Comparative evaluation
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30.  Smith, R.P. Alkaitis, A.A. and Shafer, P.R.  Chemically
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31.  Hashimoto, T.  Changes of methemoglobin with daily adminis-
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32.  Dorigan, J. and Hushon, J.  Air pollution assessment of nitro-
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33.  Bringmann, G.  and Keuhn, R.  Biological decomposition of
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36.  Piotrowski, J.  Further investigations on the evaluation
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     (1967) .

37.  Hyslak, Z., Piotrowski, J.K. and  Ilusialowicz, E. Acute
     nitrobenzene poisoning.  Arch. Toxicol. 28 (3) : 208-312  (1971).
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38.   Pisharn,  V.   Experimental  nitrobenzene  intoxication.   Igiena
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39.   Lu,  P.  and Metcalf,  R.   Environmental fate  and  biodegradability
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40.   Pinching, A.J.,  Doeving, K.B.   Selective  degeneration in
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41.   Barnhart, E.L.  and Campbell/ G.R.   The  effect of  chlorination
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42.   Boswer, B.B., Plant  Environmentalist for  American Cyanamid.
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43.   Yordanova, F.,  Perfanoc, K. , Uzunov, P.,  and  Slivkova,  L.
      Hematological changes caused by chronic nitrobenzene  exposure.
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45.   Malaney,  C.W. and  McKinney, R.C.   Oxidative abilities of
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46.   Allen,  L.A.  The effect  of  nitro-compounds and some  other
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      (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

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                             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

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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

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             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

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 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

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                        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

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                              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

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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

-------
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

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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

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                             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

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                             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

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                                 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

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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

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            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

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                                   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

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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

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                                   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

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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

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                                   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

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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

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                                            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

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                       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

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                               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

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     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

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     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

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                                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

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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

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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

-------
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                             X-28

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-------
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                          X-30

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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
     concentrations of xylene.  Vrach. Delo. 8:109-111 (1968).

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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