&EPA
United States
Environmental Protection
Agency
Office of Pesticides
and Toxic Substances
Washington DC 20460
EPA 560/2-89-001
March 1989
Preliminary Evaluations
of Initial TSCA
Section 8(e)
Substantial Risk Notices
January 1987 - December 1968
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NOTICE TO ADMINISTRATOR OF SUBSTANTIAL RISKS. Any person who
manufactures, [imports,] processes, or distributes in commerce a
chemical substance or mixture and who obtains information which
reasonably supports the conclusion that such substance or mixture
presents a substantial risk of injury to health or the environ-
ment shall immediately inform the [EPA] Administrator of such
information unless such person has actual knowledge that the
Administrator has been adequately informed of such information.
-- section B(e), Toxic Substances Control Act (1976)
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EPA 560/2-89-001
MARCH 1989
PRELIMINARY EVALUATIONS OF INITIAL
V
TSCA SECTION 8(e) SUBSTANTIAL RISK NOTICES
JANUARY 1, 1987 TO DECEMBER 31, 1988
Office of Toxic Substances
Office of Pesticides and Toxic Substances
Washington, D.C. 20460
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDES AND TOXIC SUBSTANCES
WASHINGTON, D.C. 20460
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Disclaimer
This volume has been reviewed by the Office of Pesticides and
Toxic Substances (OPTS), U.S. Environmental Protection Agency,
and approved for publication. The status reports contained in
this volume present the Agency's preliminary evaluations of the
submitted information and do not represent final Agency policy or
intent with respect to the submissions or subject chemicals. The
mention of company names, trade names, or commercial products
does not constitute an Agency endorsement or recommendation for
or against use.
ii
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Foreword
This volume contains, in ascending submission number order,
"status reports" (i. e. , preliminary evaluations) prepared by
staff of the Office of Toxic Substances (OTS) in the Office of
Pesticides and Toxic Substances (OPTS) for initial submissions
received by the Agency from chemical manufacturers, importers,
processors, distributors and others between January 1, 1987, and
December 31, 1988, pursuant to section 8 (e), the "substantial
risk" information reporting provision of the Toxic Substances
Control Act (TSCAi 90 Stat. 2029, 15 U.S.C. 2607(e)). Status
reports are prepared by OTS for all initial TSCA Section 8 (e)
submissions and reflect only part of the initial phase of the OTS
evaluation process for such information.
This volume is being distributed through the TSCA Assistance
Office (TAO) in OTS/OPTS. Persons wishing to obtain a copy of
this volume of section 8(e) status reports should write to:
TSCA Assistance Office (TS-799)
u.S. Environmental Protection Agency
401 "M" Street, S.W.
Washington, D.C. 20460
EPA plans to print a limited number of copies of this volume.
Once EPA's supply is exhausted, copies can be purchased through
the National Technical Information Service (NTIS), 5285 Port
Royal Road, Springfield, Virginia 22161. Copies of the five
previously published TSCA section 8(e) status report compendiums
(PB# 80-221609, PB# 81-145732, PB# 83-187815, PB# 87-129409 and
PB# 87-176004) are currently available through NTIS.
The Agency welcomes the submission of additional information for,
or comments on, the evaluations presented in this volume. The
submission of unpublished information relating to biological or
environmental effects, production/importation volumes, use(s),
and worker, consumer, and environmental exposure to the subject
chemical substances and mixtures would be especially valuable.
Such information will be considered at subsequent steps in the
OTS chemical assessment process. The submission of additional
information for, or comments on, these evaluations should be
directed to:
Mr. Frank D. Kover (TS-778)
Chief, Chemical Screening Branch
Existing Chemical Assessment Division
Office of Toxic Substances/OPTS
U.S. Environmental Protection Agency
401 "M" Street, S.W.
Washington, D.C. 20460
iii
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Non-confidential versions of section 8 (e) submissions and EPA
status reports can be viewed in the OPTS public files located at
EPA Headquarters, Room G-004 Northeast Mall, 401 "M" Street S.W.,
washington, D. C. Copies of TSCA section 8 (e) submissions and
status reports can be obtained by writing to EPA' s Freedom of
Information Office at the following address:
Freedom of Information Office
u.S. Environmental Protection
401 "M" street, S.W.
Washington, D.C. 20460
(A-101)
Agency
This and previous volumes of status reports have been published
by EPA for two reasons. First, volumes of status reports will
make reported information more accessible. Second, such volumes
may, by providing specific examples of submitted information and
EPA's evaluation of that information, help those persons subject
to section 8(e) understand better the types of information that
should be submitted.
It is important to note that EPA's overall implementation of TSCA
section 8(e) has resulted in heightened chemical industry aware-
ness of the potential risks posed by chemical substances. This
heightened awareness has led in many cases to voluntary corporate
actions designed to protect human health or the environment. For
example, many companies have reported that in direct response to
submitted section 8 (e) data, the following types of voluntary
health and environmental protection measures were initiated:
o
formal notification of others (e.g., workers, customers)
about the reported data by way of letters and modifications
to product labels and Material Safety Data Sheets;
o
changes made in manufacturing, processing and handling
procedures to reduce or eliminate chemical exposure;
o
use or production of chemicals
discontinued altogether; and
halted
temporarily
or
o
additional toxicologic and monitoring studies undertaken to
improve understanding of chemical toxicity or exposure.
The chemical industry's increased awareness of potential risks is
evidenced further by EPA's receipt thus far of over 670 voluntary
"For Your Information" (FYI) submissions that contain valuable
toxicologic, exposure and vo tary risk reduction information.
h J. Merenda, Director
ting Chemical Assessment DivisionjOTS
iv
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Acknowledgment
In preparing the status reports contained in this compendium,
EPA's Office of Toxic Substances (OTS) has frequently found it
necessary to request additional information about, or clarifi-
cation of, the submitted data. OTS appreciates the efforts and
cooperation of the following companies, agencies and organiza-
tions that have submitted information reflected in this volume:
3M Company
American Cyanamid Company
American Telephone and Telegraph Company
Antimony Oxide Industry Association
Amoco Chemical Company
Amoco Corporation
Amoco oil Company
Atlantic Richfield Company
BASF Corporation
Boeing Company
Borg-Warner Chemicals, Inc.
Chemical Manufacturers Association
CIBA-GEIGY Corporation
Dow Chemical Company
Dow Corning Corporation
Eastman Kodak Company
E. I. DuPont de Nemours & Company, Inc.
Eli Lilly and Company
Gelman Sciences Inc.
General Electric Company
Henkel Corporation
Hoechst Celanese Corporation
International Isocyanate Institute, Inc.
Koppers Company, Inc.
Lever Brothers Company
Mobay Corporation
Mobil Research and Development Corporation
Monsanto Company
National Toxicology Program
Olin Corporation
Pennzoil Company
PPG Industries, Inc.
Procter & Gamble Company
Reilly Tar & Chemical Corporation
Sandoz Crop Protection Corporation
Shell oil Company
Society of the Plastics Industry, Inc.
Stauffer Chemical Company
Texaco Inc.
Union Carbide Corporation
Valent U.S.A. Corporation
vista Chemical Company
Wacker Chemicals (USA), Inc.
Westvaco Corporation
Xerox Corporation
v
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Contents
Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. i i i
Acknowledgment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
v
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
section 8(e) Submission Review Process Diagram ..............
4
status Reports 8EHQ-0187-0649 S through 8EHQ-1288-0778 ......
5
Appendix A.
section 8(e) Policy statement (43 FR 11110) .... 492
Technical Amendment citation (52 FR 20083) ..... 499
Appendix B.
status Reports Listed by CAS Number ............ 500
Appendix C.
status Reports Listed by Chemical Name ......... 521
Appendix D.
status Reports Listed by Information Type ...... 552
Appendix E.
status Reports Listed by Submission Number ..... 561
Report Documentation Page ................................... 581
vii
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Introduction
Section 8(e) of the Toxic Substances Control Act (TSCA; the Act)
states that "any person who manufactures, [imports,] processes,
or distributes in commerce a chemical substance or mixture and
who obtains information which reasonably supports the conclusion
that such substance or mixture presents a substantial risk of
injury to health or the environment shall immediately inform the
[EPA] Administrator of such information unless such person has
actual knowledge that the Administrator has been adequately
informed of such information."
In view of the fact that section 8 (e) was self-implementing
(i.e., required no implementing rules), chemical manufacturers,
importers, processors and distributors became subject to the
Section 8(e) reporting provision as of January 1, 1977, the
effective date of TSCA. In order to clarify the types of informa-
tion to be submitted and the procedures for doing so, the Agency
(following receipt and review of public comments) published its
TSCA Section 8(e) policy statement ("Statement of Interpretation
and Enforcement Policy; Notification of Substantial Risk" 43 FR
11110; March 16, 1978). For easy referral when using this volume,
EPA's TSCA Section 8(e) policy statement has been reproduced as
Appendix A in the back of this volume.
The March 16, 1978 TSCA section 8(e) policy statement expresses
the Agency's policy that the information subject to section 8(e)
reporting is any "new" information that "reasonably supports" a
conclusion that a chemical substance or mixture presents a sub-
stantial risk of injury to health or the environment but need not
necessarily indicate conclusively that such a risk exists. A
determination of "substantial risk" does not include an evalu-
ation of economic or social benefits of the use of the chemical
and, therefore, is not synonymous with the term "unreasonable
risk" which is found in other sections of the Act. Although
EPA's receipt of information under section 8(e) of TSCA does not
necessarily trigger immediate regulatory action, the information
that is submitted under TSCA section 8(e) does receive priority
review and evaluation by EPA in order to determine an appropriate
course of Agency action.
Thus far, EPA and the chemical industry have devoted significant
efforts in fulfilling their respective responsibilities under
section 8(e) of TSCA. Since January 1, 1977, approximately 780
initial TSCA section 8(e) submissions covering a broad range of
toxici ty and exposure-related information on a wide variety of
chemicals have been received and given priority evaluation and
follow-up attention by the Office of Toxic Substances (OTS) in
EPA's Office of Pesticides and Toxic Substances (OPTS). (The OTS
TSCA section 8(e) submission review process is shown on page 4.)
In general, each initial TSCA Section 8(e) submission is promptly
reviewed and evaluated by OTS scientific staff to determine both
1
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the degree of concern that should be attached to the submitted
information and the initial course of any warranted OTS follow-up
action(s). A "status report" is prepared which contains a brief
description of the submitted information, the results of the OTS
preliminary evaluation, a statement with respect to the produc-
tion and use of the subject chemical(s), and the recommendations
for appropriate follow-up actions. Upon approval of the status
report, recommended follow-up actions are initiated. A letter
containing the status report and any EPA requests for additional
information is sent to the submitting company. In addition,
copies of all status reports are transmitted to the OPTS public
files, other designated EPA Program Offices and Federal Agencies,
and to the TSCA Assistance Office (TAOjOTSjOPTSjEPA) for further
distribution. Other OTS follow-up actions include consideration
of further, more in-depth assessment of the reported chemical
hazard or risk. It should be noted also that OTS immediately
reviews, evaluates, and initiates appropriate follow-up actions
or activities for all information contained in "follow-up" and
"supplemental" TSCA Section 8(e) notices. By definition, follow-
up notices are those that contain information submitted directly
in response to an EPA request, whereas supplemental notices are
those that contain information not specifically requested by EPA.
A Document Control Number is used by EPA to identify TSCA section
8(e) submissions and takes the following form: 8EHQ-0000-0000.
Starting at the left, the first four symbols identify the infor-
mation as a section 8(e) submission received by EPA Headquarters;
the next four digits identify the month and year (e.g., -0588-)
of the Agency's receipt of the information; the final four digits
identify the submission's chronological number. In addition to
the basic numerical sequence, additional characters may be added
to the right end of the Document Control Number to convey other
information. These additional characters and their meaning are
as follows:
S:
P:
indicates that the TSCA section 8 (e) submission
was sanitized to delete information that was
claimed by the submi tting company to be TSCA
Confidential Business Information (TSCA CBI) ;
indicates that the TSCA section 8 (e) submission
contained names or other identification (e.g.,
Social Security Numbers) of individuals, the
release of which may violate the Privacy Act (such
documents are sanitized to remove an individual's
name or other identifiers); and
* :
indicates that, based on a preliminary evaluation,
the submission was considered by the Agency to be
unwarranted for reporting pursuant to section 8(e)
of TSCA.
2
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When reviewing the status reports contained in this volume, the
reader should realize that the purpose of the OTS preliminary
evaluation is to determine the significance of the submitted
information in terms of a need for possible follow-up action by
the Agency. This determination involves a critical analysis of
the submitted data to assess the extent that the reported hazard
or risk is supported by the provided information. The scope of
this initial evaluation, however, is generally limited to the
submitted documents and to any closely related information known
by the OTS reviewer. Neither a literature search to identify
other reported effects nor an in-depth analysis of possible
sources of exposure to subject chemicals is part of the evalua-
tion process. Therefore, a status report should be viewed only
as a preliminary evaluation of the submitted information and not
as a comprehensive assessment of the chemical substance or mix-
ture for which a TSCA Section 8(e) notice has been filed.
3
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ProcessinQ of 8(e) Notices of Substantial Risk
-.-._.._-------------------------------~
I I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
,
I
I
I
I
I
I
I
I
I
: Claim
L . . . . . - - - . - - . - - - - - - .Wailled.
TSCA CBI Procedures
In Effect; Only Authorized
Persons Involved in Process
Public File
IMD: Information Management Dlvision/OTS
CRIS: Chemical Risk Identification Section/CSB
HERD: Health & Environmental Review Division/OTS
CSB: Chemical Screening Branch/ECAD/OTS
OGC: OHice of General Counsel
OCM: OHice of Compliance Monitoring
DCO: Document Control Office/IMD
OTS: OHice of Toxic Substances
ECAD: Existing Chemical Assessment Division/OTS
CBI: Confidential Business Information
David R. Williams
Section 8(e) Coordinator
Telephone: (202) 382-3468
FTS: 382-3468
James F. Darr
Section Head/CRIS/CSB
Telephone: (202) 382-3470
FTS. 382-3470
Frank D. Kover
Branch Chief/CSe
Telephone: (202) 382-3436
FTS 382-3436
Production
Use
Exposure
Chem. Eng.
Review
Consult
OCM
OGC
IMD
Distribution
Appropriate File
Confidential
Public
Foliowup
Letter to
Submitter
EPA
CPSC
FDA
NIOSH
OSHA
Others
Further
Information
Requested
No
Information
Requested
Etc.
4
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
FEB 2 5 1987
Page 1 of 2
SUBJECT:
;:;t"'J.tus Report*
8EHQ-0187-0649 S
ADProved:~
~2-<5f7
FROM:
James F. Darr, Sect ion Head ~MJ." r ~
Chemical Risk Identification~~~~ion/CSB
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company claimed its name and the exact identity of
the subject chemical to be TSCA Confidential Business Information
(TSCA CBI). The Information ~1anagement Division (Irm/OTS) will
ask the submitting company to substantiate these TSCA CBI claims.
In the "sanitized" version of this TSCA Section 8(e) notice, the
submi tter reported non-confidentially that the subject chemical
was an "alkoxylated aromatic diamine" currently in research and
development (R&D) and intended for commercialization.
Submission Description
The submitting company reported that a crude preparation of the
subject chemical, when tested in an Ames Salmonella typhimurium
(bacteria) mutagenicity assay, was found to be positive in strain
TA 1538 in the presence of metabolic activation. A partially
puri f i ed (i. e., semi-crude) sample tes ted in the Ames assay was
reportedly positive in strains TA 1538, TA 100, and TA 98 in the
presence of metabolic activation. According to the submitting
company, this semi-crude material was non-genotoxic when tested
in an in vitro Unscheduled DNA Synthesis (UDS) assay using rat
hepatocytes. The submitter reported that the semi-crude material
was tested also in an in vitro Chinese Hamster Ovary (CHO) cell
mutagenici ty assay and 'was non-mutagenic in the presence of meta-
bolic activation. In the absence of activation in the CHO cell
assay, the submitter reported that the semi-crude preparation was
posi ti ve at certain doses but a dose-response was not observed.
According to the submitter, the testing laboratory classified the
posi tive CHO cell assay findings as be ing "suspect." The sub-
mi tting company reported further that a "highly purified" sample
of the semi-crude material was tested alone and as a "blend" in
the Ames assay and was found to be negative with and without
metabolic activation. In conclusion, the submitter stated that
the observed mutagenic acti vi ty could be due to an impuri ty in
the prepara tion.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chem;cal(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
5
EPA FORM 1320-6 (REV. 3-76)
-------
8EHQ-0187-0649 S
Page 2 of 2
Submission Evaluation
In order for EPA to eval uate the overall signif icance of the
reported find ings, the submi t ter should be asked to ensure that
the Agency rece ives full copies of the final reports (including
the actual experimental protocols, data, resul ts of statistical
analyses, etc.) from all of the studies cited in this submission.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information with
regard to the current TSCA Chemical Substance Inventory status of
the subject material will appear in this status report.
Comments/Recommendations
The submitting company reported that its R&D personnel have been
notified about the reported findings.
Although a positive in vitro genotoxicity test finding, when
considered by itself, may not be sufficient to offer reasonable
support for a conclusion of substantial risk (as defined in EPA's
TSCA Section 8(e) policy statement ("Statement of Interpretation
and Enforcement Policy; Notification of Substantial Risk" 43 FR
11110; March 16, 1978», EPA does believe that such a finding is
of value in assessing the possible risk(s) posed by exposure to
the tested chemical or mixture. Also, EPA believes that a posi-
tive genotoxicity test result, in combination with additional
information (e.g., the knowledge of potential/actual exposure to
and/or high production of the tested chemical or mixture), would
suggest a need, in many cases, to conduct other studies designed
to determine better the toxicity of and/or the exposure to that
chemical or mixture. The results of such additional tests should
be considered also for submission to EPA under Section 8(e).
a)
The Chemical Screening Branch will ask the submi t ting
company to ensure that the Agency receives full copies
of the final reports (including the actual experimental
protocol s, data, resul ts of any stat is tical analyses,
etc.) from all studies that were cited in the company's
Section 8(e) notice. In addition, the submitter will be
asked to keep the Agency apprised about the results of
further studies conducted by the company to determine
the cause(s) of the observed mutagenic activity.
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical(s).
b)
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
6
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UNITED STATES ENV"IRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
JAN 2 9 1987
SUBJECT: Status Report * 8EHQ-018 7-0 650 Approved: (/t)0- l~ft7
FROM: James F. Darr, Sect ion Head 11.- ~. f7 ~
Chemical Risk Identification~iOnjCSB
TO: Frank D. Kover, Branch Chief
Chemical Screening BranchjECADjOTSjOPTS
Submission Description
On behal f of the "Vinyl Acetate Task Force" (the Union Carbide
Corporation, the U.S. Industrial Chemicals Company, the Celanese
Corpora tion and E. I. DuPont de Nemours & Company, Inc.), the
Society of the Plastics Industry, Inc. (SPI) provided the follow-
ing information regarding the conduct and preliminary results of
a two-year inhalation study of vinyl acetate (CAS No. 108-05-4)
in rats:
"In this [inhalation] study, groups of Sprague-Dawley
rats were exposed to concentrations of vinyl acetate of
0, 50, 200 and 600 ppm for six hours a day, five days a
week for two years. A preliminary pathology report shows
10 tumors have been observed in the nasal cavities in
the 77 high dose animals examined. Two of those tumors
were squamous cell carcinomas~ the balance were papil-
lomas. No tumors were observed in the other exposure
concentrations or in the control animals."
It should be noted that in a previous TSCA Section 8(e) notice
(8EHQ-l086-0642), SPI submitted the following information with
regard to the conduct and preliminary findings from a two-year
inhalation study of vinyl acetate in mice:
"Groups of 90 CD-l mice were exposed to concentrations
of vinyl acetate of 0, 50, 200 and 600 ppm for six hours
a day, five days a week, for two years. The preliminary
pa thology rev iew. . ind ica ted that the only adverse
effects observed were in the respiratory tract. Mice
exposed to the 600 ppm level exhibited bronchiolar epi-
thelial lesions in the lung which included one animal
with one squamous cell nodule of a terminal bronchial
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
7
EPA FORM 1320-6 (REV. 3-76)
-------
8EHQ-0187-0650
Page 2 of 3
airway and another animal with one squamous cell car-
cinoma in a major airway. No such tumors were observed
at the other exposure [concentrations] or in the
control animals. The 50 ppm concentration appeared to be
a no observable effect level."
Submission Evaluation
Immediately upon receipt of these TSCA Section 8(e) submissions,
the Chemical Screening Branch (CSB/ECAD/OTS) provided copies of
the notices to the Risk Analysis Branch (RAB/ECAD/OTS) for inclu-
sion in the ongoing review of available toxicologic and exposure
data on vinyl acetate.
The Agency has received a number of TSCA Section 8(e) and "For
Your Information" (FYI) notices on vinyl acetate. It should be
noted also that the Chemical Screening Branch prepared (in 1984)
a Chemical Hazard Information Profile (CHIP) on vinyl acetate.
Finally, it should be noted EPA published (on December 27, 1985)
a TSCA Section 8(d) information gathering rule on vinyl acetate
(50 FR 52923).
Current Production and Use
A review of the production range (includes importation volumes)
statistics for vinyl acetate (CAS No. 108-05-4), which is listed
in the initial TSCA Chemical Substance Inventory, has shown that
521 million to 2.6 billion pounds of this chemical were reported
as manufactured/imported in 1977. This production range informa-
tion does not include any data claimed to be TSCA Confidential
Business Information (CBI) by the person(s) reporting for the
initial TSCA Inventory, nor does this production range informa-
tion include any data that would compromise TSCA CBI. All of the
information reported for the initial TSCA Inventory, including
the production range data, is subject to the limitations con-
tained in the TSCA Inventory Reporting Regulations (40 CFR 710).
According to Chemical & En~ineering News (June 9, 1986 issue),
2.02 billion and 2.11 bil110n pounds of vinyl acetate were pro-
duced in the U.S. during 1984 and 1985, respectively. According
to secondary 1 i tera ture sources, the major use of v inyl acetate
is in the production of polymers (e.g., poly(vinyl acetate),
poly(vinyl alcohol), vinyl chloride copolymer, ethylene-vinyl
acetate copolymers).
Comments/Recommendat!ons
To date, EPA has received a number of Section 8(e) submissions
from trade associations on behalf of their member companies. In
the ,Comments/Recommendations section of the status report that
was prepared by EPA in response to Section 8(e) submission 8EHQ-
0185-0543, the Agency reiterated its position with regard to the
TSCA Section 8(e) reporting obligations of trade associations and
their member companies.
8
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8EHQ-0187-0650
Page 3 of 3
In the present TSCA Section 8 (e) notice, SPI stated that copies
of future interim reports and the final report from the chronic
vinyl acetate inhalation study in rats will be provided to EPA as
soon as those reports become available.
a)
The Chemical Screening Branch will ask SPI to ensure
that copies of this status report are provided to the
U.S. co-sponsors of the cited two-year inhalation study
of vinyl acetate in rats. SPI will be asked also to en-
sure that EPA receives a full copy of the final report
(including the actual experimental protocol, results of
gross and histopathological examinations, results of any
statistical analyses performed, etc.) from this two-year
vinyl acetate inhalation study in rats.
b)
As in the case of the initial Section 8(e) submission,
the Chemical Screening Branch will immediately send all
reported information to the Risk Analysis Branch for in-
clusion in their ongoing review of available toxicologic
and exposure data on vinyl acetate.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS and RAB/ECAD/OTS. In
addition, copies of this report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
9
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
MAR
2 1987
Page 1 of 2
SUBJECT:
Status Report * 8EHQ-0187-0651 Aoproved: ~
James F. Darr, Section Head (lA.,,,,,,;J: ~
Chemical Risk Identificatiod7~~~~on/CSB
:)3/11
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Xerox Corporation provided preliminary findings from a study
designed to assess the mortality experiences of Xerox service and
manufacturing workers employed by Xerox from 1960 to 1982 with a
followup performed to the end of 1984. In the cover letter to
the submission, Xerox presented the following summary regarding
the study findings:
"A preliminary analysis of mortality data conducted by
Xerox Corporation identified two clusters involving an
increased risk of cancer of the stomach and esophagus
respectively. [with] only the former being statistically
significant. No correlation with any chemical or group
of chemicals is known or suspected. Similarly; no corre-
lation between job category or work location could be
determined. Efforts will continue to define the causal
factors, if any, in the workplace. Efforts are
underway to complete the mortality study in a timely
fashion. "
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported information, Xerox should be asked to ensure that the
Agency is apprised of any significant findings obtained during
the company I s ongoing efforts to identify the cause (s) of the
apparent increases in esophageal and stomach cancer. Also, Xerox
should be asked to ensure that EPA receives a full copy of the
final report from this mortality study upon completion.
====================================================================================
*
NOTE: This status report is the result of a oreliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting orovision of the Toxic Substances Control
~ct (TSCA). The statements made in this report should not be regarded
as expressing final EPA oolicy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
10
EPA FORM 1320-6 (REV. 3-761
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8EHQ-0187-0651
Page 2 of 2
Comments/Recommendations
In addition to completing the cited mortality study, Xerox stated
that Xerox "employees in work groups reflected in the esophagus
and stomach cancer clusters, their supervisors, and their union
representatives in the appropriate work locations will be advised
of the preliminary findings of the study." According to Xerox,
the "discussions with these employees will focus on known risk
factors with respect to cancer in general and stomach cancer spe-
cifically." In addition, Xerox reported that "an assessment of
the work site and potential exposures represented by this group
will be performed" and "will include a systematic review of en-
vironmental and administrative protective measures in place and
the need for additional measures."
According to EPA's March 16, 1978 TSCA Section 8(e) policy
statement ("Statement of Interpretation and Enforcement Policy;
Notification of Substantial Risk" 43 FR 11110), epidemiological
findings involving increased cancer incidence, for example, would
be required to be reported under Section 8(e) "if one (or a few)
chemical (s ) is strongly implicated." Considering that in the
present Section 8(e) submission there is no correlation at this
time with regard to the apparent increased incidence of stomach/
esophageal cancers and job category, job location or chemical ex-
posure(s), the Xerox Corporation's submission does not appear to
have been required under Section 8(e) of TSCA. In making this
statement concerning TSCA Section 8(e)-reportability, the reader
should bear in mind that EPA' s position is based solely on the
submitted information and does not take into account any addi-
tional pertinent information that may have been considered by
Xerox in deciding to submit the subject findings to EPA under
Section 8(e) of TSCA.
a)
The Chemical Screening Branch will ask Xerox to ensure
that EPA is apprised in a timely manner about any sig-
nificant findings obtained during the company's ongoing
efforts to identify the cause (s) of the apparent in-
creased incidence of esophageal/stomach cancers. Xerox
will be asked also to ensure that EPA receives a full
copy of the final report from this mortality study.
b)
The Chemical Screening Branch will review the reported
information in greater detail in order to determine the
need for further OTS assessment of the information at
this time.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH and OSHA. In addition, copies of
this status report will be sent to the TSCA Assistance
Office (TAO/OTS) for further distribution.
11
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
OA TE:
FEB \ 3 \987
SUBJECT: St.a t.us Report. * 8EHQ-028 7-06 52 S Approved: (J;t--
FROM: James F. Darr, Sect. ion Head r r ~
Chemical Risk Ident.ificat.ion Sect.ion/CSB
~j; 7/'?7
I ..
TO:
Frank D. Kover; Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Not.e
(See NOTE on page 3 of this status report)
The At.lant.ic Richfield Company (ARCO) has claimed t.he exact.
ident.it.ies of t.he const.it.uent.s of t.he subject. mixt.ure t.o be TSCA
Confident. ial Business Informat.ion (TSCA CBI). The Informat.ion
Management. Divis ion (IMD/OTS) will request. ARCO t.o subst.ant.iat.e
t.his TSCA CBI claim. In t.he "sanit.ized" version of t.he TSCA
Sect.ion 8(e) not.ice, ARCO report.ed non-confident.ially t.hat. t.he
t.est.ed product. was an amine mixt.ure.
Submission Descript.ion
ARCO submit.t.ed t.he following summary information wit.h regard t.o
the conduct and result.s of primary rabbit skin and eye irrit.at.ion
studies of the subject. amine mixture:
"In the primary dermal irrit.at.ion st.udy, six albino
rabbit.s (2.0 t.o 3.0 kg) had 0.5 ml of t.his product. ap-
plied t.o t.heir shaved backs at. four sit.es, t.wo int.act.
and t.wo abraded. The liquid was held in place by 2.5 em
square gauze pat.ches with tape and t.he t.orso was loosely
wrapped with plastic and secured wit.h adhesive t.ape.
Aft.er 24 hours, the pat.ches, t.ape and wrapping were
removed and each si te was observed and scored for t.he
appearance of irrit.ation and/or corrosion. This
scoring was repeated at 48 and 72 hours and at 7 and 14
days for t.he surviving animals. Based on t.he scores ob-
tained and the eschar noted, this product. was designated
as corrosive to skin.
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be reqarded
as expressing final EPA policy or intent with respect to the subJect
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
12
EPA FORM 1320-6 (REV. 3-761
-------
8EHQ-0287-0652 S
Page 2 of 3
"In addition to these findings, unexpectedly, five out
of six animals died on test: one after 48 hours, two
after 72 hours, one after 96 hours, and one after 10
days. The one remaining rabbit survived 14 days after
treatment and demonstrated healing at the si tes of ap-
plication. Necropsy of the two longest surviving animals
revealed substant ial damage to internal organs. Since
2.0 ml of the product was applied on each rabbit back,
the approx imate dose of this. [amine mix ture] was
0.7 to 1 ml/kg.
"In a second study, the primary eye irritation potential
of th is product was assessed using nine albino rabbi ts
(2.0 to 3.0 kg). Six animals had 0.1 ml of the product
inst illed into the conj uncti val sac of one eye wi thout
any subsequent washout and three were instilled with
this material followed by a washout with lukewarm water
20-30 second s later for about one minute. Rabbi t eyes
were [then] observed and scored by the Draize technique
at 24 and 48 hours. By the 48-hour observation
time after instillation, the treated eyes in all of the
rabbits, regardless of whether they were washed or not,
exh ibi ted pronounced corros ion of the cornea and con-
junctival membranes. Due to these results, the animals
were sacrificed at that time."
In submitting these findings to EPA under Section 8(e), ARCa
stated that the acute toxici ty studies were conducted "due to a
lack of data regarding acute dermal and eye irritation potential
for this product." ARCa stated further that in conducting these
studies, the company "hoped to provide a scientific basis for
representing the product's potential irritation hazards following
acute dermal and eye exposure on its label and on the product
material safety data sheet [(MSDS)]."
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported acute toxicologic findings, ARca should be asked to
ensure that EPA receives complete copies of the final reports
(including the actual experimental protocols, data, resul ts of
gross and histopa tholog ical examinations r etc.) from the acute
primary eye and dermal irritation studies cited in the company's
submission.
Current Prod uct ion and Use
(See NOTE on page 3 of this status report)
In view of ARCa's TSCA CBI claims, no information regarding the
use(s) or TSCA Inventory status of the tested product or its con-
stituents will appear in this status report.
13
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8EHQ-0287-0652 S
Page 3 of 3
Comments/Recommendations
ARCO stated that the current product MSDS reflects the company's
"earlier conservative judgement that this material is likely to
be irritating to skin and eyes on contact. ." In addition,
ARCO stated that the compa.ny believes the "protection recommended
for handling this product also is effective in preventing dermal
absorption which may be responsible, as well, for toxic systemic
effects." ARca stated further that the company was I) updating
the product MSDS to reflect the reported tox icolog ic fi nd ings,
and 2) notifying ARCO workers and customers about those findings.
a)
The Chemical Screening Branch will ask ARCO to ensure
that BPA receives complete copies of the final reports
(including the actual experimental protocols, results of
gross and histopathological examinations, etc.) from the
acute primary dermal and eye irritation studies cited in
the company's Section 8(e) notice. In addition, ARCO
will be requested to provide the CAS Registry Number for
each constituent in the tested amine mixture.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure information, ARCO will be requested to
describe the na ture and resul ts, if available, of all
stud ies (other than those ci ted in the open scienti fic
li"tera ture or those subm i t ted already to the Agency)
about which ARCO is aware or that ARCO has conducted, is
conducting or plans to conduct to determine the toxicity
of or the exposure to the subj ect amine mixture or its
constituents.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the mixture and/or its constituents.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, NTP, FDA, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
NOTE:
In a followup letter dated March 3, 1987, the Alantic Richfield
Company reported non-confidentially that the tradename under which
the subject amine mixture is sold is "Antistat for ArcelTM Resin."
,~~ 2/(gt
14
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
APR 11 1987
Page 1 of 7
SUBJECT:
Status Report* 8EHQ-0287-0653
Frank D. t!~c!:~~
Chemical Screening Branch/ECAD
Aoproved:~P; ~
/
APR I 7 1987
FROM:
TO:
Joseph J. Merenda, Director
Existing Chemical Assessment Division/OTS
Note
On a "For Your Information" (FYI) basis (FYI-OTS-0187-0527), the
CIBA-GEIGY Corporation submitted the following information with
regard to the conduct and preliminary results of a 28-day oral
gavage study of 4-(hydroxymethyl)-4-methyl-l-phenyl-3-pyrazoli-
dinone (Irgaform 1266: Dimezone S: CAS No. 13047-13-7) in rats:
" .[The performed study] shows a dose dependent toxic
anemia with the formation of inclusion bodies, as well
as spermatogenesis reduction with atrophy of the testi-
cular canals in the highest dose group (150 mg/kg bw.).
The animals were treated with 10, 40 and 150 mg/kg by
ga vage: 10 mg /kg proved to be the no obse rvable ef fect
level. The demonstrated findings, especially the sperma-
togenesis reduction, are toxicologically significant.
They show great similarity to the findings which were
obtained for. . .[1-phenyl-3-pyrazolidinone (phenidone:
CAS No. 92-43-3) and submitted previously to EPA by the
Eastman Kodak Company under Section 8(e) of TSCA (8EHQ-
0984-0529 et seq.)J."
In its FYI submission, CIBA-GEIGY 1) stated that it had received
the above information in a "Flash Report" and 2) provided copies
of both the original "Flash Report" (in German) and an English
translation of that report. (Based on the form and substance of
the reports, it appeared to EPA that the Irgaform 1266 28-day
oral gavage study had been conducted by CIBA-GEIGY Ltd., Basel,
Switzerland). In submitting these reports to the Agency on an
FYI basis, CIBA-GEIGY stated that the company would be unable to
judge the real significance or TSCA Section 8(e)-reportability of
the toxicologic findings until a full copy of the final report
from the 28-day study was received and evaluated by the company.
The final report from the Irgaform 1266 28-day oral gavage study
in rats is the subject of the present Section 8(e) submission.
====================================================================================
*
NOTE: This status report is the result of a oreliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be reqarded
as expressing final EPA Dolicy or intent with respect to the sub3ect
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
15
EPA FORM IUO-6 (REV. 3-761
-------
8EHQ-0287-0653
Page 2 of 7
Submission Description
Under Section 8(e) of TSCA, ClBA-GEIGY submitted a complete copy
of the final report from the 28-day study cited in FYl-OTS-0187-
0527. (As anticipated, this study was conducted by ClBA-GEIGY
Ltd. in Switzerland.) In submitting this final report to EPA
under Section 8 (e) of TSCA, ClBA-GEIGY stated that "anemia and
testicular lesions were the primary effects induced in animals
which received the highest [Irgaform 1266] doses (40 and 150
mg/kg/day) by gastric intubation." CIBA-GEIGY stated also that
"the NOEL [( "no observed effect level")] was determined to be 10
mg/kg/day." CIBA-GEIGY stated further that the "primary effects,
while significant, were produced after administration by gastric
intubation and mainly had a minimal grade of severity." Finally,
CIBA-GEIGY reported that the observed toxicologic effects "may be
reversible."
In addition to submitting a full copy of the 28-day study final
report, CIBA-GEIGY provided an updated Irgaform 1266 Material
Safety Data Sheet (MSDS) and product label. According to the
MSDS, Irgaform 1266 has an oral (rat) LD50 of 1000 mg/kg and a
dermal (rat) LD50 of greater than 2000 mg/kg. The MSDS states
further that Irgaform 1266 is minimally irritating to rabbit skin
and moderately irritating to rabbit eyes. With regard to skin
sensitization, the MSDS reports that Irgaform 1266 was positive
when tested in a modified maximization study in guinea pigs "with
2/20 positive after [the] first challenge and 3/19 positive after
[the] second challenge." The MSDS states also that Irgaform 1266
was negative in an Ames Salmonella typhimurium (bacteria) assay.
In addition, the MSDS states that the results of a modified Sturm
Test indicate that Irgaform 1266 is not biodegradable. Finally,
the MSDS reports that Irgaform 1266 has a 96-hour LC50 of 32 ppm
for rainbow trout, a 96-hour LC50 of 43 ppm for zebra fish and a
24-hour EC50 of 7.1 ppm for Daphnia magna.
Submission Evaluation
The information presented in FYI-OTS-0187-0527 (particularly the
English translation of the German "Flash Report") indicates that
Irgaform 1266, when administered orally by gavage to rats for 28
days, produced a toxic anemia with inclusion body formation as
well as reduced spermatogenesis and testicular atrophy at the
highest daily dose administered. Based solely on the information
presented in FYI-OTS-0187-0527, it is quite reasonable to believe
that the observed toxic effects are compound-related especially
when one considers that phenidone (a close structural analog) has
been reported to cause similar adverse effects when administered
via the feed to rats. (The reader's attention is directed to the
status report prepared by the Agency in response to the initial
TSCA Section 8(e) submission (8EHQ-0984-0529) on phenidone.)
A review of the final report from the 28-day oral gavage study of
Irgaform 1266 shows that although no animals died and there were
no outward signs of systemic toxicity, there was a mild, slightly
16
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8EHQ-0287-0653
Page 3 of 7
macrocytic (abnormally large erythrocyte) anemia in both sexes in
the high dose group. The high dose females exhibited anemia with
Heinz bodies and showed decreases in blood cell count, hemoglobin
concentration, and packed cell volume, and increases in mean cor-
puscular volume and mean corpuscular hemoglobin. The same trends
were evident in the high dose male rats. The increased number of
reticulocytes observed in the high dose males and females is a
sign of increased hematopoiesis in order to compensate for the
dec line in red blood cells. Al though no relevant gros s changes
were seen at terminal sacrifice, noteworthy microscopic changes
were found in the male and female rats in the two highest dose
levels. The major microscopic changes were as follows:
Spleen: congestion, hemosiderosis and extramedullary
hematopoiesis in males (40 and 150 mg/kg) and females
(40 and 150 mg/kg)
Li ver: hepatocellular hemosiderosis in females (150
mg/kg) and Kupffer cell hemosiderosis in females (40 and
150 mg/kg)
Kidney (proximal convoluted tubule): partially PAS-
positive eosinophilic bodies in males (40 and 150 mg/kg)
Epididymis: slight occurrence of cellular debris (40
and 150 mg/kg) and bilateral and unilateral spermatic
granulomas (150 mg/kg)
Testis: slight atrophy of the spermatogenic epithelium,
presence of a few spermatogenic giant cells, and slight
hyperplasia of the Leydig cells (150 mg/kg).
Overall, the submitted final report confirms the information
presented in the "Flash Report" that oral (gavage) administration
of Irgaform 1266 for 28-days caused adverse hematopoietic effects
in male and female rats and adverse reproductive organ effects in
male rats. Based on the data contained in the final report, the
no-observable-adverse-effect-level (NOAEL) for Irgaform 1266 in
the 28-day study appears to be 10 mg/kg.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for CAS No. 13047-13-7, which is listed in the initial
TSCA Chemical Substance Inventory, has shown that between 10,000
and 101,000 pounds of this chemical were reported as manufactured
and/or imported in 1977. This production range information does
not contain any information claimed as TSCA Confidential Business
Information (TSCA CBI) by the person(s} who reported for the TSCA
Inventory, nor does it include any information that would compro-
mise TSCA CBI. All of the information reported for the initial
TSCA Inventory, including the production range information, is
subject to the limitations that are contained in the initial TSCA
Inventory Reporting Regulations (40 CFR 710).
17
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8EHQ-0287-0653
Page 4 of 7
According to the submitted MSDS, Irgaform 1266 is a water-soluble
solid with a slight odor and has a melting po~nt of approximately
120°C and a vapor pressure of less than 3XIO- mm Hg at 20°C.
In FYI-OTS-0187-0527, the CIBA-GEIGY Corporation provided the
following information regarding the current production volume and
use of Irgaform 1266:
"Irgaform 1266 is a phenidone derivative used as a
photographic developing agent. . [CIBA-GEIGY has J
imported approximately 1,200 Ibs. over the past two
years, 880 Ibs. of which is still in inventory. Three to
five major potential customers in the U.S. are already
using this chemical substance commercially. Additional-
ly, there are many smaller photographic developing
companies which would purchase developer chemicals con-
taining this substance in solution. The total U. S.
market for the substance, which has been in use commer-
cially for about 20 years, is about 110,000 Ibs."
In its Section 8(e) submission, CIBA-GEIGY reported further that
the "vast majority of this chemical substance used in the U.S. is
produced or imported by other companies. . [and] CIBA-GEIGY is
a very minor supplier to this market." In the TSCA Section 8(e)
notice, CIBA-GEIGY also provided the following information with
regard to the potential for exposure to Irgaform 1266:
"Because. . [Irgaform 1266] is a skin sensitizer, the
recommended handling precautions on . [the MSDS and
label] would result in minimal exposure. These precau-
tions are designed to avoid eye, skin, and inhalation
exposure through engineering controls or the wearing of
perf'>onal protective equipment; i.e., chemical goggles,
impervious gloves, and a NIOSH approved respirator, if
neces sary. "
Finally, CIBA-GEIGY stated in its TSCA Section 8(e) submission
that the major use of Irgaform 1266 is in "professional X-ray
developing [and] the level of this product in commercial
developer solutions is only 1 to 2 gms/Liter, i.e., 0.1 to 0.2%."
According to CIBA-GEIGY, "developer personnel wear impervious
gloves. when handling the product either neat (powder form)
or in solution. II
Comments/Recommendations
At the time of EPA's receipt of this TSCA Section 8(e) notice,
EPA was in the process of preparing a statement outlining EPA's
initial position on the Section 8(e)-applicability/reportabil~ty
of the toxicologic information presented in FYI-OTS-0187-0527.
It is appropriate, therefore, that this status report will serve
as the forum for EPA to present its position on this matter.
18
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8EHQ-0287 -0653-
Page 5 of 7
Based on an EPA review of the toxicologic information contained
in FYI-OTS-0187-0527 alone, EPA believes that the information
(especially the adverse male rat reproductive system findings
presented therein) should have been reported under Section 8(e),
the substantial risk information reporting provision of TSCA.
The basis for EPA's position is as follows:
TSCA Section 8(e) states that "any person who manufac-
tures, [imports,] processes, or distributes in commerce
a chemical substance or mixture and who obtains informa-
tion which reasonably supports the conclusion that such
substance or mixture presents a substantial risk of in-
jury to health or the environment shall immediately in-
form the Administrator of such information unless such
person has actual knowledge that the Administrator has
been adequately informed of such information."
The preface in Part V of EPA' s March 16, 1978 Section
8 (e) policy statement ("Statement of Interpretation and
Enforcement Policy; Notification of Substantial Risk"
43 FR 11110) states that "a substantial risk of injury
to health is a risk of considerable concern be-
cause of (a) the seriousness of the effect. . . and (b)
the fact or probability of. . [the serious effect's]
occurrence. " Regarding the seriousnes s of the effect,
Part V of the TSCA Section 8(e) policy document explains
that the Agency considers the types of health effects
for which substantial risk information must be reported
to include "any pattern of effects or evidence which
reasonably supports the conclusion that the chemical
substance or mixture can produce toxic effects
resulting in . . . serious or prolonged incapacitation."
Information concerning such effects can be obtained
directly or inferred from designed studies (e. g., in
vi vo animal studies) as described in Part VI of the
Section 8(e) policy statement.
With regard to the "fact or probability of . [the
serious effect's] occurrence" criterion, Part V of the
Section 8(e) policy statement explains that certain
types of health effects are considered by EPA to be so
serious that virtually no weight should be attached to
the chemical's exposure in determining whether to report
under Section 8(e) of TSCA. Further, EPA's response to
Comment 31 (see Appendix B of the Section 8(e) policy
document) states that the occurrence of serious toxic
effects such as those described in Part V( a) (1) / (2) of
the policy statement presupposes exposure to the tested
chemical or mixture and must be reported to the Agency
under Section 8(e) of TSCA.
With regard to when to report information to EPA under
Section 8 (e), Part VI of the policy statement explains
that a subject "person is not to delay reporting until
19
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8EHQ-0287-0653
Page 6 of 7
he obtains conclusive information that a substantial
risk exists, but is to immediately report any evidence
which reasonably supports that conclusion." Part VI
explains also that "not only should final results from
such studies be reported, but also preliminary results
from incomplete studies where appropriate."
With regard to the immediate reporting requirement
imposed by Section 8(e), Part IV of the policy statement
explains that the EPA Administrator is considered to be
informed immediately about substantial risk information
"if [the] information is received by EPA [in accordance
with the reporting procedures outlined in Part IX of the
Section 8(e) policy statement] not later than the 15th
working day after the date. . . [a subject] person ob-
tained such information." It should be noted also that
Part III of the Section 8(e) policy statement explains
that EPA considers a subject company to have "obtained"
substantial risk information at the time any corporate
officer or employee of that company capable of appreci-
ating the significance of the information obtains (i.e.,
possesses or, knows of) such information.
Considering the preceding Section 8 (e) policy discussion, EPA
believes that the toxicologic information contained in FYI-OTS-
0187-0527 (particularly the adverse male rat reproductive effects
information) clearly offers reasonable support for a conclusion
of substantial risk as that term is defined in the Section 8 (e)
policy statement and as such should have been submitted formally
to the Agency under Section 8(e) of TSCA.
a)
The Chemical Screening Branch (CSB/ECAD) will request
CIBA-GEIGY to provide the company's rationale as to why
the information presented in FYI-OTS-0187-0527 was not
submitted to EPA under TSCA Section 8(e). After an EPA
review of CIBA-GEIGY's response, the Chemical Screening
Branch (CSB/ECAD/OTS) will, if appropriate, deliver FYI-
OTS-0187-0527 to the OTS Document Control Officer for
public filing under Section 8(e) of TSCA.
In view of EPA' s general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure information, ClBA-GEIGY will be asked
also to describe the nature and results, if available,
from all studies (other than those reported already to
EPA via the updated Irgaform 1266 MSDS or those cited in
the open scientific literature) about which CIBA-GEIGY
is aware or that CIBA-GEIGY has conducted, is conducting
or plans to conduct to determine the toxicity of or the
exposure to the subject chemical.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this phenidone derivative.
20
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8EHQ-0287-0653
Page 7 of 7
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, NTP, FDA, OSWER/EPA,
OAR/EPA, OW/EPA, ORD/EPA, and OPP/OPTS/EPA. Copies of
this status report will be provided also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
NOTE:
The reader's attention is directed to the following status report
prepared by EPA in respons~ to 8EHQ-0587-0653 Followup Response.
21
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DAT!:
JAN 2 6 1988 Page 1 of 3
status Report> 888Q-8587-8653 FLWP APprov~
Frank D. Kover, Chief '?Jb.~lL p ~ JAN 26 1988
Chemical Screening Brah{~~~A~/OTS
SUIJECT:
I"ROM:
TO:
Joseph J. Merenda, Director
Existing Chemical Assessment Division/OTS
Note
The reader's attention is directed first to the status report
that was prepared by the Agency in response to TSCA Section 8(e)
submission number 8EHQ-~287-0653 Initial.
Submission Description
In response to EPA' s questions wi th regard to the Section 8 (e)-
reportability of the toxicological information (especially the
adverse male rat reproductive system effects information) that
was presented in "For Your Information" (FYI) submission number
FYI-OTS-~l87-~527 Initial, the CIBA-GEIGY Corporation provided
the. company's rationale as to why the information was not
submitted formally to EPA pursuant to Section 8 (e) of TSCA.
According to CIBA-GEIGY, the company's rationale was based in
part on the company's opinion that the "Flash Report" on Irgaform
1266 (4-(hydroxymethy1)-4-methy1-1-phenyl-3-pyrazo1idinone; CAS
No. 13~47-13-7) was inconclusive in that the report "did not
contain pivotal information necessary to make an informed review
of this chemical, which is structurally related to phenidone [(1-
phenyl-3-pyrazolidinone; CAS No. 92-43-3)]." CIBA-GEIGY also
provided the following information concerning the company's
rationale for not reporting the findings under Section 8(e):
"The related compound, phenidone, produced similar
reproductive and blood abnormal i ti es bu t also caused
significant decreases in body weight and food consump-
tion, which made it uncertain whether the effects
[observed with Irgaform 1266] were truly compound
re1a ted. In... [EPA' s status repor t prepared in
response to a previous TSCA Section 8(e) submission on
phenidone (8EHQ-~984-~529 Initial)], EPA stated that
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on inGomplete information.
22
.~.. ~o... .... ClUV. 1-711
-------
8EHQ-0587-0653 FLvW
Page 2 of 3
'the reported adverse effects are most probably real
(trea tmen t re 1 a ted) in tha t they were dose related'
(emphasis added). However, the Agency also recognized
the existence of a confounding factor as evidenced by
the followi ng statement: 'It is not clear that these
changes [(Le., the adverse male rat reproductive
system effects)] were direct toxic effects or resulted
from impaired nutrition (either general malnutrition
from decreased food consumption or local impairment of
nutrition of stored spermatozoa as the result of damage
to the epididymides)' (emphasis added).
"The 'Flash Report' on Irgaform 1266 indicated that the
male reproductive effects occurred in the high dose
group only ([i.e., effects] were not dose-related) and
no information was given about the general health of
rats at the high dose group (body weight, food consump-
tion, or mortality). [CIBA-GEIGY] was uncertain,
therefore, whether these effects were due to direct
action of the test compound or were attributable to
general toxicity in the high dose group resulting in
malnutrition and significant weight reductions. There-
fore, [CIBA-GEIGY] considered it necessary to
await the final report, which was targeted for comple-
tion . [within about a month of the company's FYI
notice] in order to determine the significance of the
observations. The 'Flash Report' on Irgaform 1266,
which was the only information in . [CIBA-GEIGY'S]
possession at the time of . . . [the company's] initial
FYI submission, was insufficient to make a judgement
relative to an 8(e) reporting obligation. ....
"Once the final report containing the complete data was
received and evaluated, it was concluded that the male
reproductive effects were not related to a general
systemic toxicity or malnutrition, and appeared to be a
direct, specific effect. ...."
Comments/Recommendations
EPA maintains its position that the information presented in FYI-
OTS-0l87-0527 Ini tial (particularly the Eng 1 i sh trans la t i on 0 f
the German "Flash Report") provides reasonable support for the
conclusion that Irgaform 1266, when administered via gavage to
rats for 28 days, produced a dose-dependent toxic anemia with
inclusion body formation as well as reduced spermatogenesis and
testicular atrophy at the highest dose. Further, "Flash Reports"
appear to be a mechanism by which the CIBA-GEIGY Corporation is
informed by CIBA-GEIGY Ltd. (the parent company located in Basel,
Switzerland) about significant results of studies conducted by or
for C IBA-GEIGY Ltd; the "Flash Report" on Irgaform 1266 states
that "the demonstrated findingi, especially the spermatogenesis
reduction, are toxicologically significant."
23
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8EHQ-0587-0653 FLHP
Page 3 of 3
In addition, the "Flash Report" states that the toxicologic
findings for Irgaform 1266 "show great similarity to the findings
which were obtained for. [phenidone and reported to EPA by
the Eastman Kodak Company under Section 8 (e) of TSCA]." It is
also important to point out that the "Flash Report" sent to the
CIBA-GEIGY Corporation was based on a "Final Report for Audit" of
the 28-day gavage study of Irgaform 1266 in rats and not simply
on the basis of preliminary observations made during that study.
Bearing this in mind, it is likely that if the serious adverse
hematologic and testicular effects observed in the 28-day study
of Irgaform 1266 were believed by the parent company to have
resul ted from malnutri tion, for example, the "Flash Report" most
probably would have included such a caveat.
with regard to CIBA-GEIGY's remarks about certain statements made
by EPA in the Submission Evaluation section of the status report
prepared by EPA in response to Eastman Kodak's TSCA Section 8(e)
not i ce on phen idone (8EHQ-0984-0529 Ini tial), it must be noted
that the Agency's statements were not intended to minimize the
significance of the reported toxicologic findings for phenidone,
nor were the statements intended to provide a basis to conclude
that the submitted findings were considered by EPA not to be
reportable under Secti on 8 (e) of TSCA. I n fact, the overa 11
thrust of EPA's initial evaluation of the submitted preliminary
findings on phenidone was that the observed adverse effects were
most likely a direct result of treatment with the chemical.
Based on a review of CIBA-GEIGY's FYI and Section 8(e) notices on
Irgaform 1266 and considering the discussion presented previously
in the Comments/Recommendations section of the status report that
EPA prepared for 8EHQ-0287-0653 Initial, the Agency can find no
compelling reason to change its position that the toxicologic
information contained in FYI-OTS-0l87-0527 Initial should have
been submitted formally under Section 8(e), the substantial risk
information reporting provision of TSCA. Therefore, the Chemical
Screening Branch will deliver FYI-OTS-0187-0527 Initial to the
OTS Document Processing Center (DPC) to be logged in/processed as
a supplement to 8EHQ-0287-0653.
a)
The Existing Chemical Assessment Division will inform
the CIBA-GEIGY Corporation about the Agency's decision
with regard to the Section 8 (e)-reportability of the
information contained in FYI-OTS-0187-0527 Initial.
b)
The Chemical Screening Branch is continuing its review
of the reported information to determine the need for
further OTS assessment of the subject chemical.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
OCM/OPTS/EPAi copies of this status report will be sent
a 1 s 0 to the TSCA Ass i stance Off ice (TAO/OTS/OPTS/EPA)
for further distribution.
24
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
MAR
2 1987
Page 1 of 4
SUBJECT:
Status Report* 8EHQ-0287-0654 APproved:~
James F. Darr, Section Head (1.._- ~~
Chemical Risk Identificatio~tion/CSB
,/;,/n
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Union Carbide Corporation provided the following summarized
information regarding the conduct and results of a number of
acute in vivo and in vitro studies conducted with 3-methyl-2-ben-
zothiazolinone hydrazone hydrochloride (MBTH):
"Acute Peroral Toxici t~: The LD50 values (with 95%
confidence limits) for this route of exposure were cal-
culated to be as follows from the dose-mortality data:
Rat (male) =
Rat (female) =
Rabbit (male) =
Rabbit (female) =
308 (182-519)
149 (84-264)
177 (105-298)
268 (181-396)
mg/kg
mg /kg
mg/kg
mg/kg.
"Times to death were dose-related, and varied between 15
minutes and one day. Signs of toxicity included slug-
gishness, tremors, unsteady gait, excess salivation, and
(in rabbits only) convulsions. The above findings
indicate a moderately high acute peroral toxicity for
MBTH with rapid onset of signs of toxicity and death.
"Acute Percutaneous Toxicity: Currently the mortalities
are as follows by a standard 24-hour occluded cutaneous
application method. None of 5 male and 5 female rats,
and 5 male rabbits, died over a 14-day observation peri-
od following the application of 1"6.0 g/kg. Three female
rabbits, of 3 dosed, died (by one day) following 16.0
g/kg, but 2 female rabbits dosed with 8.0 g/kg survived
a 14 day observation period. Edema was seen at the site
of application of the test material to the skin for the
first post-application day. There were no signs of sys-
temic toxicity in male or female rats, but convulsions
===================================================~================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reportini provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
25
I:~A I"ORM U20-6 (REV. Ion)
-------
8EHQ-0287-0654
Page 2 of 4
were seen in rabbits at applied doses of 4.0 g/kg and
upwards. . . [and] usually occurred at 1 to 2 hours and
persisted for 2 to 15 minutes. Convulsions were not
seen at 2.0 g/kg. The above findings indicate a low
order of acute lethal percutaneous toxicity for MBTH,
but systemic toxicity was evident in one species
(rabbit) in the form of convulsions.
"Acute Inhalation Toxicity: The low vapor pressure of
MBTH would suggest a negligible potential for acute in-
halation hazard. This was confirmed by exposing 5 male
and 5 female rats for 6 hours to a statically generated
substantially saturated vapor atmosphere from MBTH (240
C). There were no deaths and no symptoms of toxicity or
irri tancy during exposure or in a 2-week post-exposure
observation period.
"Primary Skin Irri tation: Using a standard 4-hour
occluded application of 0.5 g of MBTH to each of 6
rabbits, no signs of local inflammation were seen on re-
moval of the occlusive dressing, and none developed over
a subsequent 14-day inspection period. These results,
[when] coupled with the observation of transient local
edema in the acute percutaneous toxicity study, indicate
that MBTH is minimally irritant to the skin by sustained
single contact.
"Primary Eye Irri tation: The following inflammatory
reactions were seen in the rabbit eye following the in-
stillation of MBTH into the inferior conjunctival sac of
one eye of each of six rabbits per treatment group:
80 mg:
There was mild to moderate conjunctivitis
(erythema and chemosis) of 48 to 72 hours
dura tion, and minimal corneal injury which
healed within 24 to about 72 hours.
10 mg: There was a just detectable conjunctivitis
of less than 24 hours duration.
"The above findings indicate
primary eye irritant without
manent injury.
that MBTH
potential
is
to
a moderate
cause per-
"Mutagenici ty: MBTH was tested for potential mutagenic
activity using a Salmonella typhimurium mutagenicity as-
say procedure. Based on cytotoxici ty studies,
MBTH was tested with and without metabolic activation
(rat liver S9 system) using 5 concentrations of MBTH in
the range of 0.3 to 5.0 mg per plate. Dose-related muta-
genic activity was seen without metabolic activation in
strains TA98, TAIOO, TA1535 and TA1537, but not TA1538.
In the presence of the metabolic activating system,
mutagenic activity was present with TA1535 only."
26
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8EHQ-0287...0654
Page 3 of 4
In conclusion, Union Carbide stated that "taken overall, the
results of these studies indicate that MBTH is of moderate acute
peroral toxicity, has a potential to cause systemic toxicity by
percutaneous absorption of high doses applied to the skin, does
not present any short-term adverse health effects by vapor ex-
posure at ambient temperature, is a minimal skin irritant, a
rroderate eye irritant, and is mutagenic in the standard Ames
test. .... "
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported toxicologic findings, Union Carbide should be requested
to ensure that the Agency receives complete copies of the final
reports (including the actual experimental protocols, results of
gross and histopathological examinations, results of statistical
analyses, etc.) from all studies cited in this TSCA Section 8(e)
submission.
Current Production and Use
In its TSCA Section 8(e) submission, Union Carbide reported that
MBTH has the following Chemical Abstract Service (CAS) Registry
Number: 14448-67-0. According to published CAS Registry Number
indices, CAS No. 14448-67-0 has been assigned to MBTH of variable
hydrochloride composition. A review of the non-confidential com-
puterized version of EPA's TSCA Chemical Substance Inventory has
shown that CAS No. 14448-67-0 is not "listed. It should be noted,
however, that CAS No. 4338-98-1 has been assigned to MBTH mono-
hydrochloride and is listed in the TSCA Inventory. A review of
the production range (includes importation volumes) statistics
for MBTH monohydrochloride (CAS No. 4338-98-1) shows that no 1977
manufacture or importation was reported for this chemical or that
all of the manufacture/importation data reported were claimed to
be TSCA Confidential Business Information (TSCA CBI) by the per-
son(s) reporting for the TSCA Inventory and cannot be disclosed
(Section l4(a) of TSCA, U.S.C. 26l3(a». All of the information
reported for the initial TSCA Inventory, including the production
range information, is subject to the limitations contained in the
initial TSCA Inventory Reporting Regulations (40 CFR 710).
According to Union Carbide, MBTH is "a widely used reagent for
analysis of aldehydes." Union Carbide stated further that the
company does not manufacture MBTH but rather "purchases the
chemical and supplies it to customers as part of an analytical
kit for. . . [Union Carbide's] glutaraldehyde products."
Comments/Recommendations
In its TSCA Section 8(e) submission, Union Carbide stated that
its MBTH supplier as well as appropriate Union Carbide employees
and customers were being notified about the reported toxicologic
findings for MBTH.
27
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8EHQ-0287-0654
Page 4 of 4
a)
The Chemical Screening Branch will request Union Carbide
to ensure that the Agency receives full copies of the
final reports (including actual experimental protocols,
results of gross and histopathological examinations,
results of any statistical analyses, etc.) from all of
the studies cited in the company's Section 8(e) notice.
In addition, Union Carbide will be asked to provide the
exact chemical identity of the MBTH tested in the cited
studies.
In view of EPA I S general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure information, EPA will ask Union Carbide
to describe the nature and results, if available, from
all studies (other than those published in the open
scientific literature or those submitted already to EPA)
about which Union Carbide is aware or that Union Carbide
has conducted, is conducting or is planning to conduct
to determine the toxicity of or the exposure to MBTH.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and the Inventory
Team/IMD/OTS. In addition, copies of this report will
be provided to the TSCA Assistance Office (TAO/OTS) for
further distribution.
28
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATIl
MAR I I 19&
SU8JECT:
Status Report *
8EHQ-0287-0655 S
Approved :tJJt- -ft!Jf
-------
8EHQ-0287-06SS S
Page 2 of 3
only became manifested during the study. To
clarify the situation, an additional 10 male rats were
administered a single gavage dose of 5000 mg/kg. Five
of the 10 animals died; all survivors showed clinical
signs of neurological impairment. This study is still
in progress."
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported toxicologic findings, the submitting company should be
asked to ensure that the Agency receives complete copies of the
final reports (including the actual experimental protocols, re-
sults of gross and histopathological examinations, results of any
statistical analyses performed, etc.) from all studies cited in
the company's TSCA Section 8(e) notice.
Immediately upon receipt of the company's initial Section 8(e)
notice, the Chemical Screening Branch transmitted copies of the
submitted information to appropriate individuals in the Chemical
Control Division (CCD/OTS) responsible for administration of the
OTS "New Chemicals Program" (NCP).
Current Production and Use
(See NOTE on page 3 of this status report)
According to a Material Safety Data Sheet (MSDS) provided by the
company in its Section 8(e) notice, this I-phenyl substituted 2-
pyrazolin-S-one is a dark brown solid that has a melting point of
138°C (280°F) and negligible vapor pressure. In its Section 8(e)
notice, the submitter stated that the chemical "is to be used as
a low volume, site-limited intermediate." The submitter stated
also that "potential employee exposure has been minimized during
the manufacture and isolation of the damp intermediate by use of
face shields, gloves, and aprons." Finally, the submitter stated
that company employees "handling the dry intermediate wear air-
line respirators and Tyvek@ suits."
Comments/Recommendations
In its Section 8(e) notice, the submitting company stated that
the MSDS for the subject chemical has been updated to include the
reported neurotoxicological effects. In addition, the submitter
reported that the company" is currently evaluating the need for
further testing."
a)
The Chemical Screening Branch will ask the submitting
company to ensure that EPA receives full copies of the
final reports (including the actual experimental proto-
cols , results of gross/histopathological examinations,
results of any statistical analyses, etc.) from all
studies cited in the initial Section 8(e) submission.
30
-------
8EHQ-0287-0655 S
Page 3 of 3
In view of EPA' s general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure data, the Chemical Screening Branch
will ask the submitting company to describe the nature
and results, if available, from all studies (other than
those submitted already to the Agency) about which the
company is aware or that the company has conducted, is
conducting or plans to conduct to determine the toxicity
of or the exposure to the subject chemical substance.
b)
The Chemical Screening Branch will immediately send all
reported information to the OTS New Chemicals Program
for appropriate fOllow-up attention/action.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS, and CCD/OTS/OPTS.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS) for further
distribution.
NOTE:
In a followup letter dated April 13, 1987, the submitting company
provided the following non-confidential and more specific generic
name for the subject chemical: 1-phenyl-alkylamino-2-pyrazolin-S-one.
ZfJL ~/ :I~
31
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
MAR 2 5 1987
Status Report' 8EHQ-0387-0656 APproved:~
James F. Darr, Section Head ~ r ~
Chemical Risk Identificatio~Section/CSB
SUBJECT:
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
PPG Industries, Inc. reported that 2-ethylhexanoyl chloride (CAS
No. 760-67-8) was found to have an acute LC50 of 1.26 mg/l when
tested via inhalation in rats. In addition, PPG stated that the
study showed that 2-ethylhexanoyl chloride is very irritating to
the respiratory tract and confirmed the fact that the chemical is
a severe skin irritant. PPG also provided a Material Safety Data
Sheet (MSDS) that had been updated by the company to reflect the
reported toxicologic findings. According to the submitted MSDS,
2-ethylhexanoyl chloride has a dermal LD50 of over 2 g/kg and an
oral LD50 of about 1. 5 g/kg (species not specified). The MSDS
also indicates that the chemical is corrosive to skin and eyes.
Submission Evaluation
It should be noted that hydrochloric acid is liberated when 2-
ethylhexanoyl chloride comes in contact with moisture. It should
be noted also that a chemical with an LC50 value in the range of
0.5 to 2.0 mg/l (i.e., approximately 50 to 200 ppm) is considered
generally to be "highly" toxic by inhalation. In this regard,
PPG stated that the observed inhalation LC50 of 1.26 mg/l in rats
would result in a Department of Transportation classification of
2-ethylhexanoyl chloride as a Class B Poison.
In order for EPA to evaluate better the overall significance of
the reported toxicologic information, PPG should be requested to
submit complete copies of the final reports (including the actual
experimental protocols, results of gross and histopathological
examinations, etc.) from all toxicologic studies the results of
which are cited in Section 4 (Health Hazard Data) of the provided
MSDS for 2-ethylhexanoyl chloride.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
EPA FORM 1120..1 (REV. 3-711
32
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8EHQ-0387-0656
Page 2 of 3
Current Production and Use
A review of the production range (includes importation volumes)
statistics for 2-ethylhexanoyl chloride, which is listed in the
initial TSCA Chemical Substance Inventory. has shown that between
200 thousand and 2 million pounds were reported as manufactured
and/or imported in 1977. This production range information does
not include any information claimed as TSCA Confidential Business
Information (TSCA CBI) by the person (s) reporting for the TSCA
Inventory nor does it include any data that would compromise TSCA
CBI. All data reported for the initial TSCA Inventory, including
the production range data, are subject to the limitations con-
tained in the TSCA Inventory Reporting Regulations (40 CFR 710).
According to the secondary literature sources consulted by EPA,
2-ethylhexanoyl chloride is used primarily as an intermediate in
the manufacture of peroxyesters, agricultural products and drugs.
According to the submitted MSDS, 2-ethylhexanoyl chloride is a
clear, slightly colored liquid with a strong pungent odor. In
addition, the MSDS states that the chemical has a boiling point
of 152-154 of at 11 mmHg and a vapor pressure of 0.014 psia at
153-154°F. The MSDS states also that PPG's Internal Permissible
Exposure Limit (IPEL) for 2-ethylhexanoyl chloride is 0.1 ppm (8-
hour Time Weighted Average (TWA» and PPG's Short-Term Exposure
Limit (STEL) is 0.3 ppm for any 15 minute excursion.
Comments/Recommendations
In the cover letter to its Section 8(e) notice, PPG stated that
in addition to updating the 2-ethylhexanoyl chloride MSDS and
product label, PPG intends to inform its customers about the
reported toxicologic findings.
a)
The Chemical Screening Branch will request PPG to submit
full copies of the final reports (including the actual
experimental protocols, results of gross/histopathologic
examinations, etc.) from all studies cited in Section 4
(Health Hazard Data) of the provided MSDS.
In view of EPA' s general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure data, the Chemical Screening Branch
will request PPG to describe the nature and results, if
available, from all studies (other than those cited in
the open scientific literature or those reported already
to EPA) about which PPG is aware or that the company has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of 2-ethylhexanoyl chloride.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of 2-ethylhexanoyl chloride.
33
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8EHQ-0387-06S6
Page 3 of 3
c)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
34
-------
UNITED STATES ENV'JRONMENTAL PROTECTION AGENCY
DATE:
MAR '8 1981
P ag e 1 0 f 3
SUBJECT:
Status Report *
8EHQ-0287-0657 S
Approved: 6fJt- ~r,q Jt7
FROM: James F. Darr, Section Head ~ T-~
Chemical Risk Identification Section/CSB
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
(See NOTE on page 3 of this status report)
-
The submitting company has claimed its company name to be TSCA
Confidential Business Information (TSCA CBI). The Information
Management Division (IMO/OTS) will request the submitting company
to substantiate this confidentiality claim. It should be noted
also that in the "sanitized" version of the TSCA Section 8(e)
submission, the company reported that the tested chemical had
been the subject of the following TSCA Section 5 Premanufacturing
Notification: PMN 86-1444.
Submission Description
(See .NOTE on page 3 of this status report)
The submitting company provided the following summary information
with regard to the conduct and results of an acute rat oral L050
study of the methyl ester of 4-hydroxy-3-ni trobenzoic acid (CAS
No. 99-42-3):
"Groups of 5 male and 5 female rats were given 1250,
2500, or 5000 mg/kg of the test compound in a single
gavage dose. ." All animals died at 5000 mg/kg.
Abnormalities noted at necropsy included hemorrhage of
the thymus and hemorrhage and edema of the glandular
stomach. At 2500 mg/kg, 1 of 5 females and 0 of 5 males
died. Necropsy of the dead female revealed hemorrhage
of the glandular stomach. Small, soft testes were ob-
served in 5 of 5 male rats at this dose. Microscopic
examination of the testes revealed treatment-related
changes consisting of seminiferous epithelium atrophy,
reduction of spermatids and spermatozoa, giant cell
formation, and interstitial cell hyperplasia. In the
epididymides, degenerated sperm forms, hypospermia, and
vacuolization of the ductal epithelium were noted in one
or more animals. No treatment-related changes were
noted in the testes or epididymides from the 1250 mg/kg
group. "
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
EPA FORM 1320-6 (REV. 3-761
35
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8EHQ-0287-0657 S
Page 2 of 3
The submitting company also provided summarized findings from
several other acute toxicity studies of the subject chemical.
According to the submitted information, this chemical l) has a
rat dermal LDSO of greater than 2 g/kgi 2) is slightly irritating
to guinea pig skin and rabbit eyesi and 3) is not a sensitizing
agent when tested in guinea pigs.
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported toxicologic findings, the submitting company should be
requested to provide to EPA complete copies of the final reports
from all studies cited in the company's Section 8{e) submission.
Immediately upon receipt of the initial TSCA Section 8{e) notice,
the Chemical Screening Branch transmitted copies of the submitted
information to appropriate individuals in the Chemical Control
Division (CCD/OTS) which is responsible for administering the OTS
New Chemicals Program (NCP).
Current Production and Use
In its TSCA Section 8(e) notice, the submitting company provided
a sanitized copy of a Material Safety Data Sheet (MSDS) for the
methyl ester of 4-hydroxy-3-nitrobenzoic acid. According to the
MSDS, this chemical is a yellow solid which has a melting point
of 74-7SoC (l6S-167°F) and a negligible vapor pressure. In its
Section 8 (e) notice, the company reported that the chemical" is
to be used as a site-limited intermediate to manufacture another
chemical. II In addition, the submitter provided the following
information regarding the potential for worker exposure to the
subject chemical:
"Potential employee exposure has been minimized during
the manufacture and isolation of the water-wet inter-
mediate by the use of coveralls (employer supplied and
laundered), a hat, boots, safety glasses with side
shields, neoprene rubber gloves, a vinyl smock, and a
cartridge respirator with an organic vapor cartridge.
The chemical is not handled as a dry material."
Comments/Recommendations
The submitting company stated that the provided MSDS for the
subject chemical had been updated to reflect the reported adverse
testicular effects. In addition, the submitter stated that the
company is considering the need for further toxicologic testing.
a)
The Chemical Screening Branch will ask the submitter to
provide full copies of the final reports (including the
actual experimental protocols, results of gross/histo-
pathological examinations, results of any statistical
analyses performed, etc.) from all toxicologic studies
cited in the company's TSCA Section 8(e) submission.
36
-------
8EHQ-0287-0657 S
Page 3 of 3
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure data, the Chemical Screening Branch
will ask the submitting company to describe the nature
and results, if available, of all studies (other than
those cited in the published scientific literature or
those submitted already to the Agency) about which the
company is aware or that the company has conducted, is
conducting or plans to conduct to determine the toxicity
of or the exposure to the methyl ester of 4-hydroxy-3-
nitrobenzoic acid.
b}
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical. In addition,
the Chemical Screening Branch will send copies of all
reported information to appropriate individuals in the
OTS New Chemicals Program.
c}
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OAR/EPA, OW/EPA, ORD/EPA, OPP/OPTS and CCD/OTS/OPTS. In
addition, copies of this status report will be sent to
the TSCA Assistance Office (TAO/OTS/OPTS) for further
distribution.
NOTE
In a letter to EPA dated April 10, 1987 (8EHQ-0487-0657 Followup
Response), the Eastman Kodak Company stated that it was dropping
the TSCA CBI claim involving the company's name.
ff~b ~ rJ>j~
37
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGEWCY
DATE:
APR 2' 19S7
Page 1 of 3
SUBJECT:
Status Report * 8EHQ-0287-0658 S Approved:
James F. Darr, Section Head ~ T ~
Chemical Risk Identificatio~Section/CSB
rft- 4{:u (!7
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
(See Note on Page 3 of this status report)
The submitting company has claimed its company name and the exact
identity and use of the subject chemical to be TSCA Confidential
Bus ines s Information (TSCA CBI). The Information Management
Division will request the submitter to substantiate these TSCA
CBI claims. In the "sanitized" version of the cover letter to
its Section 8(e) notice, the submitter stated non-confidentially
tha t the subj ect chemical substance is a "chlorophenyl triazole"
currently at the research and development (R&D) stage.
Submission Description (See Note on Page 3 of this status report)
The submitting company provided full copies of the final reports
from probe (dose range-finding) teratology and full teratology
studies in rats and rabbits. In addition, the submitter provided
assessments of the studies by four outside consultants. In the
Section 8(e) cover letter, the submitter provided the following
information with regard to the conduct and results of the full
teratology studies:
"In the rat teratology study. dosages of 12 mg/kg/day
and above resulted in maternal toxicity as evidenced by
dosage-dependent inhibition of maternal body weight gain
during the dosage period. Possible compound related
developmental toxici ty was demonstrated for litters of
dams receiving 24 or 48 mg/kg/day of the chemical and
possibly 12 mg/kg/day as well. Signs of developmental
toxicity reported included resorption, decreased litter
size, decreased fetal body weight and malformation. The
low incidence of cleft palate (2 fetuses) occurring at
48 mg/kg/day was not significant when compared to con-
trols. Although there is not agreement on these points
between consultants, [the submitter believes that] there
is biological and statistical evidence to support [the
company's] view.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act ~TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
38
I!PA FORM 1320-6 (REV. 3-76)
-------
SEHQ-0287-0658 S
Page 2 of 3
"In the rabbit study, a 10 mg/kg/day no-effect level was
demonstrated for maternal toxicity based on both body
weight loss and inhibition of food consumption at the 50
mg/kg/day level. Administration of 50 mg/kg/day of the
chemical resulted in an increase in resorptions and a
decrease in live litter size. A minimal decrease in
fetal body weight observed for litters of this group (50
mg/kg/day) was also reported but was similar to histori-
cal controls. The incidence of hydrocephalus internus (1
from each treatment level) was relatively high for this
study but was not dose related." ,
With regard to the assessments of the data by the four outside
consultants, the submitting company reported that "significant
differences of opinion exist" in that "there is no general agree-
ment as to 1) no-effect levels for maternal and developmental
toxicity, 2) whether developmental toxicity was compound-induced,
and 3) adequacy of testing and reporting procedures."
Wi th regard to its own interpretation of the results from the
performed studies, however, the submitting company reported that
although "no-effect levels were established for both maternal and
developmental toxici ty for both species", the company interprets
the data to show "compound-related developmental effects in both
species, but, if real, occurred only at maternally toxic doses."
Submission Evaluation
Considering the large amount of data submitted and the complexity
of the issues raised by the submitting company and the outside
consultants regarding interpretation of those data, full copies
of provided reports and assessments were forwarded for review to
the Reproductive Effects Assessment Group (REAG) in EPA's Office
of Research and Development (ORD). The Chemical Screening Branch
will consult with REAG/ORD in determining the needs for and scope
of further OTS assessment of this chlorophenyl triazole.
It should be noted that EPA has received other TSCA Section 8(e)
submissions with regard t,o the toxicity (including teratologic
effects) of triazole derivatives (e.g., 8EHQ-0485-0548 et seq.).
In 8EHQ-0485-0548 et seq., the Chevron Chemical Company reported
that (E)-1-(2,4-dichlorophenyl)-4,4-dimethyl-2-(1,2,4-triaz01-1-
yl)-1-penten-3-01 (CAS No. 76714-88-0), when administered orally
to pregnant rabbits at doses of 0, 62.5, 125, 250 or 500 mg/kg,
caused dose-related malformations (including c left palate) and
developmental variations at the 2 highest doses in the presence
of minimal maternal toxicity at the highest dose only-
Current Product ion and Use
(See Note on Page 3 of this status report)
In light of the submitting company's CBI claims, no information
concerning the TSCA Chemical Substance Inventory status or use of
the subject chemical will appear in this status report.
39
-------
8EHQ-0287-0658 S
Page 3 of 3
Comments/Recommendations
a)
In view of EPA's qeneral interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure information, the Chemical Screenino
Branch will ask the submittinq company 1) to descrihe
the actions the company has taken or plans to take to
notify workers and others ahout the reported toxici ty
findings, and 2) to reduce or eliminate exposure to the
subject chemical substance. In addition, the submitter
wi 11 be asked to descr ihe the nature and results, if
available, from all studies (other than those submitted
already to EPA) about which the company is aware or that
the company has conducted, is conduct i no or pla ns to
conduct to define the toxicity of or the exposure to the
subject chemical.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this chlorophenyl triazole.
c)
The Chemical Screenino Branch wi 11 send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/BPA. In addition,
copies of this status report wi 11 he sent to the TSCA
Assistance Office (TAO/OTS) for further distrihution.
NOTE
On January 11, 1988, the Chemical Screening Branch received from
the Information Management Division (IMD/OTS) the "declassified"
version of this TSCA Section 8 (e) submission. According to the
dec 1 ass if i ed no t ice, the Sandoz Crop Protecti on Corpora ti on is
the submitting company and the exact identity of the subject
chemical is "alpha-(4-chlorophenyl)-alpha-(1-cyclopropylethyl)-
1!::!.-1,2,4-triazole-l-ethanol." The declassified notice states
also that th is substance (al so known as SAN-6l9F) is undergo i ng
evaluation as a fungicide and is intended to be registered with
EPA under the Federal Insecticide, Fungicide and Rodenticide Act
( F I F RA) .
if~ r~ I!?br-
J~~es F. Darr, Section Head
Chemical Risk Identification
Section/CSB/ECAD/OTS/OPTS
40
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
APR
6 1987
Page 1 of 3
SUBJECT:
Status Report * 8EHQ-0387-0659 Approved ~
James F. Darr, Section Head ~~~
Chemical Risk Identificatiorll~ection/CSB
1/1/<$7
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The 3M Company provided a full copy of the final report from an
acute inhalation study of n-butyl acetate (CAS No. 123-86-4) in
rats. In its Section 8(e) notice, 3M stated that this study was
"recently conducted at a European toxicology laboratory at the
request of a 3M subsidiary. "The Summary section of the
submitted report contains the following information regarding the
conduct and results of this acute inhalation study:
"Three groups of Wistar rats, each comprising 5 males
and 5 females, were exposed for 4 hours to an aerosol/
vapor of. . . En-butyl acetateJ at actual concentrations
in the exposure atmosphere of 0.8, 2.2, and 5.2 mg/l,
respecti vely. The exposure was carried out in a head-
only dynamic inhalation system. The values for mass
median aerodynamic diameter (MMAD) and geometric stan-
dard deviation. . for the test atmosphere at the high
exposure level were 1.01 micrometers and 3.30 [micro-
metersJ, respectively. The mortality rate for the sexes
combined from the low dose to high dose group was 6 out
of 10, 10 out of 10, and 10 out of 10 animals, respec-
tively. There was no evident sex related effect. All
deaths occurred within 24 hours after exposure. Major
signs of toxicity were lethargy, hyperpnea, tremors and
ataxy- with the exception of one male, all animals that
showed symptoms of systemic or local respiratory toxi-
ci ty finally did not survive. Macros copic examination
at necropsy revealed bloody nose and/or mouth and hyper-
aemic lungs in animals among all exposure groups. Histo-
pathology of lung tissue revealed vesicular emphysema in
all animals. Based on the analytical concentration of
the test substance in the animal breathing zone, the
LC50 value for the sexes combined was estimated to be
0.74 mg/l or 160 ppm."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
41
EPA FORM 1320-6 (REV. 3-76)
-------
8EHQ-0387-0659
Page 2 of 3
According to 3H, "such a low LC50 was totally unexpected in light
of the existing toxicity data on. . en-butyl acetate] and its
current ACGIH [(American Conference of Governmental Industrial
Hygienists) ] Threshold Limit Value [( TLV)] of 150 ppm."
Submission Evaluation
According to the National Institute for Occupational Safety and
Health (NIOSH) "Registry of Toxic Effects of Chemical Substances"
(RTECS), the 4-hour inhalation LC50 for n-butyl acetate in rats
is 2000 ppm. Under general inhalation toxicity classification
systems, a chemical with a 4-hour LC50 value of 2000 ppm is con-
sidered to be only "slightly" to "moderately" hazardous while a
chemical with a 4-hour LC50 value of 160 ppm is considered to be
"highly" hazardous.
Considering the discrepancy between the 4-hour rat inhalation
LC50 value of record and the 4-hour rat inhalation value reported
by 3M under Section 8(e) for n-butyl acetate, a prudent action to
take at this time would be to verify the purity of the n-butyl
acetate tested in the European study performed for the 3M sub-
sidiary. This action is recommended despite the fact that page 4
of the final report provided by 3M states that the tested n-butyl
acetate was "pure." If the tested sample is determined to be
pure, the European study should be repeated in order to determine
the validity of the findings presented in the final report sub-
mitted by 3M. (It should be noted at this point that the 4-hour
n-butyl acetate inhalation toxicity study in rats that is cited
in RTECS was not reviewed by EPA as to the adequacy of design or
purity of the test material.) Finally, if the 160 ppm 4-hour rat
inhalation LC50 value for n-butyl acetate is indeed correct, a
change should be considered immediately for the current 150 ppm
TLV for this chemical substance.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for n-butyl acetate (CAS No. 123-86-4), which is
listed in the initial TSCA Chemical Substance Inventory, shows
that between 21 million and 111 million pounds of this chemical
substance were reported as manufactured/imported in 1977. This
production range information does not contain any data that were
claimed as TSCA Confidential Business Information (TSCA CBI) by
the person(s) reporting for the initial TSCA Inventory, nor does
it include any information that would compromise TSCA CBI. All
of the data reported for the initial TSCA Inventory, including
the product ion range data, are subj ect to the limitations con-
tained in the TSCA Inventory Reporting Regulations (40 CFR 710).
According to secondary literature sources, n-butyl acetate is a
fruity smelling colorless liquid used primarily as a solvent and
a gasoline additive.
42
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8EHQ-0387-0659
Page 3 of 3
Comments/Recommendations
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure information, the Chemical Screening
Branch will ask 3M to describe the actions the company
has taken or plans to take 1) to not ify workers and
others about the reported toxicologic findings, and 2)
to reduce or eliminate exposure to n-butyl acetate. In
addition, 3M will be asked to describe the nature and
results of all studies (other than those submitted al-
ready to EPA or those published in the open scientific
literature) about which the company is aware or that the
company has conducted, is conducting, or is planning to
conduct to determine the toxicity of or the exposure to
n-butyl acetate. Finally, 3M will be informed that EPA
is interested especially in results of studies designed
to determine 1) the purity of the n-butyl acetate tested
in the European inhalation study, and 2) the validity of
the results of that inhalation study.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of n-butyl acetate.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, ACGIH,
OSWER/EPA, OW/EPA, ORD/EPA, OAR/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
43
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DA TE:
APR 2 2 1987
Page 1 of 4
SUBJECT:
Status Report * 8EHQ-0387-0660 Approved: ~
James F. Darr, Section Head~ r~
Chemical Risk Identification Section/CSB
1~7/~
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
Wacker Chemicals (USA), Inc. submitted full copies of the final
reports from I-hour inhalation LC50 studies of chloracetone (CAS
No. 78-95-5) and chloracetaldehyde (CAS No. 107-20-0) in rats.
The following information regarding the conduct and results of
these studies was presented in the "SUMMARY" sections of the sub-
mitted reports:
Chloracetaldehyde
"The acute inhalation toxici ty of chloracetaldehyde was
studied by exposing different groups of 5 male and 5 fe-
male rats one single time for a period of 1 hour to test
atmospheres containing chloracetaldehyde at a concentra-
tion between 0.14 and 8.47 g/m3 in air- From the results
of the present study, it appeared that the I-hour LC50
of chloracetaldehyde for the combined male and female
responses was between 0.65 and 0.78 g/m3, the most near
to the former value. As a result of the narrow range be-
tween these values, it was not possible to give a better
estimate of the l-hour LC50 value with 95% confidence
limits. Animals which died shortly after exposure showed
signs of edema and atelectasis in the lungs after autop-
sy, in most cases accompanied by a hydro-thorax which
could be explained by an induced hypertension. These
findings together with the edema and atelectasis [ob-
served] in [the] lungs were signs of an impairment of
lung functioning. Air in the stomach as well as in [the]
intestine was due to mouth breathing."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
i~formation submitted to EPA pursuant to Section 8(e), the substantial
rlsk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA oolicy or intent with respect to the subject
che~ical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
44
EPA FORM 1320-6 (REV. 3-76)
-------
8~HQ-0387-0660
Page 2 of 4
Chloracetone
"The acute inhalation toxicity of chloracetone was
studied by exposing different groups of 5 male and 5
female rats one single time for a period of 1 hour to
test atmospheres containing chloracetone at a concentra-
tion between 0.5 and 7.9 g/m3 in air. From the results
of the present study, it appeared that the I-hour LC50
of chloracetone for the combined male and female re-
sponses was 1.9 ~/m3 with 95% confidence limits of 1.6
g/m3 and 2.2 glm . Adding sex as an extra independent
variable in the original data base allowed calculation
of the LCSO values for males and females. For the
females, the I-hour LCSO was 2.7 g/m3 with the 95% con-
fidence limits of 2.5 g/m3 and 2.9 g/m3. For the males,
the I-hour LC50 wfs 1.2 g/m3 wtth the 95% confidence
limits of 1.1 glm and 1.3 g/m. Animals which died
shortly after exposure showed signs of edema in the
lungs after autopsy, in most cases accompanied by a
hydro-thorax. Both the hydro-thorax and the observed
red coloring of the skin of the extremities could be
explained by an induced hypertension. These findings
together with the edema in [the] lungs were signs of an
impairment of lung functioning. Mouth breathing caused
[the] stomach, caecum as well as [the] intestine to be
filled with air."
In providing this acute toxicity information to the Agency under
Section 8(e). Wacker stated that the data show "a significant
risk of injury by inhalation, despite the fact [that] the extent
of toxicity of these chemicals is already recorded by oral and
dermal toxicity studies."
Submission Evaluation
Seven groups of rats (each consisting of 5 animals per sex) were
exposed (whole body) to chloracetaldehyde concentrations that
ranged from .14 mgll to 8.47 mg/l. The relative humidity range
of 51-91% was high compared to the ideal humidity range of 30-
60%) for such studies. The high relative humidity was reportedly
due to the high amount of water in the test material. Following
the I-hour inhalation exposure period, the animals were to be
observed for two weeks. Signs of discomfort included closed
eyes, salivation, wet nares and nasal discharge (in the animals
in the higher dose groups). along with wet and soiled heads and
breasts. Labored respiration accompanied by dyspnea and mouth
breathing was detected in the highest dose group animals. The
animals exposed to .78, .99, 1.91 and 8.47 mgll all died, whereas
the mortalities for animals exposed to .65, .51 and .14 mgll were
40%, 30% and 0%, respectively. The deaths were observed during
and shortly after the exposure period as well as within 1 to 2
days following exposure. Many of the rats that died had blood
stains around the nose and mouth i rats exposed to the highest
45
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8EHQ-0387-0660
Page 3 of 4
chloracetaldehyde concentrations that did not die immediately
were reported to have breathed "wheezingly." In addition, it
should be noted that 2 rats exposed to 1.91 mg/l became blind.
The animals that died during exposure or within the first 2 days
of observation showed edema of the lungs which was accompanied in
some cases by atelectasi s (i. e., collapsed lung) and in most
cases by hydrothorax (i.e., watery fluid in the pleural cavity).
In many cases, the stomachs were found to be filled with air (due
to mouth breathing) and in some cases the intes tines were also
found to contain air. Also, an occasional thrombus was detected
in the heart area. In addition, lung edema was observed in those
low dose animals that survived to terminal sacrifice.
Based on dose level conversions and considering the fact that the
recommended threshold limit value (TLV) for chloracetaldehyde is
1 ppm, the doses used in this I-hour study were extremely high
(43 to 2643 ppm). According to Patty I s Industrial Hygiene and
Toxicology (3rd Edition), inhalation of chloracetaldehyde by mice
"is acutely toxic, demonstrating a lethal time of 2.57 minutes
under conditions in which the chamber concentrations reached 45%
equilibrium with an incoming mixture of air bubbled through a 30%
solution of chloracetaldehyde."
In the chloracetone study, the same basic experimental protocol
was used with exposure levels ranging from 0.5 mg/l to 7.9 mg/l.
As was the ca se in the ch loracetal dehdye study, the humidity in
the chloracetone study was elevated - approximately 83% in the
highest dose group and from 30% to 70% in the other dose groups.
Overall, the results obtained for chloracetone were similar to
those found for chloracetaldehyde, except that no blindness was
observed. The animals exposed to 4.2 and 7.9 mg/l all died and
animals exposed to 3.1, 2.1, 1.0 and 0.5 mg/l experienced 80%,
60%, 10% and 0% mortality, respectively. Although no TLV for
chloracetone was located, the doses used in this I-hour study
also appear to be quite high (132 to 2091 ppm).
In conclusion, it should be noted that the Merck Index (9th
Edition) states that chloracetone and chloracetaldehyde are
"intensely irritating to the skin, eyes, and mucous membranes."
Current Production and Use
A review of the production range (includes importation volumes)
statistics for the subject chemicals, which are listed in the
ini tial TSCA Chemical Substance Inventory, has shown that the
following amounts were reported as manufactured and/or imported
in 1977:
CHEMICAL NAME CAS NUMBER PRODUCTION RANGE
Ch10racetaldehyde 107-20-0 1 million to 10 million pounds
Chloracetone 78-95-5 100 thousand to 1 million pounds
46
-------
8EHQ-0387-0660
Page 4 of 4
It is important to note that this production range information
does not include any data claimed as TSCA Confidential Business
Information (TSCA CBI) by the person(s) reporting for the initial
TSCA Chemical Substance Inventory nor does it include any infor-
mation that would compromise TSCA CBI. All of the information
reported for the initial TSCA Inventory, including the production
range information, is subject to the limitations contained in the
initial TSCA Inventory Reporting Regulations (40 CFR 710).
According to secondary literature sources consulted by EPA, both
cloracetone and chloracetaldehyde are used primarily as chemical
intermediates.
Comments/Recommendations
a)
In view of EPA I S general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure data, the Chemical Screening Branch
will ask Wacker Chemicals (USA), Inc. to describe the
actions the company has taken or plans to take 1) to
notify workers and others about the reported toxicologic
findings, and 2) to reduce or eliminate exposure to the
subject chemicals. In addition, Wacker will be asked to
describe the nature and results, if available, of all
studies (other than those cited in the open scientific
literature or those reported already to EPA) about which
the company is aware or that the company has conducted,
is conducting or plans to conduct to define the toxicity
of or the exposure to chloracetaldehyde or chloracetone.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of chloracetone or chloracetaldehyde.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and ACGIH. In
addition, copies of this report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
47
-------
UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
MAY 2 0 1987
Page 1 of 4
SU8JECT:
Status Report * 8EHQ-048 7-0661 S Approved:
James F- Darr, Section H€ad ~ ~~
Chemical Risk IdentificatioJlsection/CSB
~ 5fpfr7
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
(See NOTE on page 4 of this status report)
The ClBA-GEIGY Corporation has claimed the exact identity of the
subject chemical as TSCA Confidential Business Information (TSCA
CBI)i the Information Management Division (IMD/OTS) will request
CIBA-GEIGY to substantiate this CBI claim. In the "sanitized"
version of the TSCA Section 8(e) submission, CIBA-GEIGY reported
that the tested product (D17-1242) "is a 20% aqueous solution of
a high molecular weight polyquaternary compound" with a molecular
weight of 5000 ~ 2000.
Submission Description
(See NOTE on page q of this status report)
It should be noted first that D17-l242 was the subject of a
recent "For Your Information" (FYI) notice (FYI-OTS-0187-0530 S)
in which ClBA-GEIGY provided summarized results from an attempted
dermal senzitization study of D17-l242 in guinea pigs. According
to this FYI notice, all animals in the test group died following
intradermal injection of 3-4 mg/kg D17-l242 (i.e., 0.6-0.8 mg/kg
polyquaternary compound). In addition, CIBA-GEIGY reported that
guinea pigs injected intradermally with lower doses of D17-l242
died also. In subm~tting these findings to the Agency on an FYI
basis, CIBA-GEIGY reported that the D17-l242 results conflicted
significantly with the results of a guinea pig dermal sensitiza-
tion study conducted by CIBA-GEIGY in 1978 with FAT 60l34/A, a
30% solution of a "presumably identical" polyquaternary compound.
CIBA-GEIGY reported that intradermal injection of FAT 60l34/A did
not cause death or sensitization in this 1978 study. CIBA-GEIGY
stated also in its FYI notice that FAT 60134/A had an oral LD50
of >2000 mg/kg (species not specified) and was non-mutagenic in
an Ames Salmonella typhimurium (bacteria) test.
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
l~for~atlon S~bmltted t~ EPA pursuant to Section 8(e), the substantial
rlsk lnformatlon reportlng provision of the Toxic Substances Control
Act (TSCA): Th~ statements. made in this report should not be regarded
as expresslng flnal EPA POllCY or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
48
EPA FORM U20-6 (REV. 3-76)
-------
8EHQ-0487-0661 S
Page 2 of 4
In light of the vast discrepancy in the results obtained from the
guinea pig sensitization studies conducted with D17-1242 and FAT
60134/A, CIBA-GEIGY stated that although the severe toxic effects
observed in the D17-1242 study were viewed as serious enough to
merit consideration for reporting to EPA under TSCA Section 8(e),
the company could not reliably ascribe the observed toxicity to
any chemical(s) until the company received analytical data on the
composition of Dl7-1242. CIBA-GEIGY reported also that oral rat
LD50 and intraperitoneal mouse and rat LD50 studies were planned
for Dl7-l242.
In its Section 8(e) submission, ClBA-GEIGY reported that based on
recently received analytical data showing D17-1242 to be pure
(except for water), CIBA-GEIGY concluded that the highly toxic
effects observed after intradermal injection of D17-1242 in the
attempted sensitization study were attributable to D17-1242 per
se and that FYI-OTS-0187-0530 S should be treated now as a TSCA
Section 8(e) submission.
In its Section 8(e) notice, CIBA-GEIGY also provided information
concerning the results of acute oral rat LD50 and intraperitoneal
mouse and rat LD50 studies of D17-1242. According to the sub-
mitted information, no male or female rats died following oral
administration of D17-1242 at a dose of 2 g/kg; the animals were
reported to have exhibited dyspnea, exophthalmos, ruffled fur,
and curved body position but did recover within 11 days. CIBA-
GEIGY also submitted the following information regarding the
resul ts of the study in which D17-l242 was injected intraperi-
toneally at a single dose of 2, 10 or 50 mg/kg body weight (bw)
to 1 male and 1 female mouse at each dose level:
"No symptoms were observed in the animals of the 2 mg/kg
bw dose group. The animals in the 10 mg/kg bw dose group
died within 17 minutes after injection [and] the animals
in the 50 mg/kg bw dose group [died] within 6 minutes.
In both [the 10 and 50 mg/kg bw] dose groups, dyspnea,
cyanosis, ataxia, clonicotonic convulsions, exophthalmos
and abnormal body positions were observed. At autopsy,
no deviations from normal morphology were found in the
animals of the 2 mg/kg bw dose group. Narrow heart ven-
tricles were found in the animals of the 10 and the 50
mg/kg bw dose groups. Additionally, the animals of the
50 mg/kg bw dose group showed stasis of the veins (v.v.
cavae portaid)."
With regard to a study in which 2 rats (1 male and 1 female) were
injected intraperitoneally with D17-1242 at a single dose of 50
mg/kg bw, CIBA-GEIGY stated that the rats" showed similar symp-
toms as the mice and died within 15 minutes after injection."
It should be noted that CIBA-GEIGY also submitted a supplemental
FYI notice (FYI-OTS-0387-0530 S SUPp) reporting that D17-1242 had
a 48 hour EC50 of 0.038 mg/liter for Daphnia magna and a 96 hour
LC50 of 0.25 mg/liter for rainbow trout.
49
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...:...: -
" ,
'-,I,' ,
. :_} .
8EHQ-0487-0661 S
Page 3 of 4
I::
:,,' /-~. ,~~ ',-1' " .-
~,~\3hhmls sion Evaluation
The submitted data give rise to a concern for human skin exposure
(especially abraded skin exposure) to even small amounts of the
subject polyquaternary compound (D17-1242). In addition, the
submitted data from the 1978 study with FAT 60134/A indicate that
al though intradermal challenge with this material did not cause
sensitization, the epidermal challenge did evoke a sensitization
response; this particular observation indicates that FAT 60134/A
is a sensitizing agent. Further, it is important to note that in
1986, EPA received a TSCA Section 8(e) submission (8EHQ-0386-0S91
et seq.) in which cardiotoxici ty was reportedly observed as the
result of repeated dermal application of dioctyldimethylammonium
chloride (DODMAC) to rabbits; the reader's attention is directed
to the status report prepared by EPA in response to this earlier
TSCA Section 8(e) notice. Finally, it should be noted that the
submitted aquatic LCSO and ECSO values for D17-1242 are of con-
cern to EPA should there be significant environmental exposure to
this polyquaternary compound.
Current Production and Use
According to CIBA-GEIGY's TSCA Section 8(e) submission, D17-1242
is an imported research and development (R&D) material. In the
initial FYI notice, CIBA-GEIGY stated that "the only [D17-1242]
distribution in the U. S. was an 8 oz. sample to one potential
customer for evaluation" and this "customer used up some of the
sample in testing and has decided not to pursue development any
further." CIBA-GEIGY stated also in the initial FYI notice that
this customer had been informed by CIBA-GEIGY both by phone and
in writing about the results of the attempted guinea pig dermal
sensi tization study of D17-1242 and that the customer returned
the unused portion of the sample to CIBA-GEIGY for disposal.
Comments/Recommendations
The Chemical Screening Branch (CSB/ECAD/OTS) will request the OTS
Document Control Office (DCO) to process both FYI-OTS-0187-0S30 S
and FYI-OTS-0387-0S30 S SUPP as supplemental submissions to TSCA
Section 8(e) submission number 8EHQ-0487-0661 S.
a)
In light of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure data, the Chemical Screening Branch
will ask CIBA-GEIGY to describe the actions the company
has taken or plans to take 1) to notify its own workers
about the reported toxicological findings for D17-1242,
and 2) to reduce or eliminate exposure to the subject
polyquaternary compound. CIBA-GEIGY will be asked also
to describe the nature and results, if available, from
all studies (other than those reported already to EPA)
about which ClBA-GEIGY is aware or that the company has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of this polyquaternary compound.
50
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8EHQ-0487-0661 S
Page 4 of 4
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject polyquaternary compound.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, ORD/EPA, OAR/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
NOTE:
In a letter dated June 24, 1987 (8EHQ-0787-0661 FLWP), CIBA-GEIGY
withdrew its TSCA CBI claim covering the chemical identity of the
tested polyquaternary compound. According to the "declassified"
version of CIBA-GEIGY's initial Section 8(e) notice, the subject
chemical is a "poly addition product of bischloromethyldiphenyl
and N,N,N',N'-tetramethylhexanediamine" (CAS No. 63943-38-4).
iJ!I:
1/J:;) $7
51
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DATEI
SUBJECT:
UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
APR
6 1981
Page 1 of 1
FROM:
Status Report * 8EHQ-0487-0662 Approved :z;!J:<-
James F. Darr, Section Head ~?:~
Chemical Risk Identificatiorllsection/CSB
4/rs/rn
.. ..
TO:
Frank D. Kover, Branch Chief
Chemical Screening Bra.nch/ECAD/OTS/OPTS
Submission Description
The Vista Chemical Company reported that ethylene dichloride
(EDCi 1,2-dichloroethanei CAS No. 107-06-2) was detected recently
in the soil and groundwater at the company's vinyl chloride manu-
facturing facility located in Westlake, Louisiana. According to
Vista, "soil samples taken from a boring hole located on the
western fence line of the plant property indicated levels of
ethylene dichloride in the 0.3 - 1.0 ppm range." In addition,
Vista reported that" subsequent water samples taken from that
boring have indicated EDC levels of 0.3 - 2.5 ppm." Vista stated
that the reported analytical results "indicate previously unknown
la teral migration of the contamination at the site." Finally,
Vista reported that 1) the company's investigation was conducted
in response to a Louisiana Department of Environmental Quality
(LDEQ) compliance order, and 2) the company "is continuing to in-
vestigate potential off-site migration and potential for human
exposure from the groundwater in this aquifer."
Comments/Recommendations
Immediately upon receipt of the Vista Chemical Company I s TSCA
Sect ion 8 (e) not ice, the Chemical Screening Branch transmitted
copies of the notice to the Office of Groundwater/EPA Region 6
(Dallas, Texas), the Office of Water (OW/EPA), the Office of
Groundwater Protection (OGWP/OW/EPA), the Office of Solid Waste
and Emergency Response (OSWER/EPA) and the Office of Air and
Radiation (OAR/EPA) for any warranted followup attention by EPA.
The Chemical Screening Branch will send copies of this status
report to NIOSH, OSHA, OW/EPA, OSWER/EPA, OAR/EPA, OGWP/OW/EPA,
and OGW/EPA Region 6. Copies of this status report will be sent
also to the TSCA Assistance Office (TAO/OTS/OPTS) for further
distribution.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
EPA FORM 1320-6 IREV. 3-76)
52
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
OAT!,
APR 1 3 1987
Page 1 of 3
SUBJECT,
Status Report *
8EHQ-0487-0663
Approved :;:;tt- f~/17
FROM:
~A?d/d~~ /«
James F. Darr, Sect10n Head
Chemical Risk Identification Section/CSB
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
In submitting this notice under Section 8(e) of TSCA, the Eastman
Kodak Company stated non-confidentially that the tested chemical
had been the subject of a "Premanufacture Notification" (PMN No.
86-1259) filed previously with EPA under Section 5 of TSCA.
Submission Description
Eastman Kodak provided the following information with regard to
the conduct and results of an acute oral toxicity study of (1-
ethoxyethylidene)propanedinitrile (CAS No. 5417-82-3) in rats:
"Groups of 5 male and 5 female rats were given 156, 312
or 625 mg/kg of the test compound in a single gavage
dose as part of an acute oral LD50 study. All animals
died at 625 mg/kg. Abnormalities noted at necropsy in-
cluded hemorrhage of the thymus, edema, necros is and
hemorrhage of the glandular stomach, and necrosis of the
non-glandular stomach. At 312 mg/kg, 4 of 5 males and 1
of 5 females died. Treatment-related abnormalities in-
cluded edema, necrosis and hemorrhage of the glandular
stomach, enlarge~ pale livers, and fibrous adhesions be-
tween lobes of the liver. Additional abnormalities noted
in one or more animals included yellow discoloration of
the liver i rough appearance of the liver capsu Ie, and
enlarged or darkened spleens. Kidney lesions involving
the cortical tubular epithelium were seen in one female
rat. At 156 mg/kg, all animals survived. Abnormalities
included enlarged pale livers, fibrous adhesions between
lobes of the liver and darkened spleens. At the lowest
dose, liver lesions noted through histopathology exami-
nation of the tissues included diffuse and focal
necrosis, mineralization, hemorrhage, inflammation,
diffuse fibrosis, the presence of pigmented macrophages.
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
53
EPA FORM 1320-1 (REV. 3-711
-------
8EHQ-0487-0663
Page 2 of 3
and bile duct proliferation. Cellular changes in
hepatocytes included hydropic degeneration, cytoplasmic
lipid vacuolation, cytoplasmic basophilia, hypertrophy,
increased mitosis, and hyalin degeneration. .."
In its Section 8(e) notice, Eastman Kodak also submitted summary
resul ts from an acute dermal LDSO study in rats and an acute
dermal irritation study in guinea pigs. According to the pro-
vided information, the subject chemical has an acute dermal LDSO
of greater than 2 g/kg and is slightly irritating to guinea pig
skin. Finally, Eastman Kodak submitted a Material Safety Data
Sheet (MSDS) tha t had been updated to reflect the toxicologic
findings reported to EPA under Section 8(e).
Submission Evaluation
In order for the Agency to evaluate the overall significance of
the reported findings, Eastman Kodak should be asked to provide
full copies of the final reports (including the actual experi-
mental protocols, results of gross/histopathologic examinations,
etc.) from all studies cited in the Section 8(e) notice.
Immediately upon receipt of this Section 8 (e) submission, the
Chemical Screening Branch (CSB/ECAD/OTS) transmitted copies of
the notice to appropriate individuals in the Chemical Control
Di vision (CCD/OTS) responsible for administering the OTS "New
Chemicals Program" (NCP).
Current Production and Use
According to the submitted MSDS, the subject chemical substance
is a water insoluble white solid with a melting point of 9l-92°C
(196-198°F). In its Section 8(e) notice, Eastman Kodak reported
that the subject chemical "is used as a low volume site-limited
intermediate. " With regard to the potent ial for worker exposure,
Eastman Kodak provided the following information:
"Potential employee exposure has been minimized during
the manufacture and isolation of the damp intermediate
by the use of company supplied/laundered work clothes,
boots, gloves, and a face shield. Employees handling the
dry intermediate wear fresh-air supplied respirators,
company laundered work clothes,. boots and gloves."
Finally, Eastman Kodak reported that the company "is not aware of
any adverse health problems associated with [manufacture of the
subject chemical] or its use to make the final product."
Comments/Recommendations
In addition to modifying the MSDS, Eastman Kodak stated that the
company is "currently evaluating the need for further testing" of
(l-ethoxyethylidene)propanedinitrile.
54
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8EHQ-0487-0663
Page 3 of 3
a)
The Chemical Screening Branch will request Eastman Kodak
to submit full copies of the final reports (including
the actual experimental protocols, results of gross and
histopathological examinations, etc.) from all studies
cited in the company's TSCA Section 8(e) notice.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure data, the Chemical Screening Branch
will request Eastman Kodak to describe the nature and
results, if available, from all studies (other than
those submitted already to EPA or those ci ted in the
open scientific literature) about which Eastman Kodak is
aware or that the company has conducted, is conducting
or plans to conduct to determine the toxicity of or the
exposure to (l-ethoxyethylidene)propanedinitrile.
b)
The Chemical Screening Branch will send all
information to the OTS New Chemicals Program
appropriate followup attention/actions.
reported
for any
c)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS and CCD/OTS/OPTS. In
addition, copies of this status report will be provided
to the TSCA Assistance Office (TAO/OTS/OTPS) for further
distribution.
55
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
APR 2 1 1987
Page 1 of 3
SUBJECT:
Status Report * 8EHQ-0487-0664 S Aoproved: ~
James F. Darr, Section Head ~Tk
Chemical Risk Identificatio~~~c~ionjCSB
121)c7
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening BranchjECADjOTSjOPTS
Note
E. I. du Pont de Nemours & Company, Inc. has cla imed the exact
identity of the subject chemical to be TSCA Confidential Business
Information (TSCA CBI) ~ the Information Management Di visionjOTS
will request Du Pont to substantiate this confidentiality claim.
In the sanitized version of its TSCA Section 8(e) notice, Du Pont
stated non-confidentially that 1) the tested chemical is a halo-
alkyl substituted cyclic ether, and 2) the chemical had been the
subject of a "Premanufacture Notification" (PMN 85-368) submitted
to EPA under Section 5 of TSCA. According to EPA's public file
for PMN 85-368, EPA. issued a TSCA Section 5 (e) "Consent Order"
for the haloalkyl substituted cyclic ethers that were cited in
PMN 85-367, PMN 85-368 and PMN 85-369. It should be noted also
that a TSCA. Section 8(e) submission (8EHQ-0986-0633 S) was sub-
mitted previously by Du Pont on the haloalkyl substituted cyclic
ether that was the subject of PMN 85-367. The reader's attention
is directed to the status report prepared by EPA in response to
8EHQ-0986-0633 S.
Submission Description
In its Sect ion 8 (e) submis sion, Du Pont provided the following
summary information regarding the conduct and results of a two-
week inhalation study of the subject haloalkyl substituted alkyl
ether in rats:
"Groups of ten male and ten female rats were exposed by
inhalation to concentrations of haloalkyl substituted
cyclic ether of 0, 5, 50 or 500 ppm for six hours a day,
five days a week for two weeks. Male rats exposed to
500 ppm had significantly depressed body weights during
the exposure period, and depressed testes weights imme-
diately following the last exposure and at the end of
the [14-day] recovery period. Microscopic examination
revealed degeneration of the seminiferous epithelium in
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting orovision of the Toxic Substances Control
~ct (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
56
EI>A FORM 132G-6 (REV. 3-761
-------
8EHQ-0487-0664 S
Page 2 of 3
the testes of male rats from all expos1lre groups. The
lesion was discovered in two rats each from the 5 and 50
ppm exposure groups and in 03.11 rats from the 500 ppm
exposure group. The severity of the lesion was generally
dose-dependent, and no evidence of regeneration vIas ob-
served after 14 days of recovery. In addition, male and
female rats exposed to 500 ppm had hepatocellular hyper-
trophy in the liver with accomp::lnying liver weight
elevation, and clinical chemical changes indica tive of
altered hepatic metabolism. No changes were seen in
female rats exposed to either 5 ppm or 50 ppm."
In its Section 8(e) notice, Du Pont reported that another study
(using haloalkyl substituted cyclic ether concentrations that
will overlap the 5 ppm dose level in the present study) would be
conducted "to better define the toxic ef fects on the reproductive
system. "
Submission Evaluation
In view of the fact that the Agency issued a TSCA Section 5(e)
Consent Order covering PMN 85-368, copies of this Section 8 (e)
submission were sent immediately by the Chemical Screening Branch
(CSB/ECAD/OTS) for review and appropriate followup attention by
the Chemical Control Division (CCD/OTS) which is responsible for
administering the 01'8 "New Chemicals Program" (NCP).
Current Production and Use
According to the public fi le copy of PMN 85-368, this haloalkyl
substituted cyclic ether is used as an intermediate and solvent.
In its Section 8(e) submission, Du Pont stated that this chemical
substance" is currently considered [by Du Pont to be] a research
and development material and is being evaluated captively within
Du Pont." In addition, Du Pont reported that an i nterirn work-
place exposure limit of 0.1 ppm has been established for this
haloalkyl substituted cyclic ether.
Comments/Recommendations
In its Section 8(e) notice, Du Pont stated that the company plans
to notify all Du Pont workers potentially exposed to the subject
chemical about the toxicologic findings reported to the Agency
under Section 8(e) of TSCA.
a)
The Chemical Screening Branch will ask Du Pont to ensure
that EPA receives complete copies of the final reports
(including the actual experimental protocols, results of
gross and histopathological examinations, etc.) from the
two-week study and the planned followup study ci ted in
the company's TSCA Section 8(e) submission.
57
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8EHQ-0487-0664 S
Page 3 of 3
In view of EPA I S general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure data, the Chemica 1 Screening Branch
will ask Du Pont to describe the nature and results, if
available, from all studies (other than those reported
already to EPA) about which Du Pont is aware or that the
company has conducted, is conducting or plans to conduct
to determine the toxicity of or exposure to this halo-
alkyl substituted cyclic ether.
b)
f\s in the case of the initial Section 8(e) notice, the
Chemical Screening Branch will transmit immediately all
reported information to the Chemical Control Division
for review and appropriate followup attention.
c)
The Chemical Screening Branch will send copies of this
statu s report to OSfIA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS and CCD/OTS/OPTS. In
addition, copies of this status report will be provided
to the TSCA Assistance Office (TAO/OTS/OPTS) for further
di s tr i but io n .
58
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
MAY I 4 1981
Status Report" 8EHQ-0487-0665 S APproved:~ ;jltfj17
James F. Darr, Section Head ~ ~te:-
Chemical Risk Identificatioh7~e~tion/CSB
Page 1 of 3
SUIJECT:
FROM:
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will request the submitting company to substantiate these CBI
claims. In the "sanitized" version of the company's Section 8(e)
notice, the subject chemical was identified non-confidentially as
BSC-125, a research and development (R&D) surfactant. In addi-
tion, the submitter reported by phone to the OTS Document Control
Office (DCO) that the subject chemical substance could be identi-
fied non-confidentially as an "ethylene oxide/propylene oxide
blocked polymer."
Submission Description
The submitting company provided a copy of the final report from
an acute rabbit eye irritation study of BSC-125. The" ABSTRACT"
sect ion of the submitted report present s the following informa-
tion regarding the conduct and results of this study:
"BSC-125 was evaluated for potential eye irritation
using nine New Zealand White rabbits. Each rabbit was
administered 0.1 ml of the test article to the conjunc-
ti val sac of one eye. The untreated contralateral eye
of each rabbit served as a control. The treated eye of
three rabbits was irrigated with lukewarm water thirty
seconds after test article administration. Treated and
untreated eyes were examined at 1, 24, 48 and 72 hours
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be reaarded
as expressing final EPA Dolicy or intent with respect to the sUbject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
59
EPA FORM 1320-6 (REV. 3-761
-------
8EHQ-0487-0665 S
Page 2 of 3
as well as 4 days post-administration and ocular irrita-
tion scored according to the Draize method. Irri tated
eyes were further examined at 7, 10, 13, 16, 19 and 21
days post-administration. Under the conditions of this
study, BSC-125 produced corneal opacity and conjunctival
irritation to rabbits' eyes without irrigation. These
effects persisted to day 21 in all animals. Conjunctival
irritation was produced by BSC-125 in three rabbits'
eyes irrigated thirty seconds after administration.
Corneal opacity and conjunctival irritation were [found
to be] reversible by days 7 and 19, respectively."
According to the "Test Article Preparation Data" section of the
submitted final report, BCS-125 was received and tested "as is"
(undiluted liquid) by the performing laboratory. It should be
noted also that the performing laboratory determined that a 10%
weight/volume aqueous mixture of the test material had a pH of 6.
Submission Evaluation
According to the submitted information, eye exposure to BSC-125
may result in corneal opacity and eye irritation if BSC-125 is
not washed away immediately following contact with the eyes;
these effects appear to be reversible following irrigation of the
eyes immediately after eye contact with BSC-125. The submitting
company should be requested to provide the exact identity of the
subject chemical substance.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information with
regard to the current TSCA Chemical Substance Inventory status of
this ethylene oxide/propylene oxide blocked polymer will appear
in this status report. As stated previously, the subject chemi-
cal was reported to be an R&D material being considered by the
company for potential use as a surfactant. The submitter also
provided the following information regarding the potential for
exposure to this R&D surfactant:
"The extent of the risk was and is currently limited by
the fact that only a small amount of this compound has
been made under the direction of technically qualified
staff. The evaluation of the [R&D] material has been
conducted by a limited number of the submitter's per-
sonnel and qualified [outside] toxicologists . who
are normally involved in evaluating toxic effects of
chemicals. Personnel with potential for exposure are
protected by use of protective facilities, equipment and
clothing, i.e., laboratory hoods, impervious gloves, lab
coa ts and eye protect i ve equipment."
60
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8EHQ-0487-0665 S
Page 3 of 3
comments/Recommendations
In its Section 8(e) submission, tl1e company reported that 1) "all
personnel with potential exposure to . . . [BSC-125 surfactant]
will be informed of the [reported toxicological] findings and
quidelines for handling," and 2) "the Experimental Product Data
Sheet will include a statement concerning the severe eye irritant
finding as will the experimental sample label."
It should be noted that although EPA is concerned in general
about the acute toxicity of chemicals, the acute toxicologic in-
formation as presented in this Section 8(e) submission does not
appear to be of the type required for submission to EPA pursuant
to Section 8(e), the "substantial risk" information reporting
provision of TSCA. In making this statement with regard to TSCA
Section 8(e)-reportability, however, it must be noted also that
EPA is not aware of any additional information that may have been
considered by the company in making its decision to submit the
subject findings to the Agency under Section 8(e) of TSCA.
a)
The Chemical Screening Branch (CSB/ECAD) will request
the submitter to provide the exact identity (including
CAS Registry Number, if known) for the subject chemical
substance. In addition, the submitter will be asked to
provide further information with regard to the company's
rationale for submitting the subject findings to EPA
under Section 8(e) of TSCA.
In view of EPA I S general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure data, the Chemical Screening Branch
will ask the submitting company to describe the nature
and results, if available, from all studies (other than
those ci ted in the open scientific literature or those
submitted already to EPA) about which the company is
aware or that the company has conducted, is conducting
or plans to conduct to determine the toxicity of this
R&D surfactant.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS as ses sment of this ethylene oxide/propylene oxide
blocked polymer.
c)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
61
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
OAT!:
MAY 2 I 19S1
Page 1 of 5
SUIJ!CT,
Status Report *
8EHQ-P487-0666 S
APproved:~ ~~~7
FROM,
James F. Darr - Sectioo Head (1...#~ r ~
Ch~mical Risk'Identif~cationU;::~ion/CSB
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name to be TSCA
Confidential Business Information (TSCA CBI); the Information
Management Division (IMD/OTS) will request the submitter to sub-
stantiate this TSCA CBI claim.
Submission Description
The submitting company reported that it had recently received
from PPG Industries, Inc. a diallyl diglycol carbonate (CR-39@
Monomer; CAS No. 142-22-3) Material Safety Data Sheet (MSDS)
which provided the following summarized information with regard
to the results of a dermal teratology study in rabbits:
"A [CR@-39 MonomerJ teratology study using skin exposure
of pregnant rabbi ts produced significant toxici ties in
the unborn (increased rate of abortion and eye anoma-
lies) at dose levels which also caused significant
maternal toxicities (mortalities, body weight suppres-
sion and liver effects). However, there was no evidence
that CR@-39 Monomer exposure to the skin caused effects
on the unborn in the absence of significant harmful
effects to the mother. Skin irritation was present in
all monomer-treated groups. "
In reporting this information to EPA under Section 8(e) of TSCA,
the submittiny companY' stated that it was informed by PPG that
"the fetal effects were caused by maternal toxicity and were not
compound related." The submitting company reported also that it
was unable to obtain a c~py of the final report from this study
from PPG.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantia1
risk information reporting orovision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
62
EPA FORM U20-6 (REV. 3-761
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8EHQ-0487-0666 S
Page 2 of 5
Shortly after EPA's receipt of this TSCA Section 8(e) submission,
PPG Industries, Inc. provided to EPA on a "For Your Information"
(FYI) basis (FYI-OTS-0487-0538) a copy of the CR@-39 Monomer MSDS
as well as the following summarized information concerning the
conduct and results of the subject teratology study:
"The CR@-39 teratology study was conducted as part of a
series of studies investigating [the] potential toxic
endpoints of this commercial product. Because the most
probable route of exposure to CR@-39 in the workplace is
through skin contact, the teratology study was conducted
. .[by CR@-39 monomer application] to the shaved backs
of female rabbits on days 6-18 of pregnancy at doses of
0, 0.1, 0.5 or 1.0 ml monomer/kg body weight/day. The
test site remained uncovered. Exposures were terminated
6 hours after test material application by swabbing
clean the skin test sites. Salient findings of the bio-
assay were the following:
1. Significant toxicities in the maternal animals were
caused by both 0.5 and 1.0 ml monomer/kg dose levels. An
increased number of mortalities were seen at the high
dose. Depressions in body weight gain and liver changes
were seen in both dose groups. Skin lesions were present
in all monomer-treated groups.
2. Other findings in the two highest dose groups were
increased rates of abortion as well as lens opacities
and small lenses in the eyes of fetuses. Minor skeletal
findings were also seen in the 0.5 ml/kg group. These
fetal anomalies are considered minor in nature, and all
of the effects occurred only at dose levels causing harm
to the maternal animals.
3. At a dose level of 0.1 ml/kg, there were (a) no
maternal toxicities except for the skin lesions which
are not a significant indicator of maternal toxicity for
teratology studies, and (b) no developmental toxic ef-
fects as evidenced by no increase in fetal anomalies
with dose. Therefore, 0.1 ml/kg can be considered a no-
observed-effect-level (NOEL).
The finding of small lenses, lens opacities and associ-
ated anomalies in the eyes of fetuses from some high and
mid-dose litters was discussed with the Study Director
at [the pri vate contract laboratory that performed the
teratologic study]. These findings are indicative of
developmental toxic effects during the later stages of
ocular development and occurred only at doses where
there was significant maternal toxicity. Similarly, the
minor skeletal findings, which occurred only when there
was an accompanying adverse effect upon maternal weight
gain, were not considered to be of teratological sig-
nificance.
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8EHQ-0487-0666 S
Page 3 of 5
The conclusions drawn from the [performed] study were:
no teratologic findings were demonstrated at any dose
levels: the developmental toxic effects occurred at dose
levels where there was accompanying maternal toxicity:
[and] a no-observed-effect-level (NOEL) of 0.1 ml/kg was
established for both maternal and corresponding develop-
mental toxic effects."
In submitting the preceding information to EPA on an FYI basis,
PPG stated its belief that the performed teratology study is a
well-conducted "negative" study that "provides practical infor-
mation in the assessment of potential human effects because the
primary occupational exposure is dermal and the worker population
is predominantly female {ophthalmic lens production industry)."
According to the submitted MSDS, CR~-39 Monomer can be moderately
to severely irritating to human eyes and severely irritating to
human skin: accidental swallowing (by humans) of CR~-39 Monomer
can cause burns to the mouth and gastrointestinal tract, illness
and possibly death. With regard to skin absorption, the MSDS
states that studies conducted with rhesus monkeys show that the
CR~-39 Monomer "penetrates the skin and. . 90% of the amount
absorbed is eliminated from the body within 4 days." The sub-
mitted MSDS also provides the following information with regard
to the conduct, results and interpretation of an acute inhalation
toxicity study of CR~-39 Monomer in rats:
"One-hour exposures at a concentration of 0.73 mg/liter
(maximum attainable concentration at 25°C) caused no
deaths in test animals. Due to its low vapor pressure
[(2 mm Hg at 166°C)], CR~-39 Monomer is not considered
to be a hazard by inhalation of vapors: however, if
conditions exist which generate substantial vapors or
mists, inhalation would be expected to result in severe
irritation of the eyes, mucous membranes and respiratory
tract."
The submitted MSDS also contains the following information with
regard to the toxicity of CR@-39 Monomer to aquatic species:
96-hr LC50 (Bluegill) 0.57 mg/l (highly toxic)
48-hr LC50 (Water Flea) 18 mg/l (moderately toxic)
96-hr LC50 (Sheepshead Minnows) 0.7 ppm (highly toxic)
96-hr LC50 (Mysid Shrimp) 70.7 mg/l (slightly toxic)
96- hr EC50 (Marine Alga) >10.0 ul/l (moderately toxic)
Finally, PPG provided in its FYI submission a copy of a technical
bulletin detailing the conduct and results of a CR~-39 Monomer
permeation study using nine (9) different types of commercially
available protective gloves. According to the provided technical
bulletin, permeation of CR~-39 Monomer varies depending on the
type of material from which the glove is made and the duration of
exposure: the bulletin recommends that all CR@-39 Monomer users
evaluate their own glove program to minimize exposure.
64
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8EHQ-0487-0666 S
Page 4 of 5
Submission Evaluation
In order for the Agency to evaluate properly the results of the
diallyl diglycol carbonate dermal teratology study in rabbits,
PPG should be reques ted to submit a complete copy of the final
report from that study. It should be noted at the present time,
however, that there have been a number of developmental toxicity
studies conducted in which the tested chemicals caused maternal
toxicity (in some cases, severe maternal toxicity, e.g., lethal-
i ty) but did not cause adverse developmental effects. In other
words, the mere fact that maternal toxicity occurs does not pre-
clude the possibility that the tested chemical can cause develop-
mental toxicity independent of that maternal toxicity- Further,
EPA's published developmental toxicity risk assessment quidelines
(51 FR 34028-34040; September 14, 1986) state that developmental
effects that occur at maternally toxic levels should not be dis-
counted. In addition, these EPA guidelines were supported at an
Agency-sponsored public workshop on maternal and developmental
toxicity held in Rockville, Maryland in May of 1986 (proceedings
from this workshop will be published in an upcoming issue of
Teratogenesis, Carcinogenesis and Mutagenesis). Finally, it is
important to note that maternal effects may be reversible while
the effects on the offspring may be permanent.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for diallyl diglycol carbonate (CAS No. 142-22-3),
which is listed in the initial TSCA Chemical Substance Inventory,
shows that approximately 1 million to 10 million pounds of this
chemical substance were reported as manufactured and/or imported
in 1977. This production range information does not include 1)
any information claimed as TSCA Confidential Business Information
(CBI) by the person(s) reporting for the initial TSCA Inventory,
or 2) any data that would compromise TSCA CBI; all of the data
reported for the initial TSCA Inventory, including the production
range data, are subject to the limitations contained in the TSCA
Inventory Reporting Regulations (40 CFR 710).
According to information obtained by the Agency via a search of
publicly available computerized data bases, diallyl diglycol car-
bonate monomer is used in the manufacture of optical quality
transparent plastic materials (e.g., aircraft windows, lenses).
Comments/Recommendations
It should be noted that in a 1979 TSCA Section 8(e) notice (8EHQ-
0979-0311), PPG submitted final results from an acute rabbit eye
irri tation study of a mixture containing diallyl diglycol car-
bonate (75%), maleic anhydride (20%), tungsten hexacarbonyl (5%)
65
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8EHQ-0487-0666 S
Page 5 of 5
and hydroquinone monomethyl ether (100 ppm). In this earlier
Section 8(e) notice, PPG stated that the mixture produced corneal
clouding within 20 seconds after instillation to rabbits' eyes.
PPG stated also that a subsequent water wash of the affected eyes
for 1 minute did not alleviate the condition (corneal cloudiness
and ulcers were still evident 14 days post-instillation).
a)
The Chemical Screening Branch will request PPG to submit
a full copy of the final report (including the actual
experimental protocols, results of gross/histopathologic
examinations, results of statistical analyses, etc.)
from the teratology study cited in the submitted MSDS.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure data, both PPG and the submitter of the
present TSCA Section 8 (e) submission will be asked to
describe the nature and results, if available, of all
studies (other than those cited in either the published
scientific literature or the CR@-39 MSDS or those sub-
mitted already to the Agency) about which the companies
are aware or that the companies have conducted, are con-
ducting, or plan to conduct to determine the toxicity of
or the exposure to diallyl diglycol carbonate.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of diallyl diglycol carbonate.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
NOTE: The reader's attention is directed to the following status report
that was prepared by EPA in response to 8EHQ-0787-0666 FLWP.
66
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
I4B 3 I 1988
Page 1 of 8
SU8JECT:
Status Report*
8EHQ-0787-0666 FLWP
ADproved: ~Ir tj:JI/8r
FROM:
James F. Jarr, Section Head [}~ ~~
Chemical Risk Identificatio~~~~ion/CSB/ECAD
TO:
Joseph J. Merenda, Director
Existing Chemical Assessment Division/OTS/OPTS
Note
The reader's attention is directed first to the "Status Report"
prepared by EPA in response to ini tial TSCA Section 8 (e) notice
number 8EHQ-0487-0666 S.
Submission Description
In response to a written request (EPA letter dated May 26, 1987),
PPG Industries, Inc. submitted complete copies of final reports
from range-finding der~al teratology and full dermal teratology
studies of CR-39 ~10nomer (diallyl diglycol carbonate; CAS No.
142-22-3) in rabbits. In addition, PPG submitted summarized
results of a number of acute/sub-acute ani~al toxicity studies,
absorption/metabolism studies in qhesus monkeys and guinea pigs,
in vitro genotoxicity studies, a skin irritation study in humans,
and aquatic tox i city stud i es of CR-39 Monomer. (The resul ts of
most of the reported studies are presented in the CR-39 Monomer
Material Safety Data Sheet (i'1SDS) and described in the "status
Report" prepared for 8EHQ-0487-0666 S Initial.)
In the full dermal teratology study, groups of 18 inseminated New
Zealand white rabbits were exposed to the CR-39 Monomer at lev€ls
of 10.1, 10.5 or 1.10 ml/kg/day applied to the skin on days 6-18 of
gestation; control animals were exposed to a sterile isotonic
saline solution at the same dosage volume as treated animals in
the high dose group. (The CR-39 Monomer dose levels were selected
on the basis of the results from the dermal range-finding study
in which levels of 10.1, 0.5, 1.0 and 3.0 ml/kg/day were applied.)
A 4 x 9 inch section on the back of each animal was shaved free
of hair. The test liquid or control solution was spread on the
shaved area and remained unoccluded during the exposure period.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statemen~s made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
67
II~A "0"'"' ..... (REV. »-711
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Page 2 of 8
Restraint collars were fitted on each animal immediately prior to
dosage - Residual CR-39 Monomer or control solution was removed
after 6 hours by blotting the treated area with nonabsorbent
cotton. The collars were removed following this procedure.
Preqnant animals were killed by intravenous (iv) injection of a
euthanasia solution followed by exsanguination by incision of the
axillary arteries on day 29 of gestation. The ovaries were then
dissected out and the number of corpora lutea recorded. The
uterus was then removed and the following information recorded:
number and position of live fetuses, dead fetuses, empty implan-
tation sites, and early, middle and late resorptions. Next, the
fetuses were removej from the uterus, we ighed, and kill ed by a
subcutaneous injection of the euthanasia solution. All fetuses
were examined for external malformations and were sexed/examined
internally for malformations. The heads of about one-third of
the fetuses in each litter were removed and fixed for subsequent
examination. The bodies of these and the remaining fetuses were
cleared, stained and subjected to a skeletal analysis.
with regard to maternal effects, 6 animals in the 1.0 ml/kg/day
group died (3 after one or two days of treatment and 3 on days
20-22 of gestation) and 1 was killed (on day 22 of gestation) in
a moribund state. Gross pathologic findings common to the 3
rabbits that died early in the study included effects on the
stomach, vag i na and bladder. One rabbi t also exh i bi ted effects
on the endocardium and kidneys. Gross pathologic findings among
the 4 rabbits that died later in the study included effects on
the liver, kidneys and stomach. Dark red/black discrete or
diffuse areas were re?orted to be commonly seen at the dosage
sites in animals among all treatment groups. Some animals among
all treatment groups exhibited red secretions from the black
thickened areas. These lesions often developed yellow coloration
at thei r per i phery and underwent scab format ion. Accord i ng to
the submitted report, the incidence of the lesions increased in a
dose-related manner. In the 1. 0 ml/kg/day group, there was a
significant decrease in body weight on days 12, 15, 18 and 24 of
gestation. In addition, animals in this group had a significant
decrease in body weight gain during the periods of days 6-9,
9-12, 12-15, 15-18, 18-24 and 6-18. In the 0.5 ml/kg/day group,
there was a significant decrease in maternal body weight gain
during the periods of days 9-12, 15-18 and 6-18 while the body
weights and body weight gains among those animals in the 0.1
ml/kg/day group were comparable to those of control animals.
The findings at necropsy revealed adverse effects on the heart
kidney, liver, stomach, vagina, mesentery and bladder of animal~
in the 1.,0 ,ml/kg/day dose group. Rabbi ts in the (3.5 ml/kg/day
group exhlbl ted adverse effects on the mesentery and bladder.
Adverse effects were observed in the stomachs of animals in the
0.1 ml/kg/day group. The incidence of abortion among all groups
was 1, 0 , 3 and 6 for doe sin the con t r 0 1, (3. 1, '3. 5 and 1. (3
ml/kg/day group, respectively. Furthermore, one control and two
1. 0 ml/kg/day rabbits littered early. The number of pregnant.
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animals at the start of the study was 16, 18, 16 and 18 for the
control, 0.1, 0.5 and 1.0 ml/kg/day groups, respectively. At the
time of scheduled sacrifice on day 29 of gestation there were 14,
18,13 and 3 rabbits with live fetuses for the control, 0.1, 0.5
and 1.0 groups, respectively.
Wi th regard to developmental effects, there were no s igni f i cant
differences among the control, 0.1 and 0.5 ml/kg/day groups for
rabbits that survived to day 29 of gestation for the following
parameters evaluated: number of corpora lutea, implantation
sites, live fetuses, dead fetuses, resorptions, individual fetal
weights, litter weights, gravid uterine weights and preimplanta-
t ion and post implantation losses. However, 2 of the 3 does in
the 0.5 ml/kg/day group that aborted had an increased incidence
of resorptions. Furthermore, in the 1.0 ml/kg/day group, among
the rabbits that either aborted, littered early, died or were
sacrificed preterm, there was a marked increase in the incidence
of resorptions.
There was a significant increase in the incidence of ocular
opacities and small lenses among fetuses (5 out of 12 fetuses
examined in 1 of the 3 litters) in the 1.0 ml/kg/day group.
Three of these fetuses also had lenses formed in two-layers. In
addition, some of the fetuses that were prematurely delivered
also had abnormalities of the lens. There was a significant
increase in the number of fetuses (6 out of 34 examined in 3 of
12 litters) in the 0.5 ml/kg/day group that had small lenses.
Three of these fetuses in 2 litters had opacity of the lenses as
well. In addition among these three, in one fetus, one lens was
adhered to the cornea, in a second fetus, one lens was encapsu-
lated by retinal/choroid tissue, and in the third fetus, retinal
tissue covered the front of one lens and the other lens was
formed in two layers and connected to retinal/choroid tissue.
The overall incidence of what was defined in the submitted report
as minor skeletal anomalies did not jiffer among the treated and
control groups; however, the report indicated that fetuses with
major malformations were excluded from the total minor skeletal
anomalies. There was a significant increase in the number of
fetuses with absent pubic bones and reduced number of phalanges
and metatarsals among those fetuses in the 0.1 :nl/kg/day group.
According to the report, because these findings occurred among
fetuses from a single litter, the findings were dismissed as not
being treatment related.
There were no significant differences reported in the incidence
of sternebral variations in fetuses from the treated or control
animals. In fetuses from the 0.5 ml/kg/day exposure grout', there
was a significant decrease in the occurrence of single 13th rib
and a concomitant increase in the incidence of paired 13th ribs
and a significant elevation in the incidence of 27 presacral
vertebrae. The following findings were reported among fetuses in
the 1. (J ml/kg/day group that were aborted on days 19- 2 2: ope n
eyes, domed skull and eventration of the intestines and liver at
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the urnbi licus. Two fetuses in one li tter reportedly had clefts
in the vertebral column. According to the report, open eyes and
domed skull may be indicative of the early stage of development.
The other findings were regarded in the report as perhaps being
attributed to trauma during abortion.
In the June 26, 1987 cover letter to 8EHQ-0787-0666 Followup
Response, PPG stated the company "is not currently conducting any
toxicology studies on diallyl diglycol carbonate nor are any
studies olanned for the near future." PPG also stated, however,
that a ;ecently conducted study indicated that North Silver
Sh i e 1 d gloves "d id not degrade after extended exposure and the
volatile components of CR-39 Monomer did not permeate through the
glove material."
In answer to the Agency's questions concerning worker exposure to
CR-39 Monomer, PPG reported that "no exposure measurements have
been made for diallyl diglycol carbonate." PPG noted, hO\.,ever,
that "industrial hygiene reviews" of PPG manufacturing plants and
"walk-thru surveys" of certain customers' facilities have been
conducted by PPG in order to "offer advice on limiting the degree
of skin and eye contact with this chemical."
Submission Evaluation
The provided toxicologic information has numerous inconsistencies
and is incomplete wi th regard to data reporting. So:ne examples
of these problems are as follows:
o In the range-finding teratology study, the applied doses of
CR-39 Monomer are reported to be 0.1, 0.5, 1.0 anl 3.0 ml/kg/day.
The equivalent CR-39 Monomer doses in terms of mg/kg/day are
given as 0.11, 0.57, 1.14 and 3.43 mg/kg/day, respectively. In
the full teratology study, CR-39 Monomer dose levels of 0.1, 0.5
and 1.0 ml/kg/day are expressed as 114, 572 and 1143 mg/kg/day,
respectively. Because the specific gravity of CR-39 is given as
1.143, EPA assu~es that the latter figures are the accurate ones.
o In the cover letter to 8EHQ-0787-0666 Followup Response,
PPG cites a number of toxicologic studies conducted on CR-39
Monomer. The results of ti)e acute eye irritation study in Ne\17
Zealand white rabbits were sum,narized as follows: "All studies
reveal that the chemical only produces slight, reversible [eye]
irritation. .." The results of PPG's CR-39 Monomer teratology
study suggest that the chemical caused severe skin irritation.
It is jifficult to understand hO'N a che:nical that produced such
serious skin irritation would produc2 only "slight, reversible
irritation" of the eyes.
o The same cover let ter i nd i ca tes ti1a t the acute derma 1 LD 50
of CR-39 ~o~omer was in excess of 10 Dl/kg/day when testeJ in New
Zealand white rabbits. ~Jo ,nention of s~dn irritation is made;
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nor is there any such discussion under the provided descriptions
of percutaneous absorption studies conducted in the monkey and
guinea pig. The cover letter and the MSDS, however, indicate
that in humans, repeated skin contact with even small a~ounts of
CR-39 Monomer can cause severe irritation, possibly leading to
blistering and secondary infection while some individuals may
e xper i ence u r t i ca ria. The degree of react i on was repor ted to
differ significantly among individuals.
o There appear to be inconsistencies in what is presented in
the full teratology final report text under "Results" and the
resul ts presented in Table 6 (" Incidence of Gross Pathological
Findings"). From the written description, one is led to believe
that many of the exposed rabbits were adversely affected by the
dermal and systemic effects of CR-39 Monomer. However, according
to Table 6, the incidences of these effects are clearly not as
great as one was led to believe. For example, the description of
the skin effects suggests that many animals from all groups were
adversely affected, while according to Table 6, only 1-2 animals,
with one exception, exhibi ted each effect noted. Furthermore,
the severity of the effects described in Table 6 are nowhere near
as grotesque as those descr ibed in the text. Interpreta t i on of
the dermal findings are further complicated by failure of the
report to include the results of daily clinical observations.
Had this information been included in the report, it would be
easier to determine whether the findings described in the text
relate to what was observed during the course of treatment. It
is possible that once treatment stopped, the skin lesions began
to heal to the point that what was observed at necropsy and
reported in Table 6 are the results of reversible lesions.
o The text of the full teratology study final report stated:
"Qualitative assessment of food consumption and fecal volume
indicated dose-related increased incidences in the 10.5 and 1. (3
ml/kg/day groups. . II Unfortunately, it is not known to ttlhat
incidences thi s statement refers. At first glance, it appea r s
that food consumption was increased at these particular doses.
However, further in the report (in discussing the stomach lesions
found in the 1.13 ml/kg/day group), it is reported that these
lesions may be correlated with the greater occurrence of rabbits
not eating in this group. Quantitative data on food consumption
would be needed in order to attempt to interpret the significance
of the stomach lesions. At this point, however, it is impossible
to determine whether the stomach lesions were due to 1) decreased
food consumption (because it is not known for sure that this was
actually a finding) or 2) the direct result of dermal exposure to
CR-39 Monomer.
Despite the above-described inconsistencies and incomplete data,
it is clear that dermal application of CR-39 Monomer to pregnant
rabbits during the major period of organogenesis resulted in
systemic toxicity in the mothers and developmental toxicity in
their offspring.
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Page 6 of 8
Regarding ~aternal toxicity, dermal exposure to CR-39 Monomer at
the 1.0 ml/kg/day dose level caused adverse effects on the skin,
heart, kijney, liver, stomach, vagina, mesentery and urinary
b 1 add e r 0 f the dam s . T his d 0 s e 1 eve 1 a 1 sop rod u c e d mat ern a 1
mortality, abortion and early littering as well as decreased
maternal body weight and body weight gain. Exposure to CR-39
Monomer at 0.5 ml/kg/day resulted in adverse effects on the skin,
mesentery and urinary bladder in the dams. In addition, this
level also resulted in decreased illaternal body weight and body
weight gain. Further, dose levels of 0.1 ml/kg/day caused ad-
verse ef fects on the sk in and stomachs of the exposed dams. It
should be noted that there was no no-observed-effect-level (NOEL)
for maternal effects.
with regard to developmental toxicity, dermal application of
CR-39 Monomer to pregnant rabbits at doses of 1.0 ml/kg/day
produced an increased incidence of resorptions among animals that
died, aborted, littered early or were sacrificed preterminally.
Values for the 3 litters of the does that remained alive on day
29 were similar to those of the control animals. This dose level
also produced a significant increase in the number of fetuses
with ocular anomalies. EPA cannot agree with PPG's statement
that the observed ocular anomalies were caused by the maternal
toxicity. There are insufficient data available to reach this
conclusion. Further, there were several cases of aborted fetuses
with eventration of the liver and intestines; according to tbe
submitted report, the eventration may have been the result of
trauma during abortion. Again, EPA cannot agree with this
interpretation without supporting documentation. The Agency has
reviewed iTlany other teratologic studies in which fetuses were
aborted and such observations were not made - Prenatal exposure
to 0'.5 ml/kg/day resu 1 ted in an i ncrea sed i nc i dence 0 f ocu 1a r
anomalies and a significant decrease in the incidence of single
13th rib and an accompanying increase in the incidence of paired
13th ribs and 27 presacral vertebrae. Finally, there were no
statistically significant develoomental effects found following
exposure to 0.1 ml/kg/day. Therefore, 0.1 ml/kg/day is the NOEL
for developmental toxicity.
In conclusion, the performed teratologic study shows that dermal
application of CR-39 Monomer to pregnant rabbits resulted in both
maternal and developmental toxicities. It is difficult to under-
stand, therefore, why PPG stated in the April 14, 1987 cover
letter to FYI-OTS-0487-0538 Initial that "negative teratology
study resul ts were reported on the [CR-39 Monomer] MSDS "
Perhaps PPG's labeling the dermal teratology study as being
"negative" arises from a major misconception with regard to the
utility of the adult to developmental (A/D) toxicity ratio. In
the April 14, 1987 cover letter, PPG stated that "compounds with
A/D ratios near unity represent less potential risk to the unborn
than do materials with high A/D ratios." EPA disagrees with this
statement. Overall risk depends upon the hazard and the exposure
levels. If humans are exposed to levels that are hazardous then
the risk is great. This is independent of the A/D ratio value.
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An excellent example in this case is alcohol. Although alcohol
probably has an A/D ratio close to unity, humans can be exposed
to hazardous levels and the potential of fetal alcohol syndrome
is very real. Alcohol also provides a good example regarding the
fact that the mother may very well recover from the toxic effects
of the agent (e.g., headache, nausea, vomiting) but her offspring
may be adversely affected (e.g., learning disabilities, :nental
retardation, facial anomalies).
Comments/Recommendations
After reviewing the information presented in 8EHQ-0787-0666
Followup Respons~ and FYI-OTS-(3487-0538 Initial, EPA believes
tha t the f i ndi ngs from PPG' s rabbi t dermal teratolog y study of
CR-39 Monomer should have been reported earlier to EPA under
Section 8 (e), the "substantial risk" information reporting
provision of the Toxic Substances Control Act (TSCA). The
following discussion provides the basis for EPA's position on
this matter:
Section 8(e) states that "any person who manufactures,
[imports,] processes or distributes in commerce a
chemical substance or mixture and who obtains informa-
tion which reasonably supports the conclusion that such
substance or mixture presents a substantial risk of
injury to health or the environment shall immediately
inform the [EPA] Administrator of such information
unless such person has actual knowledge that the
Administrator has been adequately informed of such
information."
The preface to Part V of EPA's TSCA Section 8(e) policy
statement ("Statement of Interpretation and Enforcement
policy; Notification of Substantial Risk" 43 FR 11110;
March 16, 1978) explains that a "substantial risk of
injury to health. . is a risk of considerable con-
cern because of (a) the seriousness of the effect. . .
and (b) the fact or probability of its occurrence."
wi th regard to the ser iousness of the effect, pa r t V
explains that EPA considers the types of health effects
for which substantial risk information must be reported
to include "any pattern of effects or evidence that the
subject chemical or mixture can produce birth
defects. . or serious or prolonged incapacitation."
Information concerning such serious toxic effects can
be obtained directly or inferred from designed studies
(e.g., studies conducted in animals) as described in
Part VI of the Section 8(e) policy statement. Part VI
explains also that a subject "person is not to delay
reporting until he obtains conclusive evidence that a
substantial risk exists, but is to immediately report
any evidence that reasonably supports that conclusion."
73
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Page 8 of 8
\'V i t h reg a r d to" the fa c tor pro b a b i 1 i t Y 0 fit s [( i . e . ,
the serious effect's)] occurrence" criterion, Part V of
the Section g(e) policy statement explains that certain
types of adverse health effects (e.g., birth defects)
are considered by EPA to be "so serious that relatively
li ttle or no we ight is given to exposure [i n terms of
determining whether risk is substantial]; the mere fact
that the implicated che~ical is in commerce constitutes
sufficient evidence of exposure." Also, EPA's response
to Comment 31 in Appendix B of the TSCA Section 8(e)
pol icy statement explains that the mere occurrence of
serious effects such as those described in Part V(a) of
the po 1 icy statement (e.g., bi r th defects) presuppose
exposure to the subject chemical substance or mixture
and must be submi tted to the Agency immediately under
Section 8(e) of TSCA.
Considering the preceding discussion and EPA's evaluation of the
information presented in FYI-OTS-0487-0538 Initial and 8EHQ-0787-
0666 Followup Response, it is EPA's initial position th~~; the
results of PPG's rabbit dermal teratology study of CR-39 Monomer
should have been submitted earlier to EPA under Section 8 (e) of
TSCA. In formulating this initial position on TSCA Section 8(e)-
applicability/report ability, EPA has considered also the fact
that numerous developmental toxicity studies have been conducted
in which the tested chemicals caused maternal toxicity (in some
cases, severe maternal toxicity (e.g., death» but did not cause
adverse developmental effects. In other words, the mere fact that
maternal toxicity occurs does not preclude the possibility that
the tested chemical substance or mixture can cause adverse
developmental effects. Finally, it is important to note that
EPA's developmental toxicity risk assessment guidelines (51 FR
34028-34040; September 14, 1986) reaffirm the Agency's position
that developmental effects that occur at maternally toxic dose
levels should not be discounted.
a)
PPG will be requested to provide its rationale as to
why the findings from the company's dermal teratology
study of CR-39 Monomer in rabbits were not submitted to
EPA earlier under Section 8 (e) of TSCA. Following a
review of PPG's response, the Chemical Screening Branch
will, if appropriate, deliver FYI-OTS-0487-0538 Initial
to the OTS Document Control Office (DCO) for handling
and filing under Section 8(e) of TSCA.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of diallyl diglycol carbonate.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA; copies of
this report will be sent also to the TSCA Assistance
Office (TAO/OTS) for further distribution.
74
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
APR 2 7 1981
Page 1 of 3
SUBJECT: Status Report* 8EHQ-0487-0667 S APproved:.{!;JJt-
FROM: James F. Darr, Section Head ~ r ~
Chemical Risk IdentificatioJ/~ection/CSB
1~:~1
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
(TSCA CBI); the Information Management Division (IMD/OTS) will
request the submitter to substantiate these TSCA CBI claims. In
the sanitized version of the TSCA Section 8(e) submission (dated
April 15, 1987) the company reported non-confidentially that 1)
the tested chemical is an aryl ester of carbonochloridothioic
acid, and 2) the chemical is the subject of a "Premanufacture
Notice" (PMN) submitted to EPA on March 31, 1987 under Section 5
of TSCA. A search of the OTS public PMN files for a recent PMN
concerning an aryl ester of carbonochloridothioic acid showed
that this chemical was the subject of PMN 87-915 (received by EPA
on Apri 1 1, 1987). This status report is based on information
obtained from the non-confidential versions of PMN 87-915 and
8EHQ-0487-0667 S.
Submission Description
In the TSCA Section 8(e) submission, the company stated that a
copy of the final report from an acute (1 and 4 hour) whole body
inhalation study of this aryl ester of carbonochloridothioic acid
in rats had been submitted to EPA in the company's March 31, 1987
PMN. According to the submitting company, "the 4-hour exposure
resul ted in death to all ten rats during exposure to an atmos-
phere containing an actual mean concentration of 2.10 mg/l" and
"the I-hour exposure produced 80% mortality wi thin nine days
after exposure to an atmosphere containing an actual mean con-
centration of 1.99 mg/ 1. " In addition, the submitter reported
that "labored breathing evident in all rats prior to death sug-
gested pulmonary insufficiency as the probable cause of death."
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
75
E.-A FORM 1320-6 (REV. '-76)
-------
8EHQ-0487-0667 S
Page 2 of 3
In its TSCA Section 8(e) submission, the company stated further
that "it is important to note that the vapor pressure of the sub-
stance required that an aerosol be artificially generated in
order to conduct the inhalation toxicity test, i.e., a worst case
situation." The submitting company reported also that "during
manufacture, aerosol formation is unlikely and, in addition, ex-
posure to the substance is prevented by the protective means.
[described in the Current Production and Use section of this
status report]." Finally, the submitting company reported that
based on the results of the acute inhalation study, the chemical
would be labelled as a Class B Poison under U. S. Department of
Transportation regulations.
Submission Evaluation
The acute inhalation toxicity study cited in this Section 8(e)
submission is being evaluated by EPA at this time in conjunction
with the Agency's review of PMN 87-915. Immediately upon receipt
of this Section 8(e) submission, the Chemical Screening Branch
sent copies of the submission to the Chemical Control Division
(CCD/OTS) which is responsible for administering the OTS "New
Chemicals Program" (NCP).
It should be noted that the final report of the acute inhalation
study that was attached to PMN 87-915 states that "post exposure
body weighings and necropsies were not obtained because of the
unpleasant odor of this material and its ability to penetrate
protective clothing." In addition, PMN 87-915 states that the
subject chemical substance was found to have an oral (rat) LD50
of approximately 3 g/kg and a dermal (rabbit) LD50 of in excess
of 2 g/kg. The chemical was reported also to be a moderate skin
irritant and a mOderate/severe eye irritant (test species not
specified) .
Current Production and Use
According to PMN 87-915, this aryl ester of carbonochloridothioic
acid is an "extremely odoriferous" colorless to yellow to black
liquid with a molecular weight of 186.5, a boiling point of 80°C
at 0.13 mm Hg, and a specific gravity of 1.269; a vapor pressure
study is reported to be currently underway. In addition, this
chemical reportedly reacts with water and is soluble in organic
solvents (e.g., acetone and toluene).
According to the Section 8 (e) submission, the chemical" is a
site-limited, destructive use intermediate which is completely
destroyed in the manufacture of another product." In addition,
the Sect ion 8 (e) submission presented the following information
with regard to the potential for exposure to this aryl ester of
carbonochloridothioic acid:
76
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8EHQ-0487-0667 S
Page 3 of 3
"During the manufacturing process, engineering, work
practice, and protective equipment controls prevent
operator exposure. During sampling and sample analysis,
the operator and technician are equipped with a NIOSH-
approved respirator, rainsuit, rubber gloves, rubber
boots, and chemical safety goggles. During the manufac-
ture of the final product and [the] cleaning of the
storage tanks, there is no potential for operator ex-
posure. During removal of the filter, which contains the
residual new substance, the operator is equipped with
the above-mentioned safety equipment. The process is
designed to prevent any atmospheric release of the new
substance. Any other releases to the environment will be
controlled by the use of RCRA-approved waste handling
sites and commercial solvent recovery. "
Comments/Recommendations
It should be noted that Part VII of the Agency's March 26, 1978
TSCA Section 8(e) policy statement ("Statement of Interpretation
and Enforcement POlicy; Notification of Substantial Risk" 43 FR
llIlO) explains that information need not be submitted separately
under Section 8(e) if that information has been submitted already
to the Agency under another mandatory TSCA reporting provision.
In general, the Agency's TSCA Section 5 "Premanufacture Notice"
rule (40 CFR Part 720) requires a company that submits a PMN to
also submit studies/data (that are in the company's possession or
control or that are reasonably ascertainable by the company) that
address the subject chemical's toxicity or lack thereof. In the
case of the present TSCA Section 8(e) submission, therefore, once
the acute inhalation toxicity data were submitted to the Agency
as required under Section 5 of TSCA, submission of the results of
that same study under Section 8(e) of TSCA became unnecessary.
a)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP /OPTS, and CCD/OTS/OPTS.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS) for further
distribution.
77
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
Page 1 of 5
DATE:
MAY 2 7 1987
SUBJECT: Status Report * 8EHQ-0487-0668 Approved: ~
FROM: James F. Darr, Section Head ~ f' ~
Chemical Risk IdentificatioY-s~ction/CSB
b/3/~7
, ,
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
For background information on xerographic toners, the reader's
attention is directed first to the "status report" prepared by
EPA in response to data submitted by the Xerox Corporation on a
"For Your Information" (FYI) basis (FYI-OTS-0480-0070 et seq.).
In addition, it should be noted that EPA has received a number of
Section 8(e) and FYI notices regarding photocopying toners and/or
proces ses (8EHQ-0480-0339 et seq., 8EHQ-0880-0351 et seq., FYI-
OTS-0680-0099 et seq., FYI-OTS-1181-0145 et seq.) The reader's
attention is directed also to a draft production/exposure profile
(PEP) on chemical substances used in plain paper copying (EPA
Contract No. 68-01-6239: October 8, 1983: Dynamac Corporation,
Rockville, MD). Finally, it should be noted that the Agency has
prepared "Chemical Hazard Information Profiles" (CHIPs) on a
number of chemicals associated with photocopying processes.
Submission Description
In its TSCA Section 8(e) notice, the Xerox Corporation submitted
the protocol and interim findings from an ongoing chronic study
of a Xerox 9000-type photocopying toner administered at doses of
1.0, 4.0 and 16.0 mg/m3 by inhalation to Fischer 344 rats. (The
composi tion of the tested material can be found in the Current
Production and Use section of this status report.) According to
the submitted information, the doses used in this chronic inhala-
tion study correspond to American Conference of Governmental
Industrial Hygienists (ACGIH) respirable concentrations of 0.35,
1.4 and 5.6 mg/m3, respectively. In its submission, Xerox stated
that in addition to air-only controls, silicon dioxide (Si02' a
known fibrogenic agent) and titanium dioxide (Ti02' a "nuisance
dust") were evaluated in this chronic inhalation study. The
following summarized information concerning the IS-month sac-
rifice was presented by Xerox in its Section 8(e) submission
cover letter:
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
78
EPA FORM 1320-6 (REV. 3-76)
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8EHQ-0487-0668
Page 2 of 5
"A preliminary evaluation of the chronic rat study data
indicates no unusual histopathological findings
The low (l mg/m3) and middle (4 mg/m3) exposure grou~s
are similar to the negative control (TiO~) at 5 mg/m .
The high toner exposure group (16 mg/m3) 1S essentially
similar except for minimal increase in collagen possibly
the result of [an] artifact associated with thickly cut
histologic sections. Animals in the toner-exposed groups
are es sentially heal thy at this time and without evi-
dence of decrease in body weight. At the high toner
exposure level, however, there is evidence of increased
lung weight, increased retention of the test material as
a function of exposure concentration over time, and
retardation of alveolar macrophage mediated clearance.
It should be noted that the toner material used in this
study has been enriched ten-fold in respirable size
particles with respect to the commercially available
toner material. Wi th respect to the [ongoing] study,
the high toner exposure level (16 mg/m3 total or 5.6
mg/m3 respirable) should be compared with the present
[Occupational Safety and Health Administration (OSHA)]
nuisance dust limit of 5 mg/m3. Measurements of res-
pirable dust in [Xerox manufacturing, service and
customer environments] are far below the respirable
level referred to above. All of the validated health
and safety information in Xerox I s data base are con-
sistent with the categorization of Xerox toners as
"Nuisance Dusts" and of low inherent toxicity."
In addition to submitting the above described interim findings
from the chronic inhalation study, Xerox provided a complete copy
of the final report from a subchronic inhalation study of the
subject toner in Fischer 344 rats. The Abstract section of the
submitted report presented the following information with regard
to the purposes, conduct and results of the 90-day study:
"The primary purposes of this [subchronic inhalation]
study were to ensure the suitability of the inhalation
facilities, dedicated instrumental designs and the ex-
perimental layout of the study for long-term exposures
as well as to find an appropriate range of dose levels
of the test material for a lifespan study. Particular
attention was focussed upon lung dynamics influenced by
the deposition and retention of the test material and
upon the occurrence of a Maximum Functionally Tolerated
Dose (MFTD).
"The test material used was a specially prepared and
characterized powder sample identical to 9000-type xero-
graphic test material, except that its ACGIH respirable
fraction was enriched about 10-fold to 35%. The [toner]
exposure concentrations used were 0, 1.0, 4.0, 16.0 and
64.0 mg/m3 of total mass concentration corresponding to
0, 0.35, 1.2, 5.6 and 22.4 mg/m3 of respirable material.
79
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8EHQ-0487-0668
Page 3 of 5
"The MFTD of a test material is defined as the maximum
lung burden for which macrophage mediated lung clearance
is not significantly impaired. In order to establish
MFTD value and suitable lifespan exposure concentrations
for the test material, a 90-day subchronic inhalation
study of a test material fraction was conducted by ex-
posure of groups of [Fischer 344] rats for 6 hours/day,
5 days /week for 13 weeks.
"No unscheduled death occurred during the study. A
Sendai virus infection was detected about half-way
through the study., but its source could not be
identified. Body weights, organ weights and food con-
sumption were normal in groups exposed to [the] 1 and 4
mg/m3 exposure concentration levels. An increase in lung
weight was observed at the 16 and 64 mg/m3 dose levels.
At the highest [toner] exposure level of 64 mg/m3, food
consumption in both male and female rats was slightly
decreased, but body weight was not affected.
"Alveolar lung clearance results of the toner test
material and an iron oxide tracer were essentially un-
changed at exposure concentrations of 0, 1 and 4 mg/m3.
At 16 mg/m3, some indications of slightly retarded iron
oxide tracer clearance were noted after 90 days of ex-
posure. At the 64 mg/m3 level of the test material, no
appreciable toner material clearance was observed after
60 and 90 days of exposure, and clearance of the iron
oxide tracer material was significantly retarded after
30, 60 and 90 days. Histopathological examination of
the lungs indicated a dose-related increase in particle-
laden alveolar macrophages. A slight thickening of
alveolar walls was observed in the high exposure groups.
"Based upon the above observations, the. [MFTD] in
this subchronic study of the toner test material was ex-
ceeded at the 64 mg/m3 exposure level. For a chronic
inhalation test using the same material over 2 years ~
the MFTD would probably be exceeded at the 16 mg/m
level. "
In its Section 8 (e) notice, Xerox also provided several papers
and poster presentations that address the conduct and results of
the 90-day enriched toner inhalation study as well as inhalation
studies in general.
S'lbmis s ion Evaluation
EPA I S review of the results from Xerox I s ongoing chronic toner
inhalation study in rats will be conducted in context with other
available data on photocopying toners received to date by EPA
(see Note at the top of the first page of this status report).
Xerox should be asked to ensure that EPA receives a full copy of
the final report (including any protocol amendments, results of
80
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8EHQ-0487-0668
Page 4 of 5
gross/histopathological examinations, results of any statistical
analyses, etc.) from the chronic toner inhalation study cited in
the company's TSCA Section 8(e) notice.
Current Production and Use
According to the submitted information, the tested toner is
90%/10% mixture of the following constituents, respectively:
l-butylmethacrylate/styrene random copolymer
(ratio 42:58: CAS No. 25213-39-2): and
a
high purity medium color furnace carbon black
(CAS No. 7440-44-0).
Further, the tested toner (which had been enriched 10-fold to
increase the amount of respirable particles) was reported to be a
combustible, pigmented plastic powder with a solid density of
about 1.1-1.2 g/cm3, a softening range of approximately 80-l00°C,
a mas s median aerodynamic diameter of almost 4.0 urn (geometric
standard deviation of about 1.3 urn) and a molecular weight of
approximately 70,000 Daltons. According to the submission, the
respirable fraction of the tested toner is about 35% (determined
by using ACGIH criteria) while the respirable fraction of the
commercially available Xerox 9000 toners ranges from 2-5%.
Finally, Xerox provided the following information with regard to
toner exposure in Xerox toner manufacturing plants and customer
facilities:
"Currently available industrial hygiene information from
[Xerox Corporation] toner manufacturing plants,
where presumably the highest airborne toner dust levels
may be found, appears to be quite satisfactory~ Limited
respirable sampling data indicate that more than 95% o~
the airborne respirable dust levels are below 0.25 mg/m
and corresponding respirable toner levels are less than
0.15 mg/m3. [Note: The OSHA limit for "nuisance dusts"
in occupational settings is 15 mg/m3 total or 5.0 mg/m3
for respirable particles.] Based on other available
data, the respirable dust levels with respect to both
[the Xerox machine service] population and the customer
environment are far below the levels mentioned above."
Comments/Recommendations
In the cover letter to its Section 8(e) submission, Xerox stated
that in accordance with standard company practices, Xerox toner
manufacturing employees will continue to be apprised about toner
exposure levels as well as further results of the ongoing chronic
toner inhalation study in rats. In addition, Xerox stated that
the company is continuing "to evaluate respirable dust levels in
all appropriate operations." Finally, Xerox stated that the com-
pany's "Exposure Limit Committee is in the process of reviewing
81
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8EHQ-0487-0668
Page 5 of 5
all health and safety data with respect to
other materials, and will determine whether.
internal [exposure] limit for toner (5 mg/m3
be modified."
toner, as well as
. . [the company's]
total dust) should
It should be noted that the Agency has received TSCA Section 8(e)
and FYI notices on titanium dioxide (8EHQ-I083-0497 et seq. and
FYI-OTS-0880-0125) and silicon dioxide (8EHQ-0780-0354 et seq.
and FYI-OTS-0880-0125).
a)
The Chemical Screening Branch will ask Xerox to ensure
that EPA receives a complete copy of the final report
(including any protocol amendments, results of all gross
and histopathologic examinations, results of statistical
analyses, etc.) from the company's ongoing chronic toner
inhalation study in rats.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the tested toner or its constituents.
c)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, ORD/EPA and OAR/EPA. In addition, copies of
this status report will be sent to the TSCA Assistance
Office (TAO/OTS/OPTS) for further distribution.
82
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
Page 1 of 3
DA TI! I
MAY
7 1981
SUIJICTI
Status Report *
8EHQ-0487-0669
Approved: ~ ~~/~
FROM:
James F. Darr, Section Head Lr~
Chemical Risk Identificatio«~~~~tion/CSB
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description (See NOTE on page 3 of this status report)
PPG Industries, Inc. provided the following information regarding
the conduct and results of acute rabbit eye irritation studies of
two halogenated imidazolidinones (C7N2Cl2H120 and C7N2Br2Hl20):
"[Two] eye irritation studies in rabbits were conducted
wi th these materials in their pure form (100% active
ingredient) . Resul ts for both materials indicate that
they caused severe irritation to the eye that resulted
in irreversible destruction."
It should be noted that PPG did not provide any additional
information concerning the identities of the tested materials or
the acute eye irritation studies conducted with those materials.
Submission Evaluation (See Note on page 3 of this status report)
In order for EPA to evaluate the overall significance of the
reported data, PPG should be asked to submit l) full copies of
the final reports from the ci ted acute rabbit eye irritation
studies, and 2) exact identities of the tested chemicals.
Current Production and Use
In its Section 8(e) submission, PPG stated that these halogenated
imidazolidinones are research and development (R&D) chemicals
"being evaluated for use as biocides and possible other uses."
PPG stated also that because the chemicals are at an R&D stage,
"only a limited number of technically qualified personnel are
potentially exposed to these chemicals." In addition, PPG stated
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
83
EPA FORM nao-6 (REV. 3-76)
-------
8EHQ-0487-0669
Page 2 of 3
that "PPG personnel with potential exposure are protected by the
use of protective facilities, equipment, and clothing, e.g.,
laboratory hoods, protective gloves and eye protection." PPG
stated further that samples of these halogenated imidazolidinones
"sent outside the company for evaluation are always accompanied
by an Experimental Product Data Sheet that indicates these
materials cause eye irritation and prescribe the appropriate
protective measures."
Comments/Recommendations
In its Section 8(e) submission, PPG stated that 1) "all personnel
with potential exposure to these materials will be informed of
these [toxicologic] findings and guidelines for handling," and 2)
"the Experimental Product Data Sheet will be modified to include
a statement about the severity of the eye irritation associated
with exposure to these materials."
Based on an initial review of the information presented in this
TSCA Section 8(e) submission, it is not entirely clear that the
provided information warranted reporting under Section 8(e), the
"substantial risk" information reporting provision of TSCA. The
submitter's rationale for reporting the subject findings to EPA
pursuant to TSCA Section 8(e) may become more apparent upon EPA's
receipt of further information concerning the performed studies
and the identities of the tested chemical substances.
a)
The Chemical Screening Branch will ask PPG to submit
complete copies of the final reports (including the
actual experimental protocols, results of gross and
histopathologic examinations, etc.) from the acute
rabbi t eye ir ri tation studies ci ted in the company's
Section 8(e) notice. In addition, PPG will be asked to
report 1) the exact identities (including CAS Registry
Numbers, if known), and 2) additional information with
regard to actual/planned use(s) of the tested chemicals.
In view of EPA I S general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure data, the Chemical Screening Branch
will request PPG to describe the nature and results, if
available, from all studies (other than those submitted
already to the Agency or those ci ted in the published
scientific literature) about which PPG is aware or that
PPG has conducted, is conducting or plans to conduct to
determine the toxicity of or the exposure to these halo-
genated imidazolidinones.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substances.
84
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8EHQ-0487-0669
Page 3 of 3
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
ORD/EPA, OAR/EPA, OW/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
NOTE:
In a letter dated June 4, 1987 (8EHQ-0687-0669 FLWP), PPG
reported non-confidentially that the subject chemicals were
1,3-dichloro-4,4,5,5-tetramethyl-2-imidazolidinone and 1,3-
dibromo-4,4, 5, 5-tetramethyl-2-imidazolidinone.
~
(II!? In
85
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DA TE,
MAY
7 1987
SU8JECT,
Status Report*
8EHQ-0487-0670 S
APproved:~
1'( 1'87
FROM:
James F. Darr, Section Head a~~~
Chemical Risk Identificatio~~ec~ionjCSB
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECADjOTS/OPTS
Note
The submitting company claimed its identity and the identity of
the subject chemical substance to be TSCA Confidential Business
Information (CBI)i the Information Management Division (IMDjOTS)
will request the submitter to substantiate these TSCA CBI claims.
In the "sanitized" version of this TSCA Section 8(e) notice, the
submitter reported non-confidentially that the tested chemical is
a "substituted nitrobenzene" currently in research and develop-
ment (R&D).
Submission Description
The submi tting company reported that a significant increase in
corneal opacity was found at all substituted nitrobenzene dose
levels in a feeding study conducted using Sprague Dawley rats.
In submitting these preliminary findings under Section 8(e), the
submitter stated that "while corneal opacity is unusual, it is
not unique to this [substituted nitrobenzene] substance, but has
been reported to occur from the administration of several drugs,
including indomethacin, chloroquine, amiodarone and others."
Submission Evaluation
In order for the Agency to evaluate the overall significance of
the submitted toxicologic findings, the company should be asked
to submit a full copy of the final report (including the actual
experimental protocol, results of gross and histopathological
examinations, results of statistical analyses, etc.) from the
performed dietary feeding study of this substituted nitrobenzene
in rats.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
86
EPA FORM 1320-6 (REV. 3-76)
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8EHQ-0487-0670 S
Page 2 of 3
It should be noted that in 1986, EPA received two other TSCA
Section 8(e) notices (8EHQ-0986-0624 Sand 8EHQ-0986-0625 S) in
Which corneal opacity was reportedly observed in dietary feeding
studies conducted with rats. The reader's attention is directed
to the single status report prepared by EPA in response to these
particular Section 8(e) notices.
Current Production and Use
According to the submitting company, the subject R&D chemical is
being evaluated as an "experimental pesticide candidate. II In
addition, the submitter provided the following information con-
cerning the potential for exposure to the subject chemical:
"Since the [tested] material is an R&D chemical, it has
only been manufactured in small quantities with limited,
controlled distribution. The material is handled only
by technically qualified persons including consulting
scientists and company scientific personnel using
prudent laboratory practices."
Comments/Recommendations
In its TSCA Section 8(e) submission, the submitter stated that in
accordance with standard policy, the company has notified all
persons evaluating this particular class of chemicals about the
reported toxicological findings. In addition, the company stated
that "personnel protection and work practices will be evaluated
and modified if necessary."
a)
The Chemical Screening Branch will request the company
to submit a complete copy of the final report (including
the actual experimental protocol, results of gross and
histopathological examinations, results of statistical
analyses, etc.) from the dietary feeding study cited in
the submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure data, the Chemical Screening Branch
will ask the submitting company to describe the nature
and results, if available, from all studies (other than
those submitted already to th~ Agency) about which the
company is aware or that the company has conducted, is
conducting or plans to conduct to determine the toxicity
of this substituted nitrobenzene.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this substituted nitrobenzene.
87
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8EHQ-0487-0670 S
Page 3 of 3
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
88
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
MAY
7 1987
Page 1 of 2
SU8JECT:
Status Report* 8EHQ-0487-067l APproved:c:;1Jl.
James F. Darr, Section Head ~rb
Chemical Risk Identification Section/CSB
iftf/q7
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Koppers Company, Inc. provided the following information with
regard to a recent incident at a Koppers Company facility located
in Oroville, California:
"On April 6, 1987, an accident occurred at the mixing
unit for the Cellon process of wood preservation treat-
ment at the Koppers Company, Inc. plant in Oroville,
California. The accident resulted in a fire which burned
for approximately nine hours. The Cellon process is a
proprietary process which employs pressure treatment of
wood with pentachlorophenol (CAS No. 87-86-5) in a mix-
ture of butane, isopropyl ether and diesel oil. As a
result of the fire and fire-fighting procedures, an un-
determined amount of pentachlorophenol was released onto
the immediate site around the Cellon mixing unit or
burned. It is possible that some pentachlorophenol was
dispersed into the air. The maximum amount of penta-
chlorophenol potentially involved in the fire was 9000
lbs., but subsequent visual inspection of pentachloro-
phenol levels remaining in the equipment indicates that
perhaps the pentachlorophenol loss was limited to 3000
lbs. The combustion of pentachlorophenol may have led
to the formation of polychlorinated dibenzo-p-dioxins
and polychlorinated dibenzofurans. Pentachlorodi-benzo-
p-dioxins as well as hexachloro-, heptachloro-, and
octachloro-isomers were present in the soil at the site
prior to the accident on April 6, and [the Koppers
Company is] now aware of one measurement of 2.4 ppb
2,3,7,8-tetrachlorodibenzo-p-dioxin in ashed material on
the ground at the fire site. Soil and wipe samples have
been collected by Koppers as 'well as State and Federal
agencies for additional chemical analyses. The fire site
and surrounding areas are now secure and stabilized ac-
cording to California OSHA and U.S. EPA specifications.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
89
I!~" FORM U20-1 (RE'J. 3-761
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8EHQ-0487-0671
Page 2 of 2
"Because of the possibility of pentachlorophenol
becoming airborne during the fire and because of con-
cerns that hazardous levels of pentachlorophenol may
settle in some off-site areas, warnings were given to
local residents and a health clinic was established to
evaluate residents who believe they may have been over-
exposed to chemicals as the result of the fire. The
clinic was staffed by California Department of Health
Service physicians. On Monday, April 13, 1987, Koppers
learned that a physician at the clinic [who] examined a
number of citizens. . . felt that she had seen symptoms
that could be attributable to acute exposure to penta-
chlorophenol. [Koppers understands] that the symptoms
reported to the clinic physician included mucous mem-
brane irri tation and skin irritation. [Koppers does]
not have further information about these individuals or
their complaints. [Koppers reported also] that
there are no reports of adverse health affects related
to chemical exposure among the Koppers employees on-site
during and after the fire. .. In addition, the.
[California State Health Director] reports that after
analyzing more that 62 samples of soil, vegetation and
surface wipes from the facility and the community,
pentachlorophenol has not been found in significant
levels in samples taken from the community."
Comments/Recommendations
Immediately upon receipt of this TSCA Section 8(e) notification,
the Chemical Screening Branch transmitted copies of the notice to
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and to the EPA
Region IX Office in San Francisco, California. In addition, a
copy of the submission was provided immediately to the Chemical
Regulation Branch/EED/OTS/OPTS/EPA which is in the process of
finalizing a TSCA Section 4 testing/Section 8 data gathering rule
on polyhalogenated dibenzo-p-dioxins/dibenzofurans
The Chemical Screening Branch will transmit copies of this status
report to NIOSH and OSHA as well as to all EPA Offices mentioned
in the preceding paragraph.
90
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DA TI! :
JJN
91981
Page I of 3
SUBJECT: Status Report * 8EHQ-0587-0672 S Approved: ()l/I;'-
FROM: James F. Darr, Section Head a~ r C
Chemical Risk IdentificatioC~e;tion/CSB
~/q jr1
I I
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Shell Oil Company submitted a paper entitled "Teratogenicity
of Di(2-ethylhexyl) Phthalate, 2-Ethylhexanol, 2-Ethylhexanoic
Acid, and Valproic Acid, and Potentiation by Caffeine" published
recently in Teratology (1987; Vol. 35; pg. 41-46). The ABSTRACT
section of the provided paper presents the following information
regarding the conduct and results of the performed study:
"It is hypothesized that the teratogen di (2-ethylhexyl)
phthalate (DEHP) acts by in vivo hydrolysis to 2-ethyl-
hexanol (2-EHXO), which in turn is metabolized to 2-
ethylhexanoic acid (2-EHXA) , the proximate teratogen.
Teratological studies were conducted with Wistar rats,
with [a single oral] administration of [equimolar doses]
of these agents on day 12 of gestation. [According to
text of the paper, "a dose of 12.5 rnmol/kg of DEHP is
equivalent to 5.0 ml/kg; doses of 2-EHXO and 2-EHXA of
12.5 rnmol/kg are equivalent to 2.0 ml/kg."] On an equi-
molar basis, DEHP was [the] least potent, 2-EHXO was
intermediate, and 2-EHXA was the most potent of the
three agents, which is consistent with the hypothesis.
Similarity in the types of defects [( "hydronephrosis,
levocardia, iv septal defect, and other heart malforma-
tions, short and kinky tail, ectrodactyly, misplaced
digits and bowed radius")] found with these agents also
suggests a cornmon mechanism with 2-EHXA as the proximate
teratogen. All three [test] agents were potentiated by
caffeine. Valproic acid, which is an isomer of 2-EHXA,
also produced similar defects, and was approximately
twice as potent as 2-EHXA."
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
91
E~A 1"0"" 1S.6 (REV. 1-76'
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8EHQ-0587-0672 S
Page 2 of 3
In the cover letter to its Section 8(e) notice, Shell stated that
although the cited study was not well designed to demonstrate
teratogenic effects (because of deviations from "conventional"
teratologic study protocols), "these deviations do not negate the
basic finding that [2-ethylhexanol] at a one-time dose of 2 ml/kg
resulted in malformations in the offspring." In its submission,
Shell stated also that the data from the study are "not adequate
for risk assessment [in that] the effect level (2 ml/kg by the
oral route) translates to 120 ml for a 60 kg person." Shell did
state, however, that "without knowledge of the degree of skin
absorption or animal-to-man translation factor, nothing defini-
tive can be determined as to risk." Shell stated further that
the "application of the usual discount factors and moderate
degrees of skin penetration, results in projected dermal levels
of concern."
In its TSCA Section 8(e) notice, Shell also provided monitoring
data from Shell's 2-ethylhexanol manufacturing facility. With
regard to the submitted exposure data, Shell stated that because
all workplace" inhalation results were less than the detectable
limits of the methods used (1 ppm for all but one measurement
which was carried out using a method with a limit of 10 ppm),"
Shell concluded that while the inhalation risk is small, dermal
contact with 2-ethylhexanol remains the company's major concern.
Submission Evaluation
In view of the fact that di(2-ethylhexyl) phthalate, 2-ethyl-
hexanol and 2-ethylhexanoic acid are being assessed by the Test
Rules Development Branch (TRDB/ECAD/OTS) and di(2-ethylhexyl)
phthalate is being assessed by the Risk Analysis Branch (RAB/
ECAD/OTS), full copies of this Section 8(e) submission were sent
immediately by the Chemical Screening Branch (CSB/ECAD/OTS) to
TRDB and RAE for inclusion in their ongoing assessments.
Comments/Recommendations
In its Section 8(e) submission, Shell stated that the company is
1) revising its 2-ethylhexanol Material Safety Data Sheet, and 2)
informing Shell workers about the reported teratologic findings.
In submitting this particular article to EPA under Section 8(e)
of TSCA, Shell stated that although the study findings had been
published already in Teratology in 1985 and 1986 as abstracts of
oral presentations and abstracted by Biological Abstracts in
1986, all of these abstracts require actual reading in order to
learn about the teratogenic effects of 2-ethylhexanol because the
abstract titles do not indicate that 2-ethylhexanol was tested
and "scanning of the abstracts alone is not sufficient to obtain
this information."
92
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8EHQ-0587-0672 S
Page 3 of 3
Further, Shell noted that Part VII of EPA's Section 8(e) policy
statement ("Statement of Interpretation and Enforcement PolicYi
Notification of Substantial Risk" 43 FR 111l0i March 16, 1978)
explains that information need not be reported if, for example,
the information "has been published in the scientific literature
and referenced by. . Biological Abstracts. II In for-
mally submitting this article to EPA under Section 8(e) of TSCA,
however, it appears that Shell has relied quite heavily on the
statutory language of TSCA Section 8(e) (i.e., substantial risk
information must be submitted immediately to EPA under Section
8(e) of TSCA unless the person who obtains the information has
"actual knowledge" that the EPA Administrator has been already
"adequately informed" about that information). Rather than
address at this point whether the subject teratological findings
for 2-ethylhexanol have or have not been titled or referenced in
a such manner as to make the findings easily recognizable to or
readily retrievable by EPA or others, EPA believes that in this
case it is more appropriate to express the Agency's appreciation
to Shell for the company' s apparent consideration of both the
"spiri t" and statutory language of Section 8 (e) in deciding to
submit the teratologic findings formally under Section 8(e)i
other companies that are subject to Section 8 (e) are encouraged
to incorporate such prudent considerations in their own Section
8(e) reporting deliberations.
a)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA, and to TRDB and
RAB/ECAD/OTS/OPTS/EPAi copies of this report will be
sent also to the TSCA Assistance Office (TAO/OTS/OPTS)
for further distribution.
93
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
JJN 2 2 1987
Page 1 of 4
SUBJECT,
Status Report" 8EHQ-0587-0673 APproved~
James F. Darr, Se<::tion Head ~T~
Chemical Risk Identificatio6!section/CSB
'f>/r?
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Stauffer Chemical Company (a subsidiary of Chesebrough-Ponds
Inc.) provided a complete copy of a final report from an acute
(I-hour) inhalation study of N-1386 RAN, a mixture of bis (tri-
chloromethyl) sulfone. (CAS No. 3064-70-8) and petroleum naphtha
solvent (CAS No~ 64742-95-6) in rats. The SUMMARY section of the
provided report presents the following information regarding the
conduct and results of the study:
"The purpose of this study was to determine the acute
inhalation toxicity of N-1386 RAN . . . according to the
requirements set by the Department of Transportation. .
." N-1386 RAN, a yellow colored liquid at standard
temperature and pressure, was generated [by] using a
Solosphere@ nebulizer. The chamber atmosphere consisted
of a mixture of aerosol and vapor (approximately 50%
each) for both exposures conducted.
"Two groups of 5 male and 5 female Sprague-Dawley rats
received a whole-body exposure for 1 hour to an atmos-
phere containing mean concentrations of either of 6.96
mg/l or 1.91 mg/l of N-1386 RAN. Particle size analysis
indicated the mass mean aerodynamic diameter (MMADar) of
the aerosol to be 2.60 urn. Two control groups, consist-
ing of 5 male and 5 female rats for ectch group, were
sham exposed using the same experimental conditions but
without generation of the test material.
"Exposure of rats to N-1386 RAN resulted in death to all
10 rats for both the 6.96 mg/l and 1.91 mg/l exposures.
Most of the rats died during or immediately after the
exposure so that in-life clinical observations could not
be obtained. At necropsy, pulmonary congestion was evi-
dent in all of the treated rats. The lungs we~e reddened
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s): Any review of this status report should take into account
the fact that the report may be based on incomplete information.
94
IEPA FORM 1320-6 (REV. 3-761
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8EHQ-0587-0673
Page 2 of 4
and failed to collapse in all exposed animals. Measure-
ment of pulmonary edema was performed for rats exposed
to 6.96 mg/l using wet/dry lung weight ratios and sig-
nificant increases in the weight ratios were evident in
both male and female rats when compared to controls.
"In conclusion, N-1386 HAN produced significant
pulmonary effects leading to the deaths of all exposed
rats after one-hour inhalation exposures at 6.96 mg/l or
1.91 mg/l. Therefore, the one-hour LC50 for N-1386 HAN
is less than 1.91 mg/l."
In its Section 8(e) submission, Stauffer stated that in 1986, the
company reviewed N-1386 BAN in order to determine if this product
was subject to a u.S. Department of Transportation final rule on
"Liquids Toxic by Inhalation" (HM-196). According to Stauffer,
"based on preliminary inhalation data (LC50 <1,000 ppm) and a
calculated saturated vapor concentration (27,895 ppm) , it was
determined that N-1386 HAN was an inhalation hazard" and "the
product was reclassified and labeled accordingly.
Submission Evaluation
The administered dose levels of 1.91 and 6.96 mg/l correspond
approximately to 38.6 and 138.2 mg/kg/day, respectively. Six of
10 rats at the low concentration and 9/10 rats at the high con-
centration died on the day of exposure; the remaining rats were
found dead on the following day. Clinical observations were ob-
tained only for those rats surviving past the day of exposure.
Due to the high mortality, no body weight comparisons were made.
In all animals at both dose levels, the lungs were reddened and
failed to collapse. Clear fluid was found in the chest cavity in
4/5 males and 5/5 females at the 6.96 mg/l dose level. Also at
this high level, the trachea was froth-filled in 3/5 males and
4/5 females, 5/5 males and 4/5 females had gas-distended stomachs
and either one or both eyes were cloudy white in all 5 males and
3/5 females. When compared to controls, significant pulmonary
edema was observed in both sexes at both dose levels. Labored
breathing and salivation were included among the toxic symptoms
observed in this study-
According to information obtained from other available sources,
bis (trichloromethyl) sulfone has some degree of antiseptic/anti-
microbial capacity, has an oral (rat) LD50 of 651 mg/kg and an
intravenous (mouse) LD50 of 18 mg/kg.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for bis (trichloromethyl) sulfone, which is listed in
the initial TSCA Chemical Substance Inventory, has shown that no
1977 manufacture/importation was reported or that all of the
95
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8ERQ-0587-0673
Page 3 of 4
manufacture and/or importation information reported was claimed
to be TSCA Confidential Business Information (TSCA CBI) by the
person(s) reporting for the initial TSCA Inventory and cannot be
disclosed (Section l4(a) of TSCA, D.S.C. 26l3(a».
A review of the production range (includes importation volumes)
statistics for petroleum naphtha sol vent (CAS No. 64742-95-6),
which is listed also in the initial TSCA Inventory, has shown
that over 1 billion pounds were reported as manufactured and/or
imported in 1977. This production range information does not
contain any data claimed as TSCA CBI by the person(s) reporting
for the initial TSCA Iventory nor does it include any information
that would compromise TSCA CBI.
It should be noted that all data provided for the initial TSCA
Inventory, including the production range data, are subject to
the limitations that are contained in the initial TSCA Inventory
Reporting Regulations (40 CFR 710).
According to the submitted information, N-1386 RAN is a light
yellow liquid with a vapor pressure of 25.8 rnrn Hg at 250 C. In
the cover letter to its Section 8(e) submission, Stauffer stated
that although bis(trichloromethyl)sulfone is an active ingredient
registered with EPA under the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA), N-1386 RAN is not a registered pesticide
but is sold (primarily to one customer at the present time) as an
intermediate in formulating a FIFRA-registered pesticide.
Comments/Recommendations
According to Stauffer. N-1386 RAN customers are being informed in
writing about the reported toxicologic findings, and the product
has been relabeled to reflect the inhalation toxicity findings.
It should be noted that bis(trichloromethyl)sulfone was the
subject of a FIFRA "Data-Call-In" issued by EPA in March 1987.
In addition, it should be noted that EPA has received many TSCA
Section 8(e) and "For Your Information" (FYI) submissions on
petroleum distillates, including the petroleum naphtha sol vent
ci ted in this Section 8 (e) submission. It should be noted also
that the Chemical Screening Branch (CSB/ECAD/OTS) prepared (in
1984) a Chemical Hazard Information Profile (CHIP) covering a
number of petroleum naphtha solvents and the Risk Analysis Branch
(RAB/ECAD/OTS) is currently evaluating toxicity and exposure data
on petroleum naphtha solvents.
a)
The Chemical Screening Branch will request the Stauffer
Chemical Company to report the exact amount of each com-
ponent in N-1386 HAN.
96
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8EHQ-0587-0673
Page 4 of 4
In view of EPA's general interest in corporate actions
that are taken on a voluntary basis in response to
chemical toxicity or exposure data, Stauffer will be
asked to describe the nature and results, if available,
of all stud ies (other than those submi t ted already to
EPA or those cited in the open scient if ic 1 i tera ture)
about which Stauffer is aware or that Stauffer has con-
ducted, is conducting, or plans to conduct to determine
the toxic i ty of or the exposure to N-1386 HAN or its
constituents.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of N-1386 HAN or its constituents.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, NTP, FDA, OSWER/EPA,
OW/EPA, OAR/EPA, ORO/EPA, OPP/OPTS/EPA and RAB/ECAO/OTSj
copies of this status report will be transmitted also to
the TSCA Assistance Off ice (TAO/OTS/OPTS) for further
distribution.
97
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JUL
7 1987
~age 1 of 4
SUBJECT:
Status Report * 8EHQ-058 7-0674 S Approved: -::?1/J1L-
8EHQ-0687-0674 S SUPp. ~
James F. Darr, Section Head ~ ~~
Chemical Risk IdentificatioJ!~ec~ion/CSB
7/7 / g-l
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name and the exact
identity of the subject chemicals as TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will request the submitter to substantiate these CBI claims. In
the non-confidential versions of the initial and/or supplemental
TSCA Section 8(e) notices, the submitter stated that the tested
product ("an experimental metalworking lubricant additive formu-
lation") is a chemical mixture containing a major (97%) component
identified generically as a "sulfurized olefin" and a minor (3%)
component identified generically as a "substituted anunonium car-
boxylate. " In the non-confidential version of the supplemental
Section 8(e) notice, the company stated that the minor component
of the product is the subject of a TSCA Section 5 "Premanufacture
Notification" (PMN No. 86-476) currently under review by the OTS
New Chemicals Program (NCP).
Submission Description
In its initial Section 8(e) notice, the submitter provided the
following information concerning the results of acute oral,
dermal and inhalation studies and a 28-day inhalation study of
the subject mixture qnd/or its component(s):
"The most profound effect observed in the 28-day inhala-
tion study is the death of 4 of 10 female rats durinj
the course of the exposure phase at a dose of 170 mg/M
which is the highest of three doses used in the study.
No mortality was observed in male rats at any dose
level. This observation reasonably supports the con-
clusion that substantial risk may exist, especially
because of the existence of supporting evidence that
suggests the agent toxic to females is the minor con-
sti tuent of the mixture and not the ma jor constituent
(the sulfurized olefin).
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
98
EPA FORM 1320-6 (REV. 3-76)
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8EH'I-0587-0674 S
8EHQ-0687-0674 S Supp
Page 2 of 4
"This sex-specific effect is also noted on acute inhala-
tion exposure on the same mixture. In a previously
conducted acute inhalation study, no deaths were ob-
served in male rats after a four hour exposure to 5,000
mg/M3 . Mortality was observed in female rats at this
dose. The four hour LC-50 was determined to be 2,170
mg/M3 for female rats. No other data are available on
the mixture.
"The sulfurized olefin did not cause mortality in either
sex of rats and rabbits, respectively, in acute oral and
dermal exposures. In an oral toxicity range finding
study on the minor component, a dose of 5 g/kg killed
all five female rats treated in the study, while no
deaths were observed in males at this dose. At a dose
of 2 g/kg of the minor component, no rats of either sex
died. This observation raises the suspicion that the
selective mortality to females in the 28-day study is
due to the minor component.
"Other effects noted in the 28-day study include:
"I. Urinary casts were observed at all doses (40, 80 and
170 mg/M3) in male rats. An increased accumulation of
hyaline droplets of the kidneys in males was found at
the two highest doses. The significance of these
findings is unknown. Hyaline droplet formation is an
effect unique to the kidneys of male rats and is in-
creased by many chemicals, most notably by low to medium
molecular weight hydrocarbons. Possible indication of
kidney pathology was observed in only 3 of 10 male rats
at the high dose.
"2. A slight decrease in hematocrit and blood glucose
was observed in high dose male rats. No associated
pathology was observed which was related to these
observations.
"3. A slight, but
testicular weight
all doses in male
dose.
statistically significant, increase in
to body weight ratio was observed at
rats. The effect was not graded with
"4. Irritation of the nasal turbinates was found in both
sexes at the highest dose level.
"The only other effect unique to female rats in the 28-
day study was the observation of sporadic and transient
ataxia, usually immediately after exposure to the test
material. Ataxia is commonly observed in inhalation
studies. It is believed to be related to anoxia result-
ing from [a] reduced respiratory rate as a voluntary
defensive response to toxic materials. Therefore, it is
not apparent whether the ataxia is due to a specific
99
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toxic effect of the
is available which
city in female rats
8EHQ-0587~0674 S
8EHQ-0687-0674 S
Page 3 of 4
test material. No other information
sheds light on this increased toxi-
exposed by inhalation."
supp
In its supplemental TSCA Section
provided a complete copy of the
inhalation study.
8(e)
final
submission, the company
report from the 28-day
Submission Evaluation
Immediately upon receipt of these TSCA Section 8(e) submissions,
the Chemical Screening Branch transmitted copies to the Chemical
Control Division (CCD) which is responsible for administering the
NCP under Section 5 of TSCA.
Current Production Use
In view of the submitter I s TSCA CBI claims no information with
regard to the current TSCA Chemical Substance Inventory status of
the components of the tested product will appear in this report.
In its initial Section 8(e) submission, the company provided the
following information concerning the use of and the potential for
exposure to the tested product/constituents:
"Various sulfurized olefins are supplied by many
additive manufacturers as extreme pressure antiwear
additives for industrial lubricants. They are supplied
to lubricant blenders and typically used at a concentra-
tion of 10% or less in the final lubricants. No untoward
effects have been reported in any workers handling the
substance in over 10 years experience with this and
competitive products of similar chemical structure.
"For the intended use, a typical metalworking fluid
would be 5% of this mixture in mineral oil. A maximum
concentration of the additive package would be 10%.
Users observing the TLV for oil mist would be exposed to
no more than 0.5 mg/M3 of the mixture or 1/80 of the
lowest dose tested."
Comments/Recommendations
In its initial Section 8(e) notice, the submitter stated that
although there is or will be low exposure to the constituents of
the addititive package during use of typical metalworking fluid
formulations, the following actions were being taken:
"I. [R]equest OTS to extend the review period of the
premanufacture notification. . until further inhala-
tion data is obtained on the PMN substance. If [the
submitter] determines that the product can be used
safely, the information will be added to the PMN file
wi th a request that the notice review be completed.
Otherwise, the PMN will be withdrawn.
100
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8EH0-0587-0674 S
8EHQ-0687-0674 S
Page 4 of 4
"2. Acute oral and acute dermal [toxicity] studies will
be conducted on the experimental lubricant additive for-
mulation to determine if the acute toxicity is unique to
inhalation exposure.
SU:r.>P
"3. Additional histopathology will be conducted on
other organs from the 28-day study not examined in the
original protocol to attempt to determine the etiology
of the mortality in female rats.
"4. The hyaline droplet formation data will be reviewed
with experts at the Chemical Industry Institute of
Toxicology to help determine the significance of this
effect."
It should be noted that the Agency has received a number of TSCA
Section 8(e) and "For Your Information" (FYI) notices on metal-
working fluids and/or components of such products.
It should be noted also that Part VII of EPA's March 16, 1978
TSCA Section B(e) policy statement ("Statement of Interpretation
and Enforcement Policy; Notification of Substantial Risk" 43 FR
11110) explains that information need not be reported to EPA
under Section 8(e) if, for example, the information has been
submitted already to EPA under some other mandatory reporting
provision of TSCA (e.g., Section 5) or other authority that is
administered by EPA (e.g., CERCLA, RCRA, CAA, CWA, etc.).
a)
The Chemical Screening Branch will ask the submitting
company to ensure that EPA receives full copies of the
final reports (including the actual experimental proto-
cols, results of gross/histopathological examinations,
results of statistical analyses, etc.) from all studies
cited in the company's TSCA Section 8(e) submissions.
.In view of EPA I S general interest in corporate actions
that are taken on a voluntary basis in response to
chemical toxicity or exposure data, the submitter will
be asked also to describe the actions the company has
taken or plans to take to notify its workers about the
reported toxicologic findings.
b)
As was the case for the initial and supplemental TSCA
Section 8(e) submissions, the Chemical SGreening Branch
will immediately transmit all reported information to
the Chemical Control Division for review and appropriate
followup attention.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and CCD/OTS/OPTS.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OPTS) for further
distribution.
101
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
JUN I 2 1987
Status Report* 8EHQ-0587-0675 Approved:~ ltt/t';/f1
James F. Darr, Section Head (J,~I- f ~
Chemical Risk Identificatio~~tion/CSB
Page
1 of 3
SUBJECT:
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Chemical Manufacturers Association (CMA) submitted a complete
copy of the final report from a chronic mouse skin-painting study
of a mixture containing calcium naphthenate (CAS No. 61789-36-4)
and a mineral oil. In the Section 8(e) notice cover letter, CMA
provided the following information with regard to the conduct and
resul ts of this chronic mouse skin-application study which had
been conducted by Shell Research Limited, London, United Kingdom:
". [Groups] of 50 female STCF mice were treated
twice weekly for up to two years with epidermal applica-
tions of 0.05 ml of the mixture of oil and calcium
naphthenate, undiluted oil, [or] a 37.5 ug/ml solution
of benzo(a)pyrene. The animals were observed daily and
subjected to necropsy and histological examination at
the end of the two-year period of application.
"Forty-two mice (84%) in the benzo(a)pyrene positive
control group developed a total of 104 cutaneous tumors
of the treated site, demonstrating the susceptibility of
the STCF mouse to a known skin carcinogen and the vali-
dity of the animal model. No epidermal or dermal tumors
of the shorn site were seen in the untreated negative
control mice. Eight mice (16%) developed a total of 13
tumors (12 epidermal and one dermal) of the treated site
when the mixture of mineral oil and calcium naphthenate
was applied. The tumors were two squamous-cell carcino-
mata, one basal-cell carcinoma, one dermal fibrosarcoma,
seven squamous-cell papillomata and two regressed/
sloughed papillomata, with latencies of 392 to 736 days.
Application of the carrier oil alone did not give rise
to any cutaneous tumors of the treated site.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information,
102
E~A FORM 1320-1 IREV:, 3-7"
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8EHQ-0587-0675
Page 2 of 3
"On the basis of the historical control data, the
testing laboratory concluded that the incidence of eight
tumor bearing mice in a group of 50 should be considered
biologically significant. As a result, the laboratory
[has].determined that the mixture of calcium naphthenate
and mineral oil is a cutaneous carcinogen in mice."
In providing this report to EPA under Section 8(e) of TSCA, CMA
stated that the information was being submitted on behalf of the
members of the CMA Naphthenates Program Panel (Nuodex, Inc.;
Mooney Chemicals, Inc.; the Troy Chemical Corporation; Interstab
Chemicals, Inc.; and the Shepherd Chemical Company). In addition,
CMA stated that because calcium naphthenate is the subject of a
TSCA Section 8(d) "health and safety study" reporting rule (in
support of "Test Rule Development" under Section 4 of TSCA), the
the Shell Oil Company (which is not a member of the Naphthenates
Program Panel) had already submitted full copies of the interim
and final reports of this chronic mouse skin-application study to
EPA's Test Rules Development Branch (TRDB/ECAD/OTS) and, as re-
quired, to the TSCA Section 8(d) reporting docket.
Submission Evaluation
Immediately upon receipt of this TSCA Section 8(e) submission, a
copy of the notice was sent to the calcium naphthenate project
manager in EPA's Test Rules Development Branch (TRDB/ECAD/OTS).
Current Production and Use
According to CMA, the members of the CMA Naphthenates Program
Panel that manufacture calcium naphthenate are: Mooney Chemicals,
Inc.; the Troy Chemical Corporation; Interstab Chemicals, Inc.;
and Nuodex, Inc.; the other panel member (the Shepherd Chemical
Company) only distributes this chemical. According to CMA, the
Shell Oil Company (which is not member of the CMA Naphthenates
Program Panel) "discontinued [in late 1983] the importation of
oils containing calcium naphthenate and no longer processes nor
distributes this material."
For information on the uses and additional information regarding
the manufacture/importation of calcium naphthenate, the reader's
attention is directed to 49 FEDERAL REGISTER (FR) 21411 (Monday,
May 21, 1984).
Comments/Recommendations
Part VII of EPA's March 16, 1978 Section 8(e) policy statement
("Statement of Interpretation and Enforcement Policy; Notifica-
tion of Substantial Risk" 43 FR 11110) explains that information
need not be reported to EPA under Section 8(e) if, for example,
the information has been submitted already to EPA pursuant to a
103
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8EHQ-0587-0675
Page 3 of 3
mandatory reporting provision of TSCA. Considering the fact that
the Shell Oil Company had already submitted the interim and final
reports of the chronic calcium naphthenate mouse skin-painting
study to EPA as required under TSCA Section 8(d), submission of
the final report from the study on behalf of the CMA Naphthenates
Program Panel members was not then required under Section 8(e) of
TSCA.
It should be noted also that EPA has received a number of TSCA
Section 8(e) notices that were submitted formally by chemical
industry trade associations on behalf of their member companies:
EPA has addressed this aspect of Section 8 (e) reporting in the
status reports prepared in response to several such submissions
(e.g., 8EHQ-0285-0546).
a)
The Chemical Screening Branch will ask CMA to transmit
copies of this status report to the CMA Naphthenates
Program Panel members.
b)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OAR/EPA, OW/EPA, ORD/EPA, OPP/OPTS and TRDB/OTS/OPTS. In
addition, copies of this report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution
104
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JUN
9 1987
Page 1 of 3
SU8JECT:
Status Report* 8EHQ-0587-0676 Approved: ~
James F. Darr, Section Head ~ f ~
Chemical Risk IdentificatioJlsection/CSB
It; / 'fr-7
, I
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
E. I. Du Pont de Nemours & Company, Inc. provided the following
information regarding the conduct and interim results of an on-
going 90-day inhalation study of l,2-dichloro-l,1-difluoroethane
(HCFC-132b; CAS No. 1649-08-7) in rats:
"In this study, groups of 20 rats of each sex are being
exposed by inhalation to HCFC-132b at exposure concen-
trations of either 0, 500, 2000 or 5000 ppm (v/v) for 6
hours/day, 5 days/week for approximately 14 weeks.
During the first ten weeks of the study, exposed rats of
both sexes gained less weight than the controls in a
dose-dependent fashion. At about the midpoint in the
exposure regimen, half of the rats were sacrificed for
gross and microscopic pathological examinations. In
[the HCFC-132b-treated] male rats, the testes showed
microscopic, bilateral aspermatogenesis and germ cell
degeneration. These lesions were mainly minimal to mild
in severity and seen in 10 of 10 rats at both the 5000
and 2000 ppm exposure levels, but only in 2 of 10 rats
in the 500 ppm group. No significant histopathological
effects attribut~ble to HCFC-132b were seen in female
rats at the midpo:Lnt of the experiment."
Submission Evaluation
The reported interim findings indicate that inhalation exposure
to this chlorofluorocarbon can adversely a.ffect the reproductive
organs/function in male rats; further evaluation of the findings
should be possible upon EPA's receipt of a .full copy of the final
report of the ongoing 90-day inhalation study.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
105
E.-A FORM luo..a tREY. J-7f1
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8EHQ-0587-0676
Page 2 of 3
Immediately upon receipt of DuPont's initial Section 8(e} notice,
the Chemical Screening Branch sent a copy of the submission to
EPA's Stratospheric Ozone Protection Program/Office of Air and
Radiation (OAR).
Current Production and Use
According to Du Pont, although HCFC-132b "is produced in only
research quanti ties and is not used or sold commercially by Du
Pont," this "chemical has been the subject of [research and
development (R&D)] work by Du pont and others." Du Pont stated
also that "no samples of this compound have been distributed out-
side of Du Pont or its affiliates for evaluation by customers."
Further, Du Pont stated that "a provisional workplace exposure
limit of 5 ppm (8-hour Time Weighted Average) has also been
established" for this substance.
A review of the production range (includes importation volumes)
statistics for 1,2-dichloro-l,1-difluoroethane (CAS No. 1649-08-
7). which is listed in the initial TSCA Chemical Substance
Inventory, has shown that no 1977 manufacture or importation was
reported or that all of the manufacture and/or importation data
reported were claimed as TSCA Confidential Business Information
(TSCA CBI) by the person(s} reporting for the TSCA Inventory and
cannot be disclosed (Section l4(a) of TSCAi U.S.C. 26l3(a}}. All
of the information submitted for the initial TSCA Inventory,
including the production range information, is subject to the
limitations contained in the initial TSCA Inventory Reporting
Regulations (40 CFR 7l0).
Comments/Recommendations
In its Section 8(e} submission, Du Pont reported that the company
has advised its researchers as well as other chlorofluorocarbon
producers about the submitted interim findings. Du Pont reported
also that during "recent Congressional testimony dealing with
substitutes for commercial chlorofluorocarbons, [Du Pont] advised
members of the Senate Environment and Public Works Committee of
these preliminary findings." Finally, Du Pont stated that the
company has" suspended further R&D work until after the [90-day]
test is completed and its results evaluated."
EPA's Office of Toxic Substances has
Section 8 (e) and "For Your Information"
number of chlorofluorocarbons (CFCs).
received several
(FYI) submissions
TSCA
on a
a}
The Chemical Screening Branch will request Du Pont to
ensure that I} EPA is informed in a timely manner about
any further significant toxicologic findings from the
ongoing 90-day HCFC-132b inhalation study in rats, and
2} EPA receives a complete copy of the final report
106
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8EHQ-0587-0676
Page 3 of 3
(including the actual experimental protocol, results of
gross and histopathological examinations, results of
statistical analyses, etc.) from that 90-day inhalation
study.
In view of EPA I S general interest in corporate actions
that are taken on a voluntary basis in response to
chemical toxicity or exposure data, Du Pont will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to EPA
or those published in the scientific literature) about
which Du Pont is aware or that Du Pont has conducted, is
conducting or plans to conduct to determine the toxicity
of or the exposure to l,2-dichloro-l,1-difluoroethane.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of 1,2-dichloro-l,l-difluoroethane.
c)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP. OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
107
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
Page 1 of 3
DA TE:
~ 23 1981
SUBJECT:
Status Report* 8EHQ-0687-0677 Approved: ~ 7: tJ;;;, Ii
James F. Darr, Section Head ().-~T tI::..... (/~ V/i.u.. ~/;J;'7
Chemical Risk ldentificatio~~~~ion/CSB
FROM:
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Lever Brothers Company reported that it was recently informed
(by phone) by its contract testing laboratory that Pyrazol Yellow
BG 250% (C.I. Direct Yellow 28 (CAS No. 8005-72-9) as supplied by
the Sandoz Chemicals Corporation) was found to be a weak mutagen
in a "modified" Ames Salmonella typhimurium (bacteria) assay.
According to Lever Brothers, Pyrazol Yellow BG 250% was positive
both with and without exogenous metabolic activation in bacteria
strains TA98, TA1537 and TA1538i strains TAIOO and TA 1535 were
reported to be negative.
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported genotoxicologic findings, Lever Brothers should be asked
to ensure that the Agency receives a complete copy of the final
report (including the actual experimental protocol, data, results
of any statistical analyses, etc.) from the modified Ames test
cited in the company's Section 8(e) submission.
It should be noted that in an earlier TSCA Section 8(e) notice
(8EHQ-01286-0645), Lever Brothers stated that Yellow Shade 18569
(C.I. Direct Yellow 28 as supplied by Tricon Colors Corporation)
was found to be mutagenic in strains TA98 and TA1538 in an Ames
assay. The reader's attention is directed to the status report
prepared by EPA in response to this earlier TSCA Section 8 (e)
submission.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
108
EPA FORM 13.' (REV. ,.711
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8EHQ-0687-0677
Page 2 of 3
Current Production and Use
A review of the production range (includes importation volumes)
statistics for CAS No. 8005-72-9, which is listed in the initial
TSCA Chemical Substance Inventory, has shown that between 12,000
and 120,000 pounds of this chemical were reported as manufactured
and/or imported in 1977. This production range information does
not include any information claimed as TSCA Confidential Business
Information (TSCA CBI) by the person(s) reporting for the initial
TSCA Inventory, nor does it include any information that would
compromise TSCA CBI. All of the data reported for the initial
TSCA Inventory, including the production range data, are subject
to the limitations contained in the initial TSCA Inventory
Reporting Regulations (40 CFR 710).
According to secondary literature sources, C.l. Direct Yellow 28
is a thiazole derivative [*] that is used to dye/stain a variety
of natural and synthetic materials. In its TSCA Section 8(e)
submission, Lever Brothers stated that "Pyrazol Yellow BG 250% is
not currently used in any of Lever Brothers' products."
[*] According to a C.I. Direct Yellow 28 structure obtained from
the secondary literature, the chemical identity of this dye is:
6-methyl-2-(4-(4-(6-methyl-7-su1fobenzothiazol-2-yl)phenylazo)-
pheny1)-7-benzothiazo1esu1fonic acid.
Comments/Recommendations
In its Section 8(e) submission, Lever Brothers reported that its
"decision to further investigate. . .[Pyrazo1 Yellow BG 250%] or
to conduct additional safety testing will be made after further
discussion with the [Sandoz Chemicals Corporation] and
after assessment of [Lever Brothers'] continued interest in the
material. II In addition, Lever Brothers stated that its workers
and the Sandoz Chemicals Corporation were being notified about
the reported genotoxico1ogic findings. Lever Brothers stated
further that the company will affix additional precautionary
labels on the research quantity size containers of Pyrazol Yellow
BG 250% received from Sandoz Chemicals.
It should be noted that although a positive in vitro genotoxicity
finding, when considered alone, may not be sufficient to offer
reasonable support for a conclusion of substantial risk (as that
term is defined in EPA's March 16, 1978 TSCA Section 8(e) policy
statement ("Statement of Interpretation and Enforcement Policy;
Notification' of Substantial Risk" 43 FR 11110», EPA does believe
that a single posi ti ve genotoxico1ogic finding is of value in
assessing the possible risk(s) posed by exposure to the tested
chemical substance or mixture. In addition, the Agency believes
that a positive genotoxico1ogic finding, in cOmbination with
other information (e.g., knowledge of real or potential exposure
to and/or high production of the subject chemical or mixture)
109
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8EHQ-0687-0677
1:>age 3 of 3
\,wuld suggest the need, in many cases, to conduct further studies
designed to better determine the toxicity of or the exposure to
that chemical substance or mixture. The results of such further
testing should be considered also for submission to EPA under
Section 8{e) of TSCA.
a)
The Chemical Screening Branch will ask Lever Brothers to
ensure that the Agency receives a complete copy of the
final report (including the actual experimental proto-
col, data, results of any statistical analyses, etc.)
from the modified Ames test cited in the company's TSCA
Section 8{e) submission.
In view of EPA' s general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure data, the Chemical Screening Branch
will ask the Sandoz Chemicals Corporation to describe
the actions the company has taken or plans to take 1) to
notify its workers and others about the reported geno-
toxicologic findings for C.I. Direct Yellow 28, and 2)
to reduce or eliminate exposure to this material. In
addition, Sandoz Chemicals will be asked to describe the
nature and results, if available, of all studies (other
than those reported already to EPA or those cited in the
open scientific literature) about which the company is
aware or that the company has conducted, is conducting
or plans to conduct to determine the toxicity of or the
exposu re to C. I. Direct Yellow 28. It should be noted
that similar questions were asked of the Lever Brothers
Company and the Tricon Colors Corporation in response to
Lever Brothers' earlier TSCA Section 8{e) submission on
Yellow Shade 18569 (8EHQ-1286-0645).
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of C.I. Direct Yellow 28.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
110
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
JUN I 2 1981
Page 1 of 4
SUBJECT:
Status Report*
8EHQ-0587-0678
Approved:
~ (p(i~/~'l
FRDM:
~JP. JV~ ,:6
James F. Darr, Sectio;.l Head
Chemical Risk Identification Section/CSB
TO:
Frank D. Koveri Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
In this TSCA Section 8(e) submission, the Eastman Kodak Company
reported that the tested chemical (pentachlorocyclopropane) had
been the subject of a "Low Volume Exemption" (LVE 86-218) under
Section 5, the "Premanufacture Notification" (PMN) provision of
TSCA. Immediately upon receipt of this Section 8(e) submission,
the Chemical Screening Branch transmitted copies of that notice
to the Chemical Control Division (CCD) which is responsible for
administering the Office of Toxic Substances (o'rs) "New Chemicals
Program" (NCP) under Section 5 of TSCA.
Submission Description
The Eastman Kodak Company provided the following information with
regard to the conduct and preliminary results of acute oral and
dermal toxicity studies of pentachlorocyclopropane (CAS No. 6262-
51-7) in rats:
"Groups of 5 male and 5 female rats were given 39, 78 or
156 mg/kg body weight of the test compound in a single
gavage dose as part of an acute oral LD50 study. All
animals died at 156 mg/kg. At 78 mg/kg, six of ten ani-
mals died within five days of dosing. All animals at
this dose showed significant functional abnormalities on
Day 1. These abnormalities included depression, spon-
taneous convulsions characterized by slight to severe
clonic tremors of the entire body, tail dragging, and
walking with significant hypotonic gait of the fore- and
hind-limbs. Impairment of visual orientation and of
visual placing was noted in all animals. Abnormalities
noted in animals surviving to study termination included
tremor, casual to vigorous scratching movements, varied
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
111
EPA FORM 1320-11 (REV. 3-711)
-------
8EHQ-0587-0678
Par;e 2 of 4
!":sponse to tail pinch, depres sed reflexes, and poor
muscle tone. Treatment-related pathological abnormali-
ties in [the] animals dying prior to study termination
included hemorrhage, necrosis, and congestion of the
glandular stomach, and thymic hemorrhage. [The] seminal
vesicles in all 4 males dying on Day 2 were moderately
reduced in size. No treatment-related gross pathology
abnormalities were noted in animals surviving the 14 day
observation period. At 39 mg/kg, all animals survived.
No abnormal clinical signs were observed at this dose
level.
".A.n acute dermal toxicity study was conducted on groups
of male and female rats exposed at doses of 0.5, 2 or 20
rnL/kg. At 20 mL/kg, all animals died. Abnormalities
noted at necropsy included thymic hemorrhage, and signi-
ficant congestion and necrosis of the glandular stomach.
At 2 mL/kg, significant clinical signs were observed.
Four of five females died within 2 days or were euthan-
ized. Functional abnormalities noted on Day 1 included
abnormal home cage activity, piloerection, flushed
mucous membranes, spontaneous clonic convulsions, moder-
ately severe tremors at rest, hypotonic gait of fore-
and hind-limbs, absence of extensor postural thrust
reflex, and tense or flaccid muscle tone. By Day 14,
significant abnormalities noted in survivors included
abnormal or hypotonic gait, sluggish righting reflex,
aggressive behavior, and absence of the extensor pos-
tural thrust ref lex. Abnormalities noted at necropsy
included thymic hemorrhage, and congestion and hemor-
rhage of the glandular stomach. At 0.5 mL/kg, all ani-
mals survived. Abnormalities were restricted to edema,
necrosis and eschar formation at the site of [the test
material] application. Other than dermal irritation, no
abnormal clinical si<]ns were noted. Abnormalities at
necropsy were restricted to eschars. [Note: The Section
8(e) submission did not indicate how many animals were
tested in this study.]".
Eastman Kodak's TSCA Section 8(e) submission also presented the
following information with regard to the conduct and preliminary
results of a skin irritation study of pentachlorocyclopropane in
guinea pigs:
''.In the dermal irritation study, [which was] conducted
on depilated skin of guinea pig abdomens, the test
material was rated a strong irritant. It caused edema,
erythema, necrosis, and eschar formation. Two of fi ve
animals died prior to scheduled study termination. The
three surviving animals developed eschars at the appli-
co. tion site. Two of the animals 'Nhic"h survived lost
weight during the first week of the study, and one did
not regain its initial weight over the 14-day course of
t"he study. The weight loss may have been due to [the]
112
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Page 3 of 4
irritant properties of the material, or to systemic
effects subsequent to absorption of the test material
through the skin. No necropsies were conducted on the
animals used in the dermal irritation study- [Note: The
Section 8(e) submission did not present any information
regarding the number of animals tested, the amount of
test material applied or the duration of exposure.]"
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported neurotoxicologic findings, Eastman Kodak should be asked
to submit to EPA full copies of the final reports from the acute
oral (rat) and dermal (rat and guinea pig) toxicity studies of
pentachlorocyclopropane cited in the company's TSCA Section 8(e)
submission.
Current Production and Use
According to a submitted pentachlorocyclopropane Material Safety
Data Sheet (MSDS), this chemical is a non-combustible, colorless
liquid having a vapor pressure of 9 mmHg at 54°C (129°p) and a
boiling point of 54°C (129°P) at 9 mmHg. In the Section 8(e)
notice, Eastman Kodak stated that the subject chemical "is used
as a low volume (less than 250 kg/yr) intermediate." Eastman
Kodak also provided the following information with regard to the
potential for worker exposure to pentachlorocyclopropane:
"Potential employee exposure is being minimized during
manufacture and use of the intermediate by the use of
gloves, safety glasses, full face protection, safety
shoes, rubber aprons, general and local exhaust, and
[National Institute for Occupational Safety and Health
(NIOSH)J approved organic vapor respirators."
Comments/Recommendations
In its Section 8 (e) submission, Eastman Kodak stated that the
pentachlorocyclopropane MSDS (which already carried a warning
about the strong irritating properties of the chemical) had been
updated to reflect the reported neurotoxicologic effects informa-
tion. Eastman Kodak stated also that the company is evaluating
the need for further testing of pentachlorocyclopropane.
a)
The Chemical Screening Branch will request Eastman Kodak
to submit full copies of the final reports (including
the actual experimental protocols, results of gross and
histopathologic examinations, results of any statistical
analyses performed, etc.) from the acute oral (rat) and
acute dermal (rat and guinea pig) toxicity studies cited
in the company's TSCA Section 8(e) submission.
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In view of EPA I S general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure data, Eastman Kodak will be asked to
describe the nature and results, if available, of all
studies (other than those submitted already to EPA or
those published in the open scientific literature) about
which Eastman Kodak is aware or that Eastman Kodak has
conducted, is conducting or plans to conduct to deter-
mine the toxicologic properties of or the exposure to
pentachlorocyclopropane.
b)
The Chemical Screening Branch will immediately transmit
full copies of all reported information to the Chemical
Control Division (CCD/OTS) for review and appropriate
followup attention.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS, and CCD/OTSi copies
of this report will be sent also to the TSCA Assistance
Office (TAO/OTS) for further distribution.
114
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JUL '3 1987
Page 1
of 4
SUBJECT: Status Report * 8EHQ-0687-0679 Approved: ~
FROM: James F. Darr, Section Head ,LTl;;::~
Chemical Risk Identificatio~~~~~ion/CSB
~/i~)~1
I
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The CIBA-GEIGY Corporation provided full copies of final reports
from six (6) in vitro genotoxicologic studies of the reaction
product of D-gl uci tol and epichlorohydrin (CAS No. 68412-01-1).
According to CIBA-GEIGY, the studies that gave positive results
were an Ames Salmonella typhimurium (bacteria) assay, a point
mutation assay in cultured V79 Chinese hamster cells and a chro-
mosomal abe rra tion as say in cultured human lymphocytes; studies
reportedly showing negative results were a DNA repair assay in
cultured human fibroblasts, a DNA repair assay in cultured rat
hepatocytes and a cell transformation assay in cultured BALB/3T3
mouse ce lIs. In its Section 8 (e) submis sion, CIBA-GEIGY stated
that the provided studies were conducted by CIBA-GEIGY's parent
company (CIBA-GEIGY Limited) in Basel, Switzerland.
Submission Evaluation
In the Ames as say, the subj ect chemical was tes ted (up to 5000
ug/plate) in Salmonella typhimurium strains TA98, TAlOO, TAI02,
TA1535 and TA1537 in the presence and absence of exogenous meta-
bolic activation. Posi ti ve results were obtained in the base
substi tution strains, TAlOO and TA1535, both with and without
activation. The magnitude of the observed responses were up to
3X and 13X background for TAIOO and TA1535, respectively, without
activation, and up to 5X and 37X background for TAIOO and TA1535,
respectively, with activation.
The cultured V79 Chinese hamster cell mutation test was performed
with two selection agents, 6-thioguanine (6-TG) and 8-azaguanine
(8-AG) . Without exogenous metabolic activation, an increase in
mutant frequency, up to lOX background (6-TG) and 30X background
(8-AG), was induced over the concentration range of 16-32 ug/ml.
With activation, an increase in mutant frequency, up to 3X back-
ground (6-TG and 8-AG), was induced up to concentrations of 108
and 180 ug/ml, respectively.
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
115
EPA FORM 1320-6 (REV. ]-76)
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8EHQ-0687-0679
Page 2 of 4
The tested material induced significant increases in aberration
frequency in cultured human lymphocytes. Over 50% of scored
metaphases were found to have specific aberrations under non-
activation conditions (test article concentrations of up to 54
nl/ml). Similar results were found in the presence of activation
(over 40% of scored metaphases had aberrations at test article
concentrations of up to 185 nl/ml).
No evidence of genotoxicity was found in the two Unscheduled DNA
Synthesis (UDS) assays conducted at test article concentrations
up to toxicity limits. No increases in nuclear grain counts over
cytoplasmic background were observed.
No apparent increases were seen in the cell transformation assay
using cultured BALB/3T3 fibroblasts. The assay without metabolic
activation appears to be negative at test article concentrations
of up to 20 ug/ml. In the presence of metabolic activation, how-
ever, the test cultures had the same relative viability as that
in the solvent control cultures indicating no apparent induced
toxicity by the test article. Therefore, the metabolic activa-
tion portion of this assay is considered to be inadequate to
allow a conclusion to be drawn as to the transforming capability
of the tested material in the presence of exogenous metabolic
activation.
Overall, the test article is capable of inducing gene mutations
most probably via a direct-acting mechanism. In addition, the
test article is clastogenic as evidenced by the observed increase
in aberrations in cultured human lymphocytes.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for CAS No. 68412-01-1, which is listed in the initial
TSCA. Chemical Substance Inventory, shows that no 1977 manufacture
or importatioo of the subject chemical was reported or that all
of the manufacture and/or importation data reported were claimed
as TSCA Confidential Business Information (TSCA CBI) by the per-
son (s) report ing for the initial 'T'SCA Inventory and cannot be
disclosed (Section 14(a) of TSCA; U.S.C. 2613(a)). All of the
data submitted for the initial TSCA Inventory (including the pro-
duction range data) are subject to the limitations contained in
the initial TSCA Inventory Reporting Regulations (40 CFR 710).
According to CIBA-GEIGY, the tested chemical substance, which is
toll manufactu red for CIBA-GEIGY at a purity of approximately
99%, "is a developmental resin intended primarily for use in
ilutomotive coatings. II In addition, CIBA-GEIGY reoorted that
al HlOUgh the materia 1 has not as yet been sold comr;ercially by
CIBA.-GEIC,y, "sar'1ples "have been distributed to several ootential
customers in quantities of one to five gallons for tec11n"ical per-
formance evaluations. II ClBA-GEIGY stated also that the current
Material Safety Data Sheet (MSDS) ~arries the following warning:
1]6
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8EHQ-0687-0679
Page 3 of 4
Warningl
May cause irritation, dermatitis and sensitization.
Avoid contact with eyes, skin or clothing.
Avoid breathing vapor, mist or spray.
CIBA-GEIGY reported that "when used by customers in accordance
wi th the recommended handling precautions in the MSDS, exposure
should be minimal or nil." CIBA-GEIGY stated further that "once
the product is used in its intended applica tion, it becomes a
highly crosslinked, high molecular weight, insoluble and inert
material." Finally, CIBA-GEIGY stated that "there is no consumer
exposure to the product."
Commments/Recommendations
In its TSCA Section 8(e) submission, CIBA-GEIGY stated that the
company is 1) revising the Material Safety Data Sheet (MSDS) to
reflect both the negative and positive genotoxicologic results,
and 2) informing by letter all customers who had received samples
of the subj ect product about the reported negative and posi ti ve
genotoxicologic findings.
Al though a posi ti ve in vitro genotoxici ty tes t finding, when
considered alone, may not be sufficient to offer reasonable
support for a conclusion of substantial risk (as that term is
defined in the Agency's March 16, 1978 TSCA Section 8(e) policy
statement ("Statement of Interpretation and Enforcement PolicYi
Notification of Substantial Risk" 43 FR 11110). EPA does believe
that such a finding is of value in assessing the possible risk(s)
posed by exposure to the tested chemical(s). Also, EPA believes
that a positive genotoxicity finding, in combination with other
information (e.g., the knowledge of actual/potential exposure to
and/or high production of the subject chemical(s)), would suggest
the need, in many cases, to conduct other studies designed to
determine better the toxicity of or the exposure to the subject
chemical (s) . The resu1 ts of such additional testing should be
considered also for possible submission to the Agency pursuant to
Section 8(e) of TSCA.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty or exposure information, the Chemical Screening
Branch will ask CIBA-GEIGY to describe the nature and
results of all studies (other than those submitted al-
ready to EPA or those cited in the published scientific
literature) about which CIBA-GEIGY is aware or that the
company has conducted, is conducting or plans to conduct
to determine the toxicity of or the exposure to the sub-
ject chemical substance.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical.
117
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8EHO-0687-0679
Pa~e 4 of 4
c)
~1e Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWERjEPA,
ORD/EPA, OWjEPA, OAR/EPA and OPPjOPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
118
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
n. I 4 1981
Page 1 of 4
SUBJECT:
Status Report*
8EHQ-0687-0680
Approved: (JJt- 1/''f(t?!
,
~..;",e~/4_,.~ "
FROM: James F. Darr, Section Head
Chemical Risk Identification Section/CSB
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Eastman Kodak Company submitted a copy of the final report
from a repeated oral gavage study of a mixture of di-, tri- and
tetraiodonaphthalenes in male and female rats. In the cover
letter to its Section 8(e) submission, Eastman Kodak provided the
following information with regard to the background, conduct,
results and interpretation of the performed study:
"Groups of 5 male and 5 female rats were given 200, 100,
or 20 mg/kg of the test material in corn oil for 9 doses
over 11 days or 10, 2 or 0.2 mg/kg of the test material
in corn oil for 22 doses over 30 days. Repeated doses of
the test material were lethal at doses of 10-200 mg/kg/
day and resulted in [a] dose-dependent hepatotoxicity.
Hepatic effects included elevation of serum enzymes and
total bilirubin levels, increased liver weights, dis-
coloration of the liver, and degenerative and regenera-
tive changes in the hepatocytes. Circulating white blood
cells and those in the spleen, thymus, and bone marrow
were also affected. The stomach mucosa may have been
damaged by direct contact with the test material. Toxi-
city to other organ systems, including red blood cells,
adrenal glands, kidneys, and male reproductive organs,
appeared to be secondary to [the] hepatotoxicity. The
no-observed-effect-level (NOEL) for both male and female
rats was 0.2 mg/kg. ....
"In a similar four-week oral toxicity study [conducted
with] a sample of 2,6-diiodonaphthalene that contained
approximately 1% triiodonaphthalenes and no detectable
tetraiodonaphthalenes, hepatic toxicity was found at
dietary levels of 0.3% and 1.0% (equivalent to daily
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
119
EPA FORM 1320-6 (REV. 3-76)
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8EHQ-0687-0680
Page 2 of 4
doses of 209 and 636 mg/kg/day for males and 213 and 630
mg/kg/day for females) j however, toxic effects on the
Ii ver at dietary levels of 0.1 % (equivalent to daily
doses of 73 mg/kg/day for both sexes) were so slight
that this concentration appears to be close to a NOEL.
Thus the sample of mixed di-, tri-, and tetraiodo-
naphthalenes [tested in the previously described oral
gavage study J was approximately 365 times more toxic
than the sample of 2, 6-diiodonaphthalene. From these
findings, [the Eastman Kodak Company believes] that the
components of the mixed iodonaphthalenes that are pro-
ducing the severe degree of hepatic toxicity are the
tri- and tetraiodonaphthalenes. This conclusion is
consistent with data in the scientific literature for
chlorinated naphthalenes that their toxicity increases
with increasing halogenation."
According to a submitted Material Safety Data Sheet (MSDS), the
mixed iodonaphthalenes have an average oral (male and female rat)
LD50 of approximately 1650 mg/kg and a dermal (guinea pig) LD50
of greater than 2000 mg/kg. In addition, the MSDS reports that
the mixture is slightly irritating to guinea pig skin and rabbit
eyes, but is not a sensitizing agent in guinea pigs. The MSDS
reports also that evidence of hepatotoxicity had been observed at
156 mg/kg, the lowest dose tested in the oral (rat) LD50 study.
Submission Evaluation
An initial review of the provided study shows that repeated oral
doses of the test material at levels of 10-200 mg/kg/day for up
to 30 days were lethal to male and female rats. The NOEL for the
study was 0.2 mg/kg/day. Adverse liver effects such as increased
liver weight, liver discoloration, degenerative and regenerative
changes in hepatocytes, elevated serum enzymes and elevated total
bilirubin levels were evident in the exposed animals. (It should
be noted that naphthalenes are known to cause liver injury (e.g.,
necrosis and poisoning) following ingestion, inhalation or dermal
absorption. ) In addition to the observed adverse liver effects,
circulating white blood cells and those in the spleen, thymus,
and bone marrow were affected. As stated by Eastman Kodak, the
observed hemorrhage of the stomach was most likely due to direct
contact with the test material.
In view of the fact that iodine is of great importance to the
proper functioning of the thyroid gland and even though no ad-
verse thyroid effects were found grossly or histologically in the
exposed animals, the same finding may not be evident following
chronic exposure to the test material. In occupational settings,
intermi t tent monitoring for thyroid function/dysfunction could
prove to be very beneficial in answering any questions regarding
the possible adverse effects of iodonaphthalenes on the thyroid
gland.
120
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8EHO-0687-0680
Page 3 of 4
Current Production and Use
According to the submitted MSDS, the iodonaphthalenes mixture is
a virtually odorless and water-insoluble tan solid that has a
negligible vapor pressure, a specific gravity of 2.5 (water = 1),
a melting point of 78°C (172 OF), and a boiling point of 452°C
(846°F). In its Section 8(e) submission, Eastman Kodak provided
the following information regarding 1) the company I s acti vi ties
involving iodonaphthalenes, and 2) the potential for exposure to
these chemicals:
"[The] Eastman Kodak Company is conducting research
involving iodonaphthalenes as site-limited chemical
intermediates. While the process under investigation
involves synthesis of 2,6-diiodonaphthalene, there was a
concern for the toxicity of other iodonaphthalenes since
small quantities might exist in process streams in a
commercial plant. Therefore, a sample was prepared of
iodonaphthalenes having the highest iodine content pos-
sible under the preparation conditions for use in the
[repeated oral gavage study in ratsJ. There has been no
industrial exposure to the material that is the subject
of. . [Eastman Kodak's TSCA Section 8(e)] letter.
"The analytical methods used to characterize the test
sample reported the results by area percent. This
method may underestimate the actual amount of the more
highly iodinated components. Therefore, additional
analytical characterization of this sample will be con-
ducted. The results will be incorporated into the final
report as an addendum that will be sent to the Agency.
"Approximately 50 employees work in research and
development involving potential exposure to process
streams containing low concentrations of tri- and tetra-
iodonaphthalenes. Such potential exposure is intermit-
tent and transient and averages < 2 hours/day for the
total employee group « 2.5 minutes/person/day). When
working in these operations, employees wear company
laundered coveralls, impermeable suits, gloves, boots,
and a hooded, air-supplied respirator."
Comments/Recommendations
It should be noted that Eastman Kodak had updated the provided
iodonaphthalenes.MSDS to reflect the observed hepatotoxicity.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
city or exposure information, the Chemical Screening
Branch will request Eastman Kodak to describe the nature
and results of all studies (other than those reported
already to EPA or those cited in the open scientific
121
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8ERQ-0687-0680
"Page 4 of 4
li tera tur e) a bou t wh ich Eastman Kodak is aware or that
the comDany has conducted, is conducti ng or plans to
conduct to determine the toxicity of or the exposure to
iodonaphthalenes.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of iodonaphthalenes.
c)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
122
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UNITED STATES ENV'IROHMENTAL PROTECTION AGENCY
DATE:
~231987
Page 1 of 14
SUBJECT,
Status Report* 8EHQ-0786-0681 and
8EHQ-0187-0681 FLWP
Frank D. Kover, Chief ~ Pl'~
Chemical Screening Br~h7ECAD/OTS
FROM,
TO:
Joseph J. Merenda, Director
Existing Chemical Assessment Division/OTS
Submission Description
On a "For Your Information" (FYI) basis (FYI-OTS-0786-0500), the
Monsanto Company submitted a copy of the ABSTRACT section and
several tables from the final report of a two-year oncogenicity/
chronic toxicity study of Santogard@ PVI in rats. (The company
reported by phone on July 15, 1986 that the tested product is N-
(cyclohexylthio}phthalimidei Chemical Abstract Service (CAS)
Registry Number: l7796-82-6.) The following information with
regard to the conduct and results of the performed study was
presented in the submitted ABSTRACT:
"A two-year chronic toxicity and carcinogenicity study
in the rat was conducted to determine potential adverse
toxicologic effects of . . .Santogard@ PVI when added to
the diet of rats at dietary levels [in parts per million
(ppm)] to provide daily intakes of 0, 50, 150, or 500
mg/kg bd.wt./day. [Monsanto reported by phone that this
study involved Sprague-Dawley rats.] Each experimental
group consisted of 75 males and 75 females. Body weight
was determined on each animal prior to initiation of the
study at Day "0", weekly during the first 14 weeks, bi-
weekly from weeks 16 to 30, and every four weeks there-
after. Feed cons~mption was measured on 15 animals per
sex per group prior to initiation of the study during
weekly intervals when body weights were determined.
Animals were observed daily for clinical signs of toxi-
ci ty and appearance of tumors. Blood biochemical and
hematological parameters and urinalyses were conducted
on animals sacrificed at 6, 12 and 18 months and at the
termination of the study. All animals were necropsied
and examined for gross pathological lesionsi organs/tis-
sues were preserved in 10% neutral buffered formalin for
microscopic examination. [The] organs from animals at
scheduled sacrifices were weighed after fixation for
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
123
IEPA FORM 1320..' (REV. 3-711
-------
Page 2 of 14
calculation of [the] mean organ weight and organ-to-body
weight ratios.
"The test chemical (Santogard@ PVI) at levels used in
this study did not produce adverse effects on endpoints
including clinical signs, survival, feed consumption,
blood biochemistry or urinalysis. However, body weights
and weight gains were significantly reduced in males and
females at the high-dose level, 500 mg/kg/day, and thus
were considered to be compound-related; decreased body
weights of the mid-dose (150 mg/kg/day) males probably
reflected an effect of the chemical. Feed consumption
was similar in all groups. Non-tumor clinical signs
observed in all dose groups consisted primarily of alo-
pecia and skin lesions which were incidental to chemical
treatment. Most [of the] tumors observed in animals in
the various test groups were considered to be of mammary
gland origin.
"Decreased erythrocyte indices in high-dose males and
females represented an apparent borderline response to
the chemical. Mean absolute and relative organ weights,
primarily of the liver, were significantly increased in
the high-dose males; in females, the relative hepatic
weight was also increased at the high-dose level. His-
tological lesions attributed to the chemical consisted
of benign hepatic adenomas in high-dose females (the
response was considered borderline in mid-dose females),
hepatic fatty infiltration and bile duct hyperplasia in
mid- and high-dose females and hepatic fatty infil tra-
tion in high-dose males.
"Responses obtained in this study indicate that the mid-
and high-dose levels (150 and 500 mg/kg of body weight/
day, respectively) represent apparent adverse effect
levels whereas the low-dose level (50 mg/kg of body
weight/ day) represents an apparent no effect level."
According to a submitted table that summarized several types of
observed benign/malignant tumors, there were 0, 0, 4, and 11
hepatocellular adenomas found in the control, low-, mid- and
high-dose female rats, respectively; 1 hepatocellular carcinoma
and 1 histiocytic lymphoma were found in mid-dose females but not
in females in any other dose group or in the concurrent control
group. In the male rats, there were 2 hepatocellular adenomas
observed (1 each at the low- and mid-dose levels); no hepato-
cellular adenomas were found in the high-dose males or in males
in the concurrent control group. Further, no hepatocellular
carcinomas or histiocytic lymphomas were found in male rats in
any group in the study.
In its initial FYI notice, Monsanto also provided the following
background information with regard to the company' s conclusions
on the significance of the findings:
124
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Page 3 of 14
"It was concluded at the time of receipt of the final
report [(March 6, 1984)] that the finding of benign
liver tumors in one sex [(females)] at dose levels that
were associated with liver toxicity and body weight de-
pres sion did not represent a significant health risk.
This conclusion was supported by the negative genotoxic
activity of the compound based on four in vitro and one
in vivo mutagenicity assays and the low-revels of expo-
sure monitored in the workplace." [Note: In the initial
FYI notice, Monsanto did not identify the mutagenicity
assays that the company had conducted.]
"During a recent[ly conducted] review of proposed
experimental approaches to evaluate these liver effects,
a pathology consultant noted that a trend in scientific
thought with regard to rodent tumors was that many be-
nign tumor diagnoses represent a stage of progression to
malignancy. As a result, the test results have been re-
viewed in light of a trend in scientific thinking."
Monsanto noted that during this review, the company considered 1)
the January 17. 1986 National Toxicology Program (NTP) proposal
"to continue using benign neoplasia as a useful biologic indica-
tion for selecting levels of evidence" (51 FR 2579-2582)~ and 2)
the April 7, 1986 NTP statement that when "selecting a conclusion
for a particular experiment, consideration must be given to key
factors that would extend the actual boundary of an individual
category of evidence" (51 FR 11843-11844).
Monsanto reported in its initial FYI notice that the following
key factors were among those that had been considered by the com-
pany in evaluating the results of the company's chronic feeding
study of Santogard@ PVI in male and female rats:
"A lack of progression from benign to malignant lesions.
Since the one exception [(i.e., hepatocellular carcinoma
observed in one female rat)] occurred at the mid-dose
level, there is an increased likelihood that this was a
chance event unrelated to dosing."
"[A] lack of supporting information, such as prolifera-
tive lesions from the same site in [the] other sex or
proliferative effects in other organs or tissues of
either sex."
"Negative genetic toxicology findings."
In conclusion, Monsanto stated that in the company's "judgement,
the findings in this [dietary] study do not indicate a signifi-
cant health risk." In addition, Monsanto stated also that the
"Proceedings of the International Symposium of the Society of
Toxicologic Pathologists entitled Rodent Liver Nodules: Signifi-
cance to Human Cancer Risk (Toxicologic PathologYi Vol.lO, 1982),
reflects the scientific debate about the significance of benign
125
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Page 4 of 14
tumors in rodent models." Finally, Monsanto stated that "the de-
bate continues to the present time as noted by NTP (51 FR 1579-
2582, January 17 1986) . . . [that] the issue of benign neoplasia
in relation to the carcinogenic potential of a compound remains
an area of active discussion among scientists."
In its initial review of the provided information, EPA noted that
the submitted information from Monsanto's 24-month feeding study
showed that 1) Santogard@ PVI caused a dose-related incidence of
hepatocellular adenomas in female rats, and 2) the incidence was
statistically significant at the highest dose. In addition, EPA
noted that the observed liver toxicity, body weight depression,
lack of progression of the liver tumors from a benign to malig-
nant state, and the reportedly negative genotoxicity results did
not negate the observed oncogenic activity of Santogard@ PVI.
EPA noted also that the concurrent controls were found not to
have any liver tumors. Finally, EPA noted that the historical
control incidence of liver tumors in female Sprague-Dawley rats
is considered generally to be less than 1%.
Based on EPA's review of the information contained in the initial
FYI notice, EPA informed Monsanto by letter on December 10, 1986,
that the Agency believed that the oncogenicity findings from the
company's chronic dietary feeding study of Santogard@ PVI in rats
provided reasonable support for a conclusion that this chemical
substance can cause cancer and should have been reported formally
under Section 8(e), the "substantial risk" information reporting
provision of the Toxic Substances Control Act (TSCA).
In its December 10, 1986 letter, EPA requested Monsanto to submit
a full copy of the final report from the company's 2-year feeding
study of Santogard@ PVI as well as descriptions of the results of
any other studies (especially teratologic studies that Monsanto
had conducted to determine the toxicity of this chemical). In
addition, Monsanto was requested to provide further information
regarding Monsanto's decision not to submit the chronic feeding
study findings to the Agency under Section 8(e) of TSCA.
In response to EPA's letter, Monsanto provided (FYI-OTS-0187-0500
Followup Response) all of the information requested by EPA. In
addition to a full copy of the final report from the Santogard@
PVI ~hronic feeding study, Monsanto provided full copies of the
final reports from in vitro bacteria, yeast, mouse and hamster
cell mutagenicity assaYSi in vitro/in vivo Unscheduled DNA
Synthesis (UDS) and DNA Replication assays using rat hepatocytesi
and an in vivo rat bone marrow clastogenicity study. According
to Monsanto, Santogard@ PVI did not show "any evidence of muta-
genic or DNA interactive effects [in these particular tests]."
In its followup response, Monsanto also provided full copies of
the final reports from two teratology studies of Santogard@ PVI
in rabbits. The following excerpts are from the Conclusions
sections of Monsanto documents that accompanied these reports:
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Page 5 of 14
"[In a pilot teratology study of Santogard@ PVI at oral
gavage doses of 3, 10, 30, 100 or 300 mg/kg/day on days
7 through 19 of gestation,] significant maternal toxi-
city occurred following administration of. .[300
mg/kg/day]. Slight decreases in maternal body
weight were reported during treatment for animals dosed
at . . . [100 mg/kg/day]. No significant adverse mater-
nal or fetal effects were observed at the other doses
used in this pilot study. On the basis of the results
of this pilot study, dose levels of . [10, 30 and
100 mg/kg/day] were selected for the teratogenicity
study in rabbits. . . ."
"[In the full teratogenicity study,] Santogard@ PVI,
administered [orally by gavage at doses of 10, 30 or 100
mg/kg/day] to pregnant rabbits on days 7 through 19 of
gestational development, did not produce a teratogenic
response. No difference in the number of resorptions,
live or dead fetuses, or fetal weights were present at
10 or 30 mg/kg, and these doses did not produce an in-
crease in either soft tissue or skeletal malformations
in offspring from treated animals. Slight decreases in
fetal body weight and slight increases in skeletal ossi-
fica tion variations, accompanied by decreases in [the]
maternal body weight gain during the treatment period,
were present at [the] 100 mg/kg dose level and demon-
strated a marginally toxic response at this dosage.
Thus, the no-effect level in this study was considered
to be the mid-dose level of 30 mg/kg/day."
Further with regard to the potential for reproductive system
toxicity, Monsanto submitted the following summarized information
concerning a two-generation reproduction study of Santogard@ PVI
in rats:
". . .[Santogard@ PVI] was evaluated in a two-generation
reproduction study with rats given 0, 50, 150 or 500 ppm
of the test material in the diet from gestation onward
of the first generation and through the entire duration
of the second generation. No treatment-related effects
were observed in the FO generation. Mean body weights,
were lower in the first generation (Fl) high-dose ani-
mals. High-dose females also exhibited a lower body
weight gain during gestation. A lower mean number of
live pups and an increase in the mean number of dead
pups at birth were observed for the F 2 litters at the
high dose. Pup body weights, sex ratro, and necropsy
findings were not different between the control and
treated groups. No consistent reproductive effects were
noted in this study."
In addition to providing the previously described information,
Monsanto also reported that Santogard@ PVI has been shown to be
1) slightly toxic when administered orally to rats (LD50 of 2.6
127
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Page 6 of 14
g/kg), 2) practically non-toxic when applied dermally to rabbits
(LD50 of >5 g/kg), and 3) slightly irritating to eyes and non-
irritating to skin (species tested were not specified). Monsanto
stated further that "no adverse effects were observed in a four-
week. . inhalation study with rats exposed to Santogard@ PVI
[dust] at 52, 157, or 536 mg/m3 for 6 hours per day,S days per
week." Monsanto also provided the following summary information
regarding the results of a subchronic study in which male/female
rats were exposed via inhalation to Santogard@ PVI dust at dose
levels of 15, 50 or 150 mg/m3 for 6 hours per day for 90 days:
"High-dose animals and mid-dose females had decreased
body weights. Elevations in kidney weight were found in
the high-dose males. Male rats showed dose-related in-
creases in [the] incidence of kidney lesions which were
characterized by eosinophilic droplets in the proximal
tubule, degeneration and regeneration of [the] tubular
epithelium, and granular casts occluding and causing
dilation of [the] renal tubules. Scattered granulomas
of the lung were noted in the controls and treated ani-
mals; these were more frequent in high-dose males. No
no-effect level was established for male rats in this
study. The no-effect level for females was considered
to be 15 mg/m3."
With regard to sub-acute oral toxicity, Monsanto reported that no
treatment related adverse effects had been observed (except for
reduced body weights at the two highest dose levels) in a study
in which Santogard@ PVI was administered in the diet (species not
specified) at doses of 0, 50, 150, 300, 600 or 1500 ppm for four
weeks.
Monsanto also submitted summarized information concerning the
findings of human skin patch tests conducted with Santogard@ PVI
alone and compounded with rubber stock. According to Monsanto, a
repeated insult human patch test involving 55 volunteers showed
that Santogard@ PVI alone is "a primary and cumulative irritant
and a sensitizing agent." Monsanto stated also that rubber stock
compounded with up to 2 pounds Santogard@ PVI per 100 pounds of
rubber "produced only mild cumulative irritation in a repeated
insult human patch test using 53 volunteers."
With regard to the toxicity of Santogard@ PVI to aquatic species,
the following information was contained in a Material Safety Data
Sheet (HSDS) submitted by Monsanto in its followup response:
"96-hr
96-hr
96- hr
96-hr
48-hr
LC50
LC50
LC50
EC50
LC50
Bluegill:
Trout:
Fathead Minnow:
Algae, . .
Daphnia:
1. 2 mg / 1 ,
0.4 mg/l,
.42 mg/l,
22 mg / 1 ,
32 mg / 1 ,
Moderately Toxic
Highly Toxic
Highly Toxic
Slightly Toxic
Slightly Toxic"
In addition to restating most of its previous arguments as to why
the Santogard@ PVI cancer study findings were not considered by
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Page" of 14
the company to be reportable to EPA under Section 8(e) of TSCA,
Monsanto pointed to the following documents as providing further
strength to Monsanto's position: 1) a 1986 EPA Risk Assessment
Forum publication ("Proliferative Hepatocellular Lesions of the
Rat; Review and Future Use in Risk Assessment" EPA/625/3-86/01l;
February 1986), 2) a September 1986 proposed revision to the pre-
amble to International Agency for Research on Cancer (IARC)
Monographs and 3) a 1985 Office of Science and Technology Policy
(OSTP) report ("Chemical Carcinogens; A Review of the Science and
its Associated Principles" 50 FR 10372-10442; March 14, 1985).
Submission Evaluation
Based on a review of the full final report of Monsanto's 2-year
feeding study of Santogard@ PVI in rats, EPA believes that 1) the
study was adequately designed and conducted, and 2) the doses
used were based appropriately on an accurate maximum tolerated
dose (MTD). Although body weights were significantly reduced in
the high dose male and female groups, no significant weight loss
was found in the mid or low dose groups of either sex. The dose
levels used in this chronic study did not produce adverse effects
on survival, clinical signs. feed consumption, blood chemistry or
urinalysis in any test group. Histologically, hepatic fatty in-
filtration and bile duct hyperplasia were observed in the mid and
high dose females while high dose males showed only hepatic fatty
infiltration.
Hepatocellular adenomas were found to occur in a dose-related
increased manner in the mid and high dose female rats with the
incidence showing statistical significance at the high dose
(P<.OOl). It should be noted that a combination of the adenomas
and the single hepatocellular carcinoma found among the mid dose
females also resulted in statistical significance (P=. 029) . No
hepatocellular adenomas were observed in female rats in either
the low dose or control groups. In male rats, one hepatocellular
adenoma was found in both the low and mid dose groups; no liver
tumors were found in males in either the high dose or concurrent
control groups. Historically, the incidence of spontaneously
occurring primary liver tumors in Sprague-Dawley male and female
rats is quite low (i.e., typically less than 1%). It is also im-
portant to note that serial sacrifices at predetermined intervals
in Monsanto's chronic Santogard@ PVI feeding study showed that
the "time to tumor" was shorter for the high dose female rats
than for the mid dose female rats. Hepatocellular adenomas were
induced as early as day 338 in the high dose females, while the
first tumor noted in the mid dose females occurred at day 526 of
the study. This reduced "time to tumor" observation supports the
significance of the hepatocellular adenomas as being treatment-
related.
Based on
adenomas
trend of
Armitage
a statistically significant incidence of hepatocellular
induced in the high dose females and an overall positive
induced tumors among the dosed female groups (Cochran-
Trend Test; P<.OOl). the oncogenic response observed in
129
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Page 8 of 14
female rats exposed chronically to Santogard@ PVI via the feed in
this adequately designed study is considered by the Agency to be
a direct response to exposure to this chemical substance.
With regard to the submitted genotoxicity studies, the results of
the Ames (bacteria) and yeast assays demonstrate clearly that
Santogard@ PVI was not mutagenic under the conditions of these
tes ts. In addition, the in vitro rat primary hepatocyte as say
findings demonstrate that--Santogard@ PVI did not induce un-
scheduled DNA synthesis. Further, the results of the in vivo rat
bone marrow study demonstrated that Santogard@ PVI did not induce
chromosomal aberrations, either structural or numerical, in rats
exposed via gavage. In the in vitro mouse lymphoma (L5178Y) cell
mutagenicity assay, the results were clearly negative in the ab-
sence of exogenous metabolic activation7 however, the doses used
in the exogenous metabolic activation portion of the assay may
have been insufficiently high rendering this component of the
assay inconclusive. With regard to the results of the in vivo/in
vitro rat hepatocyte DNA repair and replication assay-;-there TS
no indication that Santogard@ PVI induced unscheduled DNA syn-
thesis or S-phase replication7 it must be pointed out, however,
that this particular study may not have been conducted at a dose
level high enough to detect activity therefore rendering the in-
terpretation of the data to be inconclusively negative. Finally,
and contrary to the submitter I s statements that Santogard@ PVI
was not found to be mutagenic in cultured Chinese Hamster Ovary
(CHO) cells, the provided data do suggest that Santogard@ PVI is
a mutagen in CHO cells when tested with or without exogenous
metabolic activation (a doubling to quadrupling of mutation fre-
quencies observed as compared to controls) 7 insufficiently high
dose levels cause the data from this assay to be inconclusive.
In summary, the submitted genotoxicity data demonstrate that
Santogard@ PVI did not cause chromosomal aberrations in rat bone
marrow in vivo 7 did not induce gene mutations in prokaryotes,
lower eukaryotes or in cultured mouse cells (without metabolic
exogenous activation)7 and did not induce DNA effects in cultured
rat primary liver cells. Due to a possible failure to test a
sufficiently high dose, however, the evidence is inconclusive
that Santogard@ PVI is not mutagenic in cultured mammalian cells
in the presence of exogenous metabolic activation or that the
chemical does not induce unscheduled DNA synthesis or S-phase
replication in vivo. Further, there is some suggestion that
Santogard@ PVI can induce gene mutations in cultured CHO cells7
this particular study would need to be conducted at higher dose
levels to verify or refute the suggestive mutagenic activity. In
conclusion, the Agency believes that the weight-of-the-evidence
that Santogard@ PVI is not genotoxic is not as strong as that
claimed by Monsanto.
Wi th regard to the provided pilot teratology study report, 80%
maternal death occurred at 300 mg/kg/day. Although a maternal
weight loss was observed at 100 mg/kg/day, it should be noted
that maternal weight loss should not be considered as a reliable
130
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Page 9 of 14
indicator of toxicity in the rabbit. In addition, a 30% decrease
in fetal weight was observed at the 100 mg/kg/day dose level. In
view of the fact that the study authors concluded that maternal
and fetal effects occurred at 100 mg/kg/day and above (making 30
mg/kg/day the lowest-observed-effect-level (LOEL», 100 mg/kg/day
was chosen as the highest dose level for the full teratology
study. In view of the fact that EPA considers the maternal toxi-
city observed at 100 mg/kg/day to be minimal, EPA believes that a
dose somewhere between 150 and 225 mg/kg/day would have been more
appropriate as the highest dose for the full teratology study.
In the full rabbit teratology study, no statistically significant
effects were reportedly observed at any dose level tested. The
observed slight decrease in fetal body weight at 100 mg/kg/day,
when coupled with delayed ossification, suggests a dose-related
effect and indicates that the threshold dose level may be in that
vicinity. Also at the 100 mg/kg/day dose level, a very specific
endpoint (enlarged fontanel) showed a 19-fold increase (17.5% as
compared to 0.9% in controls). Further, there was an increased
incidence of incompletely ossified frontal bones found in fetuses
at the high dose. Therefore, 100 mg/kg/day appears to be a LOEL
for developmental effects in the absence of maternal toxicity and
the no-observed-effect-level (NOEL) appears to be 30 mg/kg/day.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for N-(cyclohexylthio)phthalimide (CAS No. 17796-82-6)
which is listed in the initial TSCA Chemical Substance Inventory,
has shown that no 1977 manufacture/importation was reported or
that all of the production range information that was reported
was claimed to be TSCA Confidential Business Information (TSCA
CBI) by the person(s) reporting for the TSCA Inventory and cannot
be disclosed (Section 14(a) of TSCA, U.S.C. 2613(a». All of the
information reported for the TSCA Chemical Substance Inventory,
including the production range information, is subject to the
limitations contained in the TSCA Inventory Reporting Regulations
(40 CFR 710).
Monsanto reported by phone on July 15, 1986, that Santogard@ PVI
is a pre-vulcanization inhibitor used in the production of both
natural and synthetic rubber products.
According to the MSDS contained in Monsanto's followup response,
Santogard@ PVI is a water-insoluble solid (light tan to white
crystals/pellets) with a slight mercaptan odor and a melting
point of approximately 90-95°C.
In its followup response, Monsanto stated that employees working
with Santogard@ PVI "have reported a strong mercaptan-like odor
on the skin which appears to be released by perspiration, washing
or showering." In order to reduce this body odor as well as skin
and eye irritation, Monsanto stated that the following workplace
modifications and exposure controls were instituted:
131
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Page 10 of 14
"In 1981, a new drier and a new exit screw conveyor from
the drier were installed. This reduced employee exposure
by improving containment and limiting equipment clean-
outs. These measures, along with the use of personal
protective equipment, such as dust respirators for short
periods, reduced the potential for irritation and odor.
To further reduce exposure potential, a new local ex-
haust ventilation system was installed in 1982 at the
[Santogard@ PVI] bagging station. In 1985, the screw
conveyor was replaced and the practice of adding oil to
the product as a dust suppressant was begun. House-
keeping in the PVI Department has always been especially
emphasized. The PVI production building at [Monsanto's]
U. S. site is washed down approximately six times per
year during routine shut-downs and maintenance over-
hauls. In 1982, Monsanto adopted an internal exposure
guideline of 1 mg/m3 Or 0.09 ppm (8-hour time-weighted
average [(TWA)]) with a skin contact precaution to mini-
mize potential irritation and odor. During the period
from 1982 to 1986, [the Santogard@ PVI] dust exposure
values were below the 1 mg/m3 [internal guideline] as
averaged over an 8-hour day; however, body odor and in-
fr equent eye ir ri ta tion cont inued to be reported. To
minimize these effects even further, Monsanto installed
a sauna for [the company's] PVI workers and lowered the
internal exposure guideline to 0.5 mg/m3 or 0.05 ppm (8-
hour TWA) with a skin contact restriction. [Monsanto
believes] that maintaining [Santogard@ PVI] airborne
exposures below 0.5 mg/m3 (8-hour TWA) , avoiding skin
contact, using personal protective equipment when ex-
posure potential exists and encouraging the use of the
sauna will eliminate irritation and body odor."
Comments/Recommendations
In its followup submission, Monsanto reported that in addition to
the previously described workplace modifications, the company had
1) updated the Santogard@ PVI MSDS to reflect the findings from
the 2-year feeding study, and 2) notified Monsanto workers and
customers formally about the findings from that chronic study.
Monsanto stated also that in an "effort to determine the biologi-
cal significance of the [rat] liver lesions, . . . [Monsanto has]
begun studies to evaluate initiation-promotion and peroxisome
proliferation effects in rat liver models."
Al though Monsanto I s FYI notices give the reader the impression
that there is a new trend of thought regarding the biological
significance of benign tumors, it should be noted that it has
been EPA I S longstanding and highly publicized position that a
treatment-related increase (especially a significant increase) in
the incidence of benign tumors, even in one sex of one species,
should be viewed as evidence that the tested chemical (s) can
132
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Page 11 of 14
cause cancer. In a May 19, 1976 press release announcing the
adoption of EPA's interim cancer assessment guidelines, then EPA
Administrator Russell Train stated that" in very few cases is it
possible to prove that a [chemical] substance will cause cancer
in man, because in most instances the evidence is limited to
animal studies." Administrator Train stated further that" in
this regard, a substance will be considered [by the Agency to be]
a presumptive cancer risk when it causes a statistically signifi-
cant excess incidence of benign or malignant tumors in humans or
animals. " According to the adopted interim cancer assessment
guidelines document, "substantial evidence [of cancer] is pro-
vided by animal tests that demonstrate the induction of malignant
tumors in one or more species including benign tumors that are
recognized as early stages of malignancies" and "suggestive evi-
dence [of cancer] includes the induction of only those nonlife
shortening benign tumors which are generally accepted as not pro-
gressing to malignancy. . . ."
It should be noted that EPA' s policy concerning the biological
significance of benign tumors observed in animals has not changed
to any great degree since 1976. For example, EPA's 1984 proposed
(49 FR 46294) and 1986 final (51 FR 33992) cancer assessment
guidelines both reflect EPA's historical position concerning the
biologic significance of benign tumors. According to EPA's 1984
proposed cancer assessment guidelines, "limited evidence of car-
cinogenici ty, . means that the data suggest a carcinogenic
effect but are limited because: (a) the studies involve a single
species, strain, or experimentr or (b) the experiments are re-
stricted by inadequate dosage levels, inadequate duration of
exposure to the agent, inadequate period of follow-up, poor
survival, too few animals, or inadequate reportingr or (c) an
increase in the incidence of benign tumors only." The term
"limi ted evidence" is defined in es sentially the same manner in
the Agency.s 1986 final cancer assessment guidelines.
It should be noted further that EPA's 1986 Risk Assessment Forum
publication ("Proliferative Hepatocellular Lesions of the Ratr
Review and Future Use in Risk Assessment" EPA/625/3-86/011)
states that "a determination of carcinogenic hazard will be based
upon consideration of the incidence of hepatocellular carcinoma
alone, neoplastic nodule alone and a combination of carcinoma and
nodule." This 1986 EPA document states also that in cases "where
increases in lesions and statistical significance are restricted
to neoplastic nodules alone, such data will be interpreted [by
EPA] as only limited evidence of animal carcinogenicity."
It is clear that EPA' s position with regard to benign tumors is
not new and is one that has been made public. Further, EPA' s
position is consistent with that of other scientific/regulatory
bodies. For example, the National Toxicology Program (NTP) an-
nounced on January 17, 1986 (51 FR 2579) that NTP would continue
to hold its position that ,"some" evidence of carcinogenicity "is
demonstrated by studies that are interpreted as showing a chemi-
cally related increased incidence of neoplasms (malignant, benign
133
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Page 12 of 14
or combined) . . . ." In addition, the September 1986 proposed
revision to the IARC Monograph preamble states that limited evi-
dence of carcinogenicity of a chemical in animal studies will be
defined by IARC as "one or more studies that show an increased
incidence of neoplasms in animals exposed to the agent in com-
parison with animals not exposed but. . only benign neoplasms
ha ve be en obse rved to be increased in incidence." Further, the
existing preamble to the IARC Monographs published since 1978
states:
"Many chemicals induce both benign and malignant tumors.
Among chemicals that have been studied extensively,
there are few instances in which the only neoplasms
induced are benign. Benign tumors may represent a stage
in the evolution of a malignant neoplasm or they may be
end-points that do not readily undergo transition to
malignancy. If a [chemical] substance is found to
induce only benign tumors in experimental animals, it
should nevertheless be suspected of being a carcinogen,
and it requires further investigation."
Further to the above point, a 1981 review article by Chu et al.
which appeared in the Journal of Toxicology and Environmenta"t
Health (Vol. 8: 250-280), reported that a previous (1975) review
of the morphology/histogenesis of rat liver tumors showed that in
general this type of tumor begins with hyperplasia which then
progresses to a neoplastic nodule and on to hepatocellular car-
cinoma which eventually becomes a metastatic carcinoma.
Finally, it is important to note that "suggestive", "limited" or
"some" evidence of carcinogenicity (as those terms are used by
EPA or others) should not be interpreted to mean that such evi-
dence can be dismissed or that the evidence is not reasonable in
terms of its ability to support a conclusion that a chemical can
cause cancer. Furthermore, EPA's March 16, 1978 Section 8(e)
policy statement ("Statement of Interpretation and Enforcement
Policy: Notification of Substantial Risk" 43 FR 11110) as it
relates to cancer has been and continues to be consistent with
EPA's cancer assessment guidelines as well as those of other
regulatory agencies and scientific organizations.
Following a review of FYI-OTS-0786-0500 and FYI-OTS-Ol87-0500
Followup Response, EPA has determined that the oncogenicity
findings from Monsanto's 2-year feeding study of Santogard~ PVI
in rats should have been submitted to EPA under Section 8(e) of
TSCA. The basis for EPA's determination is as follows:
Section 8(e) states that "any person who manufactures,
[imports,] processes, or distributes in commerce a
chemical substance or mixture and who obtains informa-
tion which reasonably supports the conclusion that such
substance or mixture presents a substantial risk of
134
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Page 13 of 14
injury to health or the environment shall immediately
inform the Administrator of such information unless such
person has actual knowledge that the Administrator has
been adequately informed of such information."
The preface in Part V of EPA' s March 16, 1978 Section
8(e) policy statement ("Statement of Interpretation and
Enforcement Policy; Notification of Substantial Risk"
43 FR 11110) states that "a substantial risk of injury
to health is a risk of considerable concern be-
cause of (a) the seriousness of the effect. . and (b)
the fact or probability of its occurrence." With regard
to the seriousness of the effect, Part V explains that
EPA considers the types of health effects for which sub-
stantial risk information must be reported to include
"any pattern of effects or evidence which reasonably
supports the conclusion that the chemical substance or
mixture can produce cancer, mutation, birth defects.
" The information concerning these effects can be
obtained directly or inferred from designed studies
(e.g., in vivo animal studies) as described in Part VI.
Part VIexplains also that a subject "person is not to
delay reporting until he obtains conclusive information
that a substantial risk exists, but is to immediately
report any evidence which reasonably supports that con-
clusion." Part V explains further that "such evidence
will generally not be conclusive as to the substantial-
i ty of the risk; it should, however, reliably ascribe
the effect to the chemical." In addition, Part VI states
that "not only should final results from such studies be
reported, but also preliminary results from incomplete
studies. . "
With regard to the "fact or probability of its [i.e.,
the serious effect's] occurrence" criterion, Part V of
the Section 8 (e) policy document states that certain
types of health effects (e.g., cancer) are considered to
be so serious that relatively little weight should be
attached to chemical exposure in determining whether a
risk is substantial. Part V explains further that "the
mere fact that the implicated chemical is in commerce
constitutes sufficient evidence of exposure." In addi-
tion, EPA' s response to Comment 31 (see Appendix B of
the Section 8(e) policy statement) explains that the oc-
currence of serious effects such as those alluded to in
Part V(a) of the TSCA Section 8(e) policy statement
(e.g., cancer, reproductive toxicity) presupposes ex-
posure to the subject chemical or mixture and must be
reported immediately to EPA under Section 8(e) of TSCA.
It is important to note that previously unknown evidence
(preliminary or otherwise) of chemical-induced oncogenic
activity observed in an animal study, regardless of how
such evidence would be classified ultimately under the
135
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Page 14 of 14
various cancer risk assessment systems/guidelines cannot
be dismissed and must be considered for immediate sub-
mission to EPA under Section 8(e) of TSCA. The Agency
views the overall assessment of the ultimate risk of
cancer in humans as requiring a broad analysis that
extends well beyond the scope of assessing the signifi-
cance of either the preliminary or final results of an
animal study. Therefore, a company's decision to submit
information to EPA under Section 8(e) of TSCA should not
involve an exhaustive human risk assessment of an impli-
cated chemical substance or mixture.
In light of the preceding discussion, EPA has determined that the
findings from the Monsanto Company's 2-year dietary feeding study
of Santogard@ PVI in rats reasonably support the conclusion that
this chemical s~bstance can cause cancer and as such should have
been submitted in a timely manner to EPA pursuant to Section 8(e)
of TSCA.
a)
The Existing Chemical Assessment Division (ECAD/OTS)
will inform Monsanto about EPA's determination with
regard to the TSCA Section 8 (e) -reportabi Ii ty of the
company's cancer findings for Santogard@ PVI. Monsanto
will be informed also that the Chemical Screening Branch
has forwarded both Monsanto's initial and followup FYI
submissions to the OTS Document Control Office for
processing/public filing under Section 8(e) of TSCA.
The Existing Chemical I\ssessment Division will request
Monsanto to submit a full copy of the final report (in-
cluding the actual experimental protocol, results of
gross and histopathologic examinations, results of any
statistical analyses, etc.) from the two-generation rat
reproduction study that was cited in Monsanto's followup
response. In addition, Monsanto will be requested to
submit a full copy of Volume I of the October 15, 1981
draft final report from the company's 2-year dietary
feeding study of Santogard@ PVI in rats.
b)
The Chemical Screening Branch will review the reported
findings in greater detail to determine the need for
further OTS assessment of N-(cyclohexylthio)phthalimide.
c)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and OCM/OPTS/EPA.
In addition, copies of this status report will be trans-
mitted to the TSCA Assistance Office (TAO/OTS/OPTS/EPA)
for further distribution.
136
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DA TE:
JUL
6 1987
Page 1 of 2
SUBJECT:
Status Report *
8EHQ-0687-0682
APproved:~
-;j6/n
.
FROM:
James F. Darr, Section Head ~~~
Chemical Risk Identificatiob7~ection/CSB
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Monsanto Company reported that "maternal toxicity, embryo-
toxicity, fetotoxicity and skeletal abnormalities" were observed
at the highest dose (300 mg/kg/day) of dodecylphenol (CAS No.
27193-86-8) administered via gavage to pregnant rats. According
to Monsanto, "no maternal or developmental toxici ty was observed
at the lower doses (100 mg/kg/day and 20 mg/kg/day) tested."
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon the Agency's receipt of a com-
plete copy of the final report (including the actual experimental
protocol, results of gross and histopathological examinations,
results of statistical analyses, etc.) from the oral teratology
study cited in Monsanto's Section 8(e) submission.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for dodecylphenol (CAS No. 27193-86-8), which is
listed in the initial TSCA Chemical Substance Inventory, shows
that 10 million to 50 million pounds of this chemical substance
were reported as manufactured and/or imported in 1977. This
production range information does not ~nclude any data claimed to
be TSCA Confidential Business Information (TSCA CBI) by the per-
son(s) who reported for the initial TSCA Inventory, nor does it
include any data that would compromise TSCA CBI. All of the data
reported for the initial TSCA Inventory, including the production
range data, are subject to the limitations that are contained in
the initial TSCA Inventory Reporting Regulations (40 CFR 710).
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements m~de in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
137
EPA FORM 1320-& (REV. 3-7&1
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8EHO-0687-0682
"?age 2 of 2
According to Monsanto, the company manufactures dodecylphenol and
uses the chemical" in the production of non-ionic detergents."
In addition, Monsanto reported that the company markets dodecyl-
phenol "on a limited basis as an intermediate chemical." Also,
Monsanto provided the following information with regard to the
potential for exposure and possible risks posed by exposure to
dodecylphenol in the workplace:
"[The Monsanto Company does not beleve thatJ exposure to
the chemical is significant. First, exposure levels in
[Monsanto's] facilities are well below 0.1 mg/m3 of air.
In calculating [the] exposure at a level of 0.1 mg/m3,
assuming absorption and retention of all inhaled
material over an eight-hour workday, there would be a
safety factor of over 5,000 with respect to the no-
effect dose of 100 mg /kg/ day. Second, [Monsanto
believes that] exposure to customers is self-limiting
because the material is non-volatile. Further, its
irri tant effects would be evident before dosages equal
to the no-effect levels in the rats were attained."
Comments/Recommendations
In its TSCA Section 8(e) submission, Monsanto reported that the
company's dodecylphenol Material Safety Data Sheet (MSDS) would
be updated to reflect the submitted toxicologic findings.
a)
The Chemical Screening Branch will request Monsanto to
ensure that EPA receives a full copy of the final report
(including the actual experimental protocol, results of
gross and histopathologic examinations, results of any
statistical analyses, etc.) from the teratologic study
cited in the company's TSCA Section 8(e) notice.
In view of EPA's general interest in corporate actions
that are taken on a voluntary basis in response to chem-
ical toxicity or exposure information, Monsanto will be
asked to describe the nature and results, if available,
of all studies (other than those cited in the published
scientific literature or those submitted already to EPA)
about which Monsanto is aware or that Monsanto has con-
ducted, is conducting or plans to conduct to determine
the toxicity of or the exposure to dodecylphenol.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of dodecylphenol.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
138
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JUL
7 1987
Page 1 of 3
SUBJECT:
Status Report* 8EHQ-0687-0683 APproved:~
James F. Darr, Section Head r. T ~
Chemical Risk Identification Section/CSB
"'/1/~7
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Union Carbide Corporation provided the following information
regarding the conduct and preliminary findings of a short-term
repeated inhalation study of NIAX@ Catalyst A-99 (i.e., bis(2-di-
methylaminoethyl)ether or DMAEE; CAS No.3033-62-3) in rats:
"The purpose of the study was to determine the potential
for adverse effects by short-term repeated exposure (9
days) of rats to vapor generated from DMAEE at ambient
tempera ture. The protocol design allowed for male and
female Sprague-Dawley rats to be exposed for 6 hours a
day for 9 days (over an 11-day period) to target DMAEE
vapor concentrations of 20, 40 and 80 ppm. An additional
air-alone exposure group served as a control. There
were 10 male and 10 female rats per exposure group, with
an additional 15 male rats in the highest concentration
group [( 80 ppm DMAEE) 1 for post-exposure recovery and
ultrastructural studies. Monitors for toxicity included
daily observations, body weight, food and water consump-
tion, peripheral blood hematology, serum chemistry,
urinalysis, necropsy, organ weight and light microscopic
examination of tissues and organs removed at necropsy.
"The results of the study to date are as follows:
"[ l] The mean analytically measured concentrations of
DMAEE [vapor] were 0, 22, 47 and 90 ppm over the expo-
sure periods.
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
139
EPA FORM 1320-6 (REV. 3-761
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8EHQ-0687-0683
Page 2 of 3
"[2J
Mortalities:
o ppm - none
22 ppm
- none
47 ppm
- all 10 males and 10 females
died between the sixth and
eleventh days from the start
of exposures.
90 ppm - all 25 males and 10 females
died on the third or fourth
exposure days.
"[3J Food and water
reduced at 47 ppm.
consumption
were
significantly
"[4J Body weight
related fashion.
loss
occurred
in
a
concentration-
"[5J Histological examination of lungs from males (the
only tissues examined at the time of. . [the company's
TSCA Section 8(e) noticeJ, showed cytoplasmic vacuola-
tion of bronchial epithelial cells at all DMAEE [vaporJ
concentrations and a mild pneumonitis at 47 and 90 ppm."
Submission Evaluation
An EPA evaluation of the overall significance of the reported
toxicologic findings should be possible upon EPA's receipt of a
complete copy of the final report of Union Carbide's short-term
repeated DMAEE vapor inhalation study in rats.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for CAS No. 3033-62-3, which is listed in the initial
TSCA Chemical Substance Inventory, shows that no 1977 manufacture
or importation was reported or that all manufacture/importation
information reported was claimed to be TSCA Confidential Business
Information (TSCA CBI) by the person(s) reporting for the initial
TSCA Inventory and cannot be disclosed (Section 14 (a) of TSCA;
D.S.C. 2613(a)). All of the information reported for the initial
TSCA Inventory, including the production range information, is
subject to the limitations contained in the initial TSCA
Inventory Reporting Regulations (40 CFR 710).
In its TSCA Section 8(e) submission, Union Carbide provided the
following information regarding the use of NIAX@ Catalyst A-99:
140
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8E~-;Q-0687-0683
Pa2e 3 of 3
"NIAX@ Catalyst A-99 is used as a catalyst in the manu-
facture of urethane foam. The prodllc,t is not used in
its pure form, but is diluted with other ingredients.
Typical use levels of A-99 in a urethane formulation
range from 0.02 to 0.15 parts per 100 parts of toluene
diisocyanate (TDI)."
Union Carbide stated further in its TSCA Section 8(e) submission
that "when viewed against current work practices, recorrunended
protective and precautionary measures, and industrial hygiene
monitoring, . [Union Carbide does] not believe that the.
[reported] preliminary findings represent an unreasonable risk."
Comments/Recommendations
a)
The Chemical Screening Branch will ask Union Carbide to
ensure that EPA receives a full copy of the final report
(including the actual experimental protocol, results of
gross and histopathologic examinations, results of any
statistical analyses, etc.) from the short-term repeated
DMAEE inhalation study cited in the Section 8(e) notice.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical toxi-
ci ty and/or exposure data, Union Carbide will be asked
to describe the actions that Union Carbide has taken or
is planning to take to notify workers and others about
the reported preliminary toxicologic findings for DMAEE.
Union Carbide will be asked also to describe the nature
and results, if available, of all studies (other than
those ci ted in the open scientific literature or those
submitted already to EPA) about which Union Carbide is
aware or that Union Carbide has conducted, is conducting
or plans to conduct to determine the toxicity of or the
exposure to DMAEE during manufacture or use.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of DMAEE.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
141
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 2
DATE:
AlXJ 3 1 1981
SUBJECT:
Status Report*
8EHQ-0787-0684 S
Approved:
Zf/7'- crfl/<67
FROM: James F. Darr, Section Head ~ T ~
Chemical Risk IdentifiCQtio~Section/CSB
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
Under Section 8(e) of TSCA,
the following information:
the Dow Corning Corporation provided
"Dow Corning Corporation received verbal information
from a customer that squamous cell carcinomas were found
in rats that were surgically implanted in the uterus
with a [U.S. Food and Drug Administration (FDA)] regu-
lated device. The specific composition of the material
used in the [implanted] device is unknown to Dow Corning
Corporation. However, based upon the information pro-
vided [by the customer, Dow Corning] believes that the
material implanted is similar in composition to Dow
Corning@ S-5370 RTV. ., [a mixture of siloxane
polymers and organic substances and a metal salt].
[Note: Dow Corning has claimed the exact composition of
Dow Corning@ S-5370 RTV to be TSCA Confidential Business
Information (CBI); the Information Management Division
(IMD/OTS) will be requesting Dow Corning to substantiate
this TSCA CBI claim.]
"The customer has informed Dow Corning that although the
data are preliminary. they have been reported to .
[FDA under an approved Investigational Device Exemption
(IDE)l.
"Based on the very preliminary nature of the information
available, it is not possible to assess the significance
or reliably establish a cause and effect relationship.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
142
!:~A '0""" U2O-I (REV. 3-711
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8EHQ-0787-0684 S
Page 2 of 2
"Published information from the supplier of the metal
salt identifies 2-ethylhexanoic acid as a reaction by-
product. Published literature has identified this
substance to be teratogenic in rats.
"Other published literature reports 2-ethylhexanoic acid
as an in vivo conversion by-product of di(2-ethylhexyl)-
phthalatelDEHP) . DEHP is [listed as a carcinogen by
the National Toxicology Program (NTP) J. It has been
suggested in the literature that 2-ethylhexanoic acid
may be associated with the cancer found in bioassays
wi th DEHP, although there is no published data which
substantiate this inference. [2-Ethylhexanoic acid] is
presently subject to a TSCA Section 4 Test Rule, which
includes a two-year bioassay in mice and rats.
"Studies previously conducted on the cured Dow Corning
device material used as the basis for the implant bio-
assay. . . [that provided the impetus for Dow Corning's
TSCA Section 8(e) notice], detected an acid in extract
solution. These data are suggestive of the presence of
2-ethylhexanoic acid."
Submission Evaluation
Immediately upon receipt of this TSCA Section 8 (e) submission,
the Chemical Screening Branch sent a copy of the submission to
the Test Rules Development Branch (TRDB/ECAD/OTS) for inclusion
in the ongoing review of 2-ethylhexanoic acid under Section 4 of
TSCA.
Current Production and Use
In the Section 8(e) notice, Dow Corning@ S-5370 RTV was reported
to be "an industrial product used almost exclusively in defense/
aerospace as a foam for potting [(encapsulation)] applications.
Comments/Recommendations
Dow Corning stated that the company is investigating the reported
matter and would keep the Agency apprised of any new relevant
information.
a)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical(s).
b)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWER/EPA,
OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS and TRDB/ECAD/OTSi
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
143
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UNITED STATES ENV"IRONMENTAL PROTECTION AGENCY
Page 1 of 4
DATE:
IW 2 8 1981
SU8JECT: Status Report *
8EHQ-0787-0685
Approved:
~ ~/~/Cj7
FROM: James F.
Chemical
Darr, Section Head L ?: ~
Risk Identificatio~~~~tion/CSB
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The CIBA-GEIGY Corporation provided full copies of final reports
from five genotoxicity studies of pentaerythritol, tetraglycidyl
ether (CAS No. 3126-63-4). According to CIBA-GEIGY, the chemical
was positive in an Ames Salmonella typhimurium (bacteria) muta-
genici ty assay, a point mutation test in cultured V79 Chinese
hamster cells and a test for chromosomal aberrations in cultured
human lymphocytes; the studies reported by CIBA-GEIGY to be nega-
tive were Unscheduled DNA Synthesis (UDS) assays using cultured
rat hepatocytes and cultured human fibroblasts.
Submission Evaluation
In the Ames assay, the subject compound induced concentration-
dependent increases in bacterial strains TA100 and TA1535 to
approximately 3X and 8X over background mutation frequencies,
respectively, in the absence of exogenous metabolic activation.
Greater increases were seen in the presence of activation (i.e.,
up to 6.5X and 40X over background in strains TA100 and TA1535,
respectively). Again, the responses were concentration-dependent.
Therefore, the compound appears to induce base-substitution
mutations (based on strain specificity) and is more active in the
presence of exogenous metabolic activation. Strains TA98 and
TA1537 were also examined in the Ames assay both with and without
activation but no mutagenic activity was seen up to test chemical
concentrations of 5000 ug/plate.
The in vitro V79 Chinese hamster cell mutation test was performed
under-two separate selection conditions. One set of exposed cell
cultures was selected with 6-thioguanine (6-TG) and the other set
was selected with 8-azaguanine (8-AG). The selected cultures
were exposed to up to 6.0 ug/ml of the test compound for 21 hours
without exogenous metabolic activation and up to 23.0 ug/ml for 5
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting orovision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
144
I:~A "OM! 11.. (REV. 1-7.'
-------
8EHQ-0787-0685
Page 2 of 4
hours (with wash and incubation for the remaining culture time)
with activation. All of the experiments conducted with 8-AG were
negative. The selection studies with 6-TG, however, revealed an
increased mutation frequency with the test compound of greater
than 8X over solvent controls in the absence of activation; a
slight increase in mutation frequency was found in the presence
of activation but this was not duplicated in a replicate assay.
Based on the test findings, the subject chemical is active in
cultured V79 Chinese hamster cells by inducing point mutations at
a specific gene locus (HPRT) under non-activation conditions.
Lymphocytes from healthy human donors were used to assay for the
induction of chromosomal aberrations. Lymphocytes were pre-
incubated for 46 hours, exposed to the test compound for 3 hours
and then washed and incubated for approximately 43.5 hours until
harvesting. Cultures were exposed to up to 7.0 nl/ml of the test
substance without exogenous metabolic activation and up to 100.0
nl/ml with activation. At the high test compound concentration
(7.0 nl/m!) without activation, 10 out of 100 metaphases had
specific aberrations (e.g., chromatid breaks and exchanges as
well as minutes). At the next two lower concentrations, fewer
cells with aberrations were seen but were still significantly
elevated over the negative control. In the presence of metabolic
activation, the highest test material concentration (i.e., 100.0
nl/m!) induced the same types of aberrations noted above in 37
out of 100 metaphases. The next lower concentration had smaller
aberration numbers but these were still s1.gnificantly elevated
over the negative control group. These test results indicate
that the subject chemical can induce chromosomal aberrations in
cultured human lymphocytes and the chemical appears to be more
active in the presence of metabolic activation.
Two in vitro UDS assays were performed with the subject chemical
substance. One assay was conducted in cultured rat hepatocytes
that maintain continuous metabolic activation; the second assay
was conducted in cultured human fibroblasts and measured direct
action of the compound. The top concentrations used (based on
cell viability) were 31.25 ug/ml in the rat cell assay and 50
ug/ml in the human cell assay. The cultures were exposed to the
test compound and tritiated (3H)-thymidine for 5 hours and then
fixed for autoradiography. Usually, cell cultures are exposed
for 18 hours and then fixed, or exposed for 4 to 5 hours, then
incubated overnight in test article-free/3H-thymidine-free medium
("chase") before fixation; these longer exposure and incubation
times are presumed to allow greater time for DNA repair to occur.
Although current EPA guidelines do not give specific exposure and
incubation times, the protocols used in the case of CIBA-GEIGY's
UDS assays are adequate. The chemical did not increase the mean
number of grains/nucleus over negative controls or in relation to
the number of grains/cytoplasm test area. Further, the cultures
produced very few nuclei with ~ore than 5 grains/nucleus. Under
the conditions used for these assays, the subject chemical did
not induce UDS in cultured rat hepatocytes or in cultured human
fibroblasts.
145
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8EHQ-0787-0685
Page 3 of 4
Current Production and Use
The subject chemical is not listed in the non-confidential
computerized version of the 'l'SCA Chemical Substance Inventory.
In its Section 8(e) notice, CIBA-GEIGY stated that the chemical
is "an imported research and development resin intended primarily
for use in automotive coatings." CIBA-GEIGY stated further that
"only 25 kg (approximately r}/2 gallons) have been imported to
date" and that "samples have been distributed to two potential
customers for technical performance evaluations." No additional
information concerning use(s) of the subject chemlcal substance
was located in the secondary literature sources consulted by EPA.
Wi th regard to the potential exposure to the subject chemical,
CIBA-GEIGY reported that the Material Safety Data Sheet (MSDS)
carries numerous warnings for workers to avoid breathing vapor,
mist or spray and recommends that workers wear impervious gloves,
splash-proof chemical goggles and protective clothing in order to
avoid personal contact with the chemical. CIBA-GEIGY stated also
that "once the product is used in its intended application, it
becomes a highly crosslinked, high molecular weight, insoluble
and inert material." Finally, CIBA-GEIGY reported that there is
no consumer exposure to the subject chemical substance.
Comments/Recommendations
In its Section 8(e) notice, CIBA-GEIGY
revising the product MSDS to reflect
negative genotoxicity findings and is
customers who have received samples of
the reported findings.
stated that the company is
the reported pos i ti ve and
notifying (in writing) all
the subject chemical about
Although a positive in vitro genotoxicity test finding, when
considered by itself, may not be sufficient to offer reasonable
support for a conclusion of substantial risk (as defined in EPA's
TSCA Section 8(e) policy statement ("Statement of Interpretation
and Enforcement PolicYi Notification of Substantial Risk" 43 FR
~IIIOi March 16, 1978)), EPA does believe that such a finding is
of value in assessing the possible risks posed by exposure to the
tested chemical or mixture. Also, EPA believes that a positive
genotoxicity test result in combination with additional relevant
information (e.g., knowledge of potential exposure to and/or high
production of the subject chemical or mixture) would suggest, in
many cases, the need to conduct other studies designed to better
define the toxicity of or exposure to that chemical or mixture.
The results of such additional studies should be considered also
for submission to EPA pursuant to Section 8(e) of TSCA.
a)
Considering EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical
toxicity or exposure information, the Chemical Screening
Branch will ask CIBA-GEIGY to describe the nature and
results, if available, of all studies (other than those
reported already to EPA or those published in the open
146
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8EHQ-0787-0685
Page 4 of 4
scientific literature) about which CIBA-GEIGY is aware
or that CIBA-GEIGY has conducted, is conducting or plans
to conduct to determine the toxicity of or exposure to
the subject chemical substance.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical.
c)
The Chemical Screening Branch will send copies of this
status report to OSHA, NIOSH, CPSC, FDA, NTP, OSWERjEPA,
OWjEPA, OARjEPA, ORDjEPA and OPPjOPTSjEPA. In addition,
copies of this status report will be sent to the TSCA
Asssistance Office (TAOjOTS) for further distribution.
147
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
OA TE:
SEP
8 1981
:?age 1 of 4
SUIJECT: Status Report* 8EHQ-0787-0686 S ADProved:{)lJ?- "lfO/?7
FROM: James F. Darr, Section Head ~ T ~
Chemical Risk Identificatio~Section/CSB
TO: Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its identity and the identity
of the subject chemical as TSCA Confidential Business Information
(TSCA CBI) ~ the Information Management Division (IMD/OTS) will
request the submitter to substantiate these TSCA CBI claims. In
the "sanitized" version of the Section 8(e) notice, the submitter
stated non-confidentially that the tested chemical substance was
a "modified alkyl phenol."
Submission Description
The submitting company provided a full copy of the final report
from a 28-day oral study of the subject chemical in rats. In the
cover letter to its Section 8(e) submission, the company provided
the following information with regard to the conduct and results
of this 28-day study:
"Doses of 30, 100 and 300 mg/kg [of the subject chemical
substance] in corn oil were administered daily [via
gavage to male and female Sprague-Dawley rats] for 28
days. The study was started with a dose of 1,000 mg/kg~
however, virtually all animals at 1,000 mg/kg died
wi thin 5 days. The acute oral LD50 was known to be
between 500 and 2,000 mg/kg based on previous studies.
Antemortem abnormalities seen in some animals in the
1,000 mg/kg group included hypoactivity, tremors, hypo-
thermia, irregular respiration, moist rales, brown
stains on the snout and fecal and urinary staining in
the anogenital area. All animals in the other dose
groups survived the treatment period.
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
lnformatlon submltted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete informatio~.
148
I[~A ~Q- 11.. un". 1-111
-------
8EHQ-0787~0686 S
Page 2 of 4
"A variety of effects were observed at the 300 mg/kg
dose. Upon gross necropsy, discolored kidneys were
observed in three of five male rats and three of five
female rats. Mean organ weights and mean organ to body
weight ratio were generally found to be elevated for the
kidney, liver and adrenal gland. Affected animals were
also found to have elevated blood urea nitrogen and
gamma glutamyl transpeptidase levels. Slight increases
in blood total protein and globulin levels were observed
in females. Histopathological examination revealed [an]
increased severity of acute/subacute inflammation of the
kidney and a significant incidence of dilated convoluted
tubules in the kidney.
"No definite treatment related effects were seen at 30
or 100 mg/kg. A slight increase in liver to body weight
ratio was seen in males at 100 mg/kg. A slight increase
in kidney to body weight ratio was observed in females
at 30 mg/kg, but not at 100 mg/kg."
[Note: The submitting company stated also that EPA would
be apprised of the results of additional histopathologic
examinations of kidney tissue from the animals in the 30
mg/kg and 100 mg/kg dose groups from the 28-day study in
order to determine a no-observed-effect level (NOEL) for
the chemical. ]
In addition to the final report from the 28-day gavage study, the
company provided final reports of an Ames Salmonella typhimurium
(bacteria) mutagenicity assay and a chromosomal aberration assay
in cultured Chinese hamster ovary (CHO) cells. According to the
submitter, the Ames assay was negative and an apparent positive
result obtained in the CHO chromosomal aberration assay was not
reproducible.
The submitting company also provided final reports from a number
of acute in vivo toxicity studies of the modified alkyl phenol.
According to the submitted reports, the chemical 1) has an oral
(rat) LD50 of greater than .5 g/kg but less than 2 g/kg, 2) has a
dermal (rabbit) LD50 of greater than 2 g/kg, 3) produces moderate
conjunctival irritation in rabbit eyes, 4) is corrosive to rabbit
skin, and 4) is not a primary skin irritant, fatiguing agent or
skin sensitizer when tested in guinea pigs.
Submission Evaluation
Based on a review of the final reports from the acute animal
toxicity studies, this modified alkyl phenol is moderately toxic
via the oral route and slightly toxic (at a maximum) via the
dermal route. These acute' studies also show that this chemical
is a strong eye irritant and severe skin irritant. However, the
chemical does not induce dermal sensitization nor does it act as
a fatiguing agent.
149
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8EHQ-0787-0686 S
Page 3 of 4
Ai though other target organs may exist among those not studied
histologically, the results of the 28-day study show that the
kidney is clearly a target organ for the tested chemical sub-
stance. Nephrotoxici ty was induced at the 300 mg/kg/ day dose
level as indicated by the discoloration of the kidneys, increased
incidence and severity of dilated convoluted tubules, increased
severity of kidney inflammation, increased absolute and relative
kidney weights, and increases in serum components indicative of
renal insufficiency (blood urea nitrogen, gamma glutamyl trans-
peptidase, and creatinine). The determination of a NOEL and/or
lowest-observed-effect level (LOEL) for nephrotoxicity should be
possible upon the Agency's receipt of the pathologic examination
reported to be currently underway for animals exposed to the test
substance at 30 and 100 mg/kg/day.
In the Ames assay. the subject chemical substance was tested with
and without exogenous metabolic activation in bacterial strains
TA98, TAIOO, TA1535, TA1537 and TA1538. A preliminary toxicity
study indicated use of 250 and 33 ug/plate as top concentrations
for activated and non-activated conditions, respectively. The
assay was performed in two separate experiments. No evidence of
an increase in mutant frequency was found in any strain at any
test chemical concentration either with or without activation.
In the cultured CHO cell assay, the subject chemical was tested
(in two separate experiments) with and without activation. A
preliminary toxicity study based on cell proliferation kinetics
indicated the use of 8 ug/plate and 5 ug/plate for activated and
non-activated conditions, respectively- Cultures were treated
for 12 hours without activation and 5 hours with activation.
Cells were then washed to remove the test chemical and harvested
2 hours later (for non-activated) or 4 and 11 hours later (for
activated) . There were no significant increases in aberration
frequency under any condition in one of the separate experiments.
In the second experiment, slight (but significant) increases were
observed at the top test substance concentrations for the non-
activated portion and for the longer (ll-hour) incubation period
in the presence of activation: the activated 4-hour incubation
was negative. These slight statistically significant increases
may be indicative of borderline positive responses. However, the
concurrent solvent controls appear much lower than the performing
laboratory's historical control average and lower than that seen
in the replicate experiment. Therefore, the test compound is
probably not active in this assay.
Current Production and Use
In view of the submitter's TSCA CBI claims involving chemical
identity, no information concerning the TSCA Chemical Substance
Inventory status of this modified alkyl phenol will appear in
this report.
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According to the submitter, the subj ect chemical" is used as a
component of a stabilizer for polymers." In addition, the com-
pany provided the following information regarding the potential
for exposure to the chemical:
"The health risks associated with this chemical in the
workplace and in end use application are believed to be
low. Based on an acute dermal study in rats, it appears
the chemical substance is not absorbed through skin. The
propensity for inhalation exposure in the workplace ap-
pears low. The chemical substance is non-volatile. The
estimated vapor pressure contribution of this chemical
in [the company 's] product is 0.3 torr. The chemical
substance is manufactured in and supplied to customers
in a liquid stabilizer formu;Lation containing mineral
oil. Compliance with the [U.S. Occupational Safety and
Health Administration (OSHA) Permissible Exposure Limit
(PEL)] for mineral oil in the workplace provides a large
margin of safety. Little potential is thought to exist
for aerosol formation under [the] conditions of use in
the workplace. Moreover, the chemical substance is not
approved for food use applications."
Comments/Recommendations
In its Section 8 (e) submission, the company reported that the
product Material Safety Data Sheet (MSDS), modified to reflect
the reported toxicologic findings, is being provided to customers
and company employees working with the subject chemical.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitting company
will be asked to describe the nature and results, if
available, of all studies (other than those submitted
already to EPA or those published in the open scientific
literature) about which the company is aware or that the
company has conducted, is conducting or plans to conduct
to determine the toxicity of or the exposure to this
modified alkyl phenol.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OS\vER/ EPA,
OW/EPA, ORD/EPA, OAR/EPA and OPP/OPTS/EPA. In addition,
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
151
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DA TE:
SEP
I 1987
SUBJECT:
Status Report* 8EHQ-0887-0687 APproved:~
James F. Oarr, Section Head f2_~ ~~
Chemical Risk Identificatio~~'~~ion/CSB
rf 1~7
,
FROM:
TO:
Frank O. Kover, Branch Chief
Chemical Screening Branch/ECAO/OTS/OPTS
Submission Description
Texaco Inc. provided summarized preliminary findings from a
chronic mouse skin-painting study of hydrodesulfurized heavy
vacuum gas oil (Cas No. 64742-86-5). According to the submitter,
this chemical "causes skin cancer on laboratory mice when [50 ul
was] appl ied und i 1 uted two times per week for six months wi th no
attempt to remove the material from the [shaved] backs of mice at
any time during the study." The reported findings are summarized
in the following table:
Group No. of Animals papillomas Advanced Tumors
A 48 0 0
B 47 0 0
C 47 13 4
0 48 15 2
A: Negative Control (no treatment)
B: Negative Control (USP Mineral Oil)
C: positive Control (Benzo(a)pyrene 0.05% in acetone)
0: Hydrodesulfurized heavy vacuum gas oil
(undiluted)
with regard to the above findings, Texaco stated that "there is a
significant increase in the incidence of papillomas and advanced
tumors" in the benzo (a) pyrene and hydrodesul fur i zed heavy vacuum
gas oil groups when compared to the negative control groups. In
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
152
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Page 2 of 3
addition, Texaco stated that the potency of the petroleum process
stream is equivalent to that of the benzo(a)pyrene "applied at
0.05% [in acetone], the standard positive control concentration."
Texaco stated also that the latency of onset of the observed
oncogenic response for this petroleum process stream was short
(i.e., approximately 6 months). -Pinally, Texaco stated that the
performing laboratory reported that "ulcerative dermatitis is
present to a clinically significant degree in a number of .
[hydrodesulfurized heavy vacuum gas oil-]treated mice."
Submission Evaluation
The submitted information indicates that the subject petroleum
process stream possesses oncogenic acti vi ty towards the skin of
mice. An evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a copy of the
final report from the performed chronic skin-painting study.
Current production and Use
A review of the production range (includes importation volumes)
statistics for hydrodesulfurized heavy vacuum gas oil (CAS No.
64742-86-5), which is listed in the initial TSCA Chemical
Substance Inventory, has shown that over 9 billion pounds were
reported as manufactured and/or imported in 1977. This produc-
tion range information does not include any information claimed
as TSCA Confidential Business Information (TSCA CSI) by the
person(s) reporting for the initial TSCA Inventory, nor does it
include any information that would compromise TSCA CBI. All of
the data reported for the initial TSCA Inventory, including the
production range data, are subject to the limitations contained
in the initial TSCA Inventory Reporting Regulations (40 CPR 710).
Appendix A of the printed TSCA Chemical Substance Inventory (1985
Edition) gives the following definition for CAS No. 64742-86-5:
"A complex combination of hydrocarbons obtained from a
catalytic hydrodesulfurization process. It consists of
hydrocarbons having carbon numbers predominantly in the
range of C20 through C50 and boiling in the range of
approximately 3500C to 6000C (662op to 11120p). This
stream is likely to contain 5 wt. % or more of 4- to 6-
membered condensed ring aromatic hydrocarbons."
In its Section 8(e) submission, Texaco reported that the subject
chemical "is a non-isolated, site limited refinery process stream
which is used as a feed to the catalytic cracking unit or is
recycled in the H-Oil process." In addition, Texaco stated that
"twelve shift personnel operate the unit; however, exposure is
1 im i ted since the un it is a closed system and closed sampl i ng
procedures are used."
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Page 3 of 3
Comments/Recommendations
Texaco stated in its Section 8 (e) notice that the reported
toxicologic findings will be included in the company's "hazard
communication program and workers will be warned again of the
potential for adverse health effects from skin contact from
certain oils and refinery streams." In addition, Texaco stated
that the company wi 11 1) keep EPA appr ised as fu r ther resu 1 ts
from the mouse skin painting study are received, and 2) provide a
copy of the final report from the study to EPA when that report
is completed.
a)
The Chemical Screening Branch will request Texaco to
ensure that EPA receives a full copy of the final
report (including the actual experimental protocol,
results of gross and histopathologic examinations,
results of any statistical analyses, etc.) from the
mouse skin-painting study cited in the company's TSCA
Section 8(e) notice.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical
toxicity or exposure information, Texaco will be asked
to describe the nature and results, if available, of
a 11 stud ies (other than those reported already to EPA
or those cited in the published scientific literature)
about which Texaco is aware or that the company has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of the subject petroleum process
stream.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this petroleum process stream.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
154
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATI:
SEP 2 8 1981
Page 1 of 4
SUIJeCT,
status Report* 8EHQ-0887-0688 Approved :(J/:}?-
James F. Darr, Section Head L?:~
Chemical Risk Identificati~-se~tion/CSB
f/t1/17
'"ROM:
TO,
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The American Cyanamid Company reported that in conducting an
epidemiologic study, the company "detected a statistically
significant excess of respiratory cancer among former employees
who worked in muriatic acid [(hydrochloric acid)] production and
packaging facilities which were operated between 1928 and 1956 at
[Amer ican Cyanamid's] Li nden, New Jersey plant." I n add i t i on,
American Cyanamid reported that its "investigation revealed a
Standard Mortality Ratio (SMR) of 1. 31 for respiratory cancer
(observed: 182; expected: 138.8) among males hired between 1925
and 1973 (7153 [men at the Linden plant site])." The company
reported also that "no statistically significant excesses were
detected for 26 other cancer types." Amer ican Cyanami d s ta ted
further that the "results of linear logistic regression analysis
indicates that this respiratory cancer excess occurred in two
groups of males, muriatic acid facility workers and short-term
workers." The following additional information with regard to
the observed excess of respiratory cancer was contained in the
company's TSCA Section 8(e) notice:
"Eleven (11) cases occurred in males working in the
muriatic acid facility between 1928 and 1956. This
excess may be due to work factors ,. though this is
unconfirmed, or may be due to chance. Muriatic acid
production was the only process in this facility from
1928 to the late 1930' s. The acid was produced by
reacting 600 Baume sulfuric acid with sodium chloride.
A by-product, sodium sulfate, was collected and bagged.
Production ceased in the late 1930's and muriatic acid
was purchased and repackaged for sale. No excess was
observed in the analysis of 26 other facilities within
the plant.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete informatio~.
155
.~A '0"" II~ ("lEV. ..,11
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8EHQ-0887-0688
Page 2 of 4
"F i fty-two (52) cases occurred in males hi red between
1940 and 1949 who worked at [the Linden] plant for less
than one year in a variety of facilities. These cases
are not, in [American Cyanamid's] opinion, related to
occupational factors at Linden because of their short
work duration and varied work histories.
"Of further interest is the fact that, where smoking
history records were available, all [of the] cases of
respiratory cancer were observed in documented smokers.
"The muriatic acid facility was shut down in 1956 and
none of the current employees ever worked there."
Submission Evaluation
Al though American Cyanamid's Section 8 (e) submission reports an
excess in respiratory cancer among all males hired at the Linden,
New Jersey plant between 1925 and 1973 (SMR = 131; P < 0.05) as
well as among males working in the muriatic acid facility between
1928 and 1956 (11 observed deaths; the SMR, expected number of
deaths, and p-value were not given in the notice), the company's
submission lacks information on a number of important aspects of
the study. American Cyanamid should be requested to ensure that
the final report (or the company's cover letter transmitting that
report to the Agency) addresses the following questions:
1)
What chemical processes were ongoing in the muriatic
acid facility after muriatic acid production ceased and
during what years were those processes ongoing? What
was the exact year in which muriatic acid production
ceased at the Linden plant?
2)
What industrial hygiene monitoring data exist for the
entire Linden plant and for the muriatic acid facility?
What were the historic exposure levels for muriatic
acid, sulfur ic ac id, and 0 ther chern i ca 1 subs tances?
Was an exposure matrix for specific jobs at the Linden
plant constructed before the mortality analyses were
performed?
3 )
what other facilities were in operation at the Linden
plant during the time period covered by the mortali ty
study?
4)
Against what population were the rates standardized
(e.g., County, State, or U.S.)? What is the racial mix
of the study population, and were rates that were age-
race specific used as standards?
156
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8EHQ-0887-0688
Page 3 of 4
5)
what are the observed and expected numbers of deaths
for a) males working in the muriatic acid facility
between 1928 and 1956, and b) males hired between 1940
and 1949 who had worked less than 1 year at the Linden
plant site?
6)
For what percent of the total study population were
smoking histories available? For those workers with
known hi stor ies, what percent were smokers? For both
questions, answers are needed for the entire Linden
plant and for each facility (e.g., the muriatic acid
facility). What data exist with regard to exposure to
alcohol? This question should be answered in the same
way as that for smoking.
7)
How many observed and expected deaths occurred among
study subjects in the muriatic acid facility for cancer
of the larynx and for other specific sites in the upper
respiratory tract? What are the resul ts of analyses
using company mortality rates as the standard? What
are the results of analyses that deal with relative
risks as opposed to SMR's?
8 )
What are the results of analyses that incorporate both
latency and length of exposure for examining total
respiratory cancer mortality and site-specific upper
respiratory cancer mortality?
Comments/Recommendations
In its Section 8 (e) submission, American Cyanamid reported that
all workers at the company's Linden, New Jersey facility are
being notified about the results of the epidemiologic study. In
addition, American Cyanamid stated that the company will be 1)
communicating the results of the study to former employees of
the muriatic acid facility, and 2) encouraging those former
workers to participate in American Cyanamid's annual physical
program and to stop smoking. It should be noted also that
American Cyanamid sent copies of the company's TSCA Section 8(e)
submission to the Occupational Safety and Health Administration
(OSHA) and the National Institute for Occupational Safety and
Health (NIOSH). Finally, American Cyanamid stated the company
expects to complete the final report of the epidemiologic study
by late 1987 and will provide a copy of that report to EPA at
that time.
a)
The Chemical Screening Branch will request the American
Cyanamid Company to ensure that the Agency recei ves a
full copy of the fincH report (including the actual
experimental protocol, results of statistical analyses,
etc.) from the cited epidemiologic study. In addition,
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Page 4 of 4
American Cyanamid will be asked to ensure that answers
are provided for each question found in the Submission
Evaluation section of this status report.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the reported epidemiologic findings.
c)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
158
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 4
DATE:
SEP 2 8 I98T
Status Report* 8EHQ-0887-0689 APproved:~
James F. Darr, Section Head 11.._6. r ~
Chemical Risk IdentificationV;:~~iOnjCSB
'11 n/~l
I
SUIJECT:
'"ROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening BranchjECADjOTSjOPTS
Submission Description
The National Institute of Environmental Health Sciences (NIEHS)
provided a copy of a manuscript detailing the final results of a
National Toxicology Program (NTP)-sponsored cytogenetic study of
isoprene (CAS No. 78-79-5) and chloroprene (CAS No. 126-99-8) in
mice. The ABSTRACT sect ion of the prov ided manuscr ipt contai ns
the following information with regard to the conduct and results
of the performed study:
"Groups of male B6C3Fl mice (N = 15) were exposed for 6
hours per day to ambient air, to isoprene (438, 1750,
and 7000 ppm) or to chloroprene (12, 32, 80, and 200
ppm) for 12 exposure days. These compounds are the 2-
methyl and the 2-chloro analogues, respectively, of
1,3-butadiene, a genotoxic and carcinogenic chemical in
B6C3Fl mice. Exposure to isoprene induced significant
increases at all [of the] exposure concen t rat ions in
the frequency of sister chromatid exchanges (SCE) in
bone marrow cells and in the level of micronucleated
polychromatic erythrocytes (PCE) and of micronucleated
normochromatic erythrocytes in per ipheral blood. In
addition, a significant lengthening of the bone marrow
average genera ti on time and a signi f icant decrease in
the percentage of circulating PCE was °detected. Under
these exposure conditions, isoprene did not induce in
bone marrow a significant increase in the frequency of
chromosomal aberrations (CA) nor did the exposure sig-
nificantly alter the mitotic index. The dose response
curves for SCE and micronuclei induction were non-
linear, appearing to saturate at 438 and 1750 ppm,
respectively. Under similar exposure conditions,
exposure to chloroprene resulted in complete mortality
among the mice exposed to 200 ppm. At exposure con-
centrations of 80 ppm and below, chloroprene did not
induce a significant increase in CA, SCE, or micro-
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
159
.~A "OMI I.'" '''EV. ..",
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8EHQ-0887-0689
Page 2 of 4
nucleated erythrocytes, nor did the exposure signifi-
cantly alter the rate of erythropoiesis or of bone
marrow cellular oroliferation kinetics. Exposure to
chloroprene did r~sult in a significantly increased
bone marrow MI."
Submission Evaluation
For positive responses such as those obtained for isoprene in
micronucleated polychromatic erythrocytes (PCES), micronucleated
normoch r oma tic e rythr ocytes (NCE s), and s i s ter chromat id ex-
changes (SCEs), one sex is sufficient to provide an unequivoc~l
positive. On the other hand, for negative responses, such as
those obtained for chromosome aberrations (CAS), percent micro-
nucleated PCEs (%PCEs), mitotic index (MI), and average cell
generation time (AGT), with isoprene and 6 of the 7 measured
endpoints for chloroprene (all but MI), data from only one sex
can only yield an equivocal result. Therefore, all of the
negative responses are considered equivocal on this basis alone.
It should be noted also that because toxici ty could not be used
in selecting the high dose in the isoprene studies, the high dose
selected was" several orders of magni tude below [the] explosive
concentration." This safety factor seems overly cautious, and
may have resulted in a high dose that was significantly lower
than necessary. On this basis, the negative responses are viewed
as inconclusive, while the positives are acceptable even at such
low doses.
It is also important to point out that slightly different dosing
reg imens were used for the chemicals. I soprene was admi ni stered
for 6 hours/day for 3 days, followed by 2 days of non-exposure, 5
days of exposure, 2 days of non-exposure and finally 4 days 0 f
exposure. Chloroprene was administered for 6 hours/day but for 4
days, followed by 2 days of non-exposure, 5 days of exposure, 2
days of non-exposure, and finally 3 days of exposure. While the
differences seem trivial, they could be important especially con-
sider i ng tha t the report ul timately compares the two chemicals
with each other and then with 1,3-butadiene.
In summary, the reported information shows that isoprene induces
significant increases in micronucleated PCEs, micronucleated
NCEs, SCEs, and AGT, while chloroprene induces a significant
increase in the MI of erythropoietic cells. Considering the
protocol deficiencies noted above, none of the negative results
obtained for either chemical are considered conclusive.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for isoprene (CAS No. 78-79-5), which is listed in the
initial TSCA Chemical Substance Inventory, shows that 191 million
to 510 million pounds of this chemical substance were reported as
manufactured and/or imported in 1977.
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8EHQ-0887-0689
Page 3 of 4
A review of the production range (includes importation volumes)
statistics for chloroprene (CAS No. 126-99-8), which is listed in
the initial TSCA Inventory, shows that 61 million to 160 million
pounds of this chemical substance were reported as manufactured
and/or imported in 1977.
The preceding production range information does not include any
information claimed to be TSCA Confidential Business Information
(CBI) by the person(s) reporting for the initial TSCA Inventory,
nor does it include any information that would compromise TSCA
CBI. All of the data reported for the ini tial TSCA Inventory.
including the production range data, are subject to the 1 imi ta-
tions that are contained in the initial TSCA Inventory Reporting
Regulations (40 CFR 710).
According to the submitted manuscript, chloroprene and isoprene
are used primarily in the production of synthetic elastomers.
Chloroprene is used primarily in the manufacture of neoprene
(polychloroprene) elastomer while isoprene is used primarily to
produce cis-l,4-polyisoprene.
Comments/Recommendations
Although anyone may submit information to EPA under Section 8(e),
the "substantial risk" information reporting provision of TSCA,
only certain persons are required to do so. According to TSCA
Section 8(e), "any person who manufactures, [imports,] processes,
or distributes in commerce a chemical substance or mixture and
who obtains information which reasonably supports the conclusion
tha t such subs tance or mi xture presents a substanti al risk of
injury to health or the environment shall immediately inform the
[EPA] Administrator of such information unless such person has
actual knowledge that the Administrator has been adequately
informed of such information." The Agency's TSCA Section 8 (e)
policy statement ("Statement of Interpretation and Enforcement
policy; Notification of Substantial Risk" March 16, 1978; 43 FR
11110) defines the term "person" to include "any natural person,
corpor a t i on, fi rm, company, joi nt-venture, sole propr ietorship,
association, or any other business entity, any State or political
subdivision thereof, any municipality, any interstate body, and
any department, agency or instrumentality of the Federal
Government." [emphasis added] While it is clear that NIEHS is a
"person" within EPA's Section 8(e) policy statement definition,
the mandatory obligation to report substantial risk information
to EPA under Section 8(e) would not be incurred by NIEHS unless
it is engaged commercially in the manufacture, import, processing
or distribution of the chemical substance or mixture about which
substantial risk information is obtained.
Further, it should be noted that Part VII of EPA' s Section 8 (e)
policy statement provides a number of examples of the kinds of
information that need not be. reported to EPA under Section 8 (e)
(i.e., information about which subject persons can automatically
assume the Agency to be "adequately informed"). In addition to
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Page 4 of 4
the examples cited in Part VII, subject persons can automatically
assume, for the purposes of Section 8(e) reporting, that EPA has
been adequately informed about substantial risk information that
is contained in a formal publication or a report made available
to the general public by an agency of the u.S. Government
(including EPA). It cannot be automatically assumed, however,
that EPA has been adequately informed about information contained
in a report not formally published or otherwise made available to
the general public by an agency of the u.s. Government (other
than EPA). Therefore, if a subj ect per son obta i ns (i. e., knows
of or possesses), for example, unpublished findings (including
preliminary findings) of a toxicologic study conducted by or for
a n agency of the U. S. Government (other than EPA), that person
should consider the need to report such information immediately
(i.e., within 15 workings days) to EPA pursuant to Section 8(e)
of TSCA. Since 1977, EPA has received a number of Section 8 (e)
notices filed by companies that obtained unpublished results of
toxicologic studies conducted by or for other Federal agencies.
In each of those instances, EPA immediately established direct
contact wi th those other agencies in order to obtai n the needed
followup information.
a)
The Chemical Screening Branch will review the reported
information in greater detail in order to determine the
need for further OTS assessment of the subject chemical
substances.
b)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA As s i s ta nce Off ice (TAO/OTS/OPTS/EPA) for
further distribution.
162
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
0,\ TE:
SEP I 0 1981
SU8JECT:
Status Report* 8EHQ-0887-0690 AD proved: (JJ?-
James F. Darr, Section Head ~~~ ~~
Chemical Risk Identificatio'~~tion/CSB
9//o/f?7
/
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Atlantic Richfield Company provided the following information
wi th regard to the conduct and prel imi nary resul ts of a Gu i nea
pig Maximization Test (GPMT) wi th N-phenyl maleimide (NPMI i CAS
No. 941-69-5):
"The test group consisted of 20 animals. In addition,
each of the following groups had 10 animals per group:
the naive controls, vehicle controls, positive controls
and naive positive controls. The test substance was
dissolved in acetone for use in the intradermal and
topical induction phases. Formalin was employed as the
positive control substance for the induction and chal-
lenge phases of this study. Following the topical
challenge, readings of the resulting dermal reaction
were recorded at approximately 24 and 48 hours there-
after.
"The results of the primary challenge indicated that
NPMI is a strong skin sensitizer: 19/20 NPMI test
animals gave a positive reaction to a 0.0625% solution
in acetone. In the positive control group, 8/9 forma-
lin treated animals reacted positively to a 5% formalin
solution. The NPMI treated animals exhibited a sig-
nificantly greater dermal response than did those in
the formalin control group. By contrast, none of the
animals in the remaining control groups exhibited a
positive reaction when challenged with their respective
test solution."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting orovision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
163
R~A "OMI 18... (~EV. 1-,.,
-------
8EHQ-0887-0690
Page 2 of 3
In its Section 8 (e) notice, Atlantic Richfield stated that its
decision to conduct the GPMT was based in part on "reports from
employees of sk i n problems which were alleged to have resul ted
from exoosure to NPMI." The submi tter added that the GPMT "was
chosen '"because it is regarded as the best predictor for skin
sensitization in man." In addition, the company reported that
previously conducted animal studies showed that NPMI was severely
irritating to the skin.
Submission Evaluation
An evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a complete copy
of the final report of the NPMI sensitization study as well as
full copies of the prev i ously conducted an imal st ud i es show i ng
NPMI to be a severe skin irritant. Further, Atlantic Richfield
should be asked to descr i be in more detai 1 the" ski n prob lems"
alleged by employees to have resulted from exposure to NPMI.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for N-phenyl male imide (CAS No. 941-69-5), which is
listed in the initial TSCA Chemical Substance Inventory, has
shown that no 1977 manufacture/importation of the chemical was
reported or that all of the manufacturing and/or importation data
reported were claimed as TSCA Confidential Business Information
(TSCA CBI) by the person(s) reporting for the initial Inventory
and cannot be disclosed (Section l4(a) of TSCAi U.S.C. 2613(a)).
All of the information submitted for the initial TSCA Inventory,
including the production range information, is subject to the
limitations contained in the initial TSCA Inventory Reporting
Regulations (40 CFR 710).
In its Section 8 (e) submission, Atlantic Richfield reported that
NPMI "i s imported and manufactured under pi lot plant cond i t ions
for research [and development (R&D)] purposes by ARca Chemical
Company. . a subsidiary of [the] Atlantic Richfield Company."
Atlantic Richfield did not provide any information regarding the
company's use(s) of NPMI nor was such information located in the
secondary literature sources consulted by EPA.
Comments/Recommendations
Atlantic Richfield reported that based on the submitted data,
"special handling procedures for NPMI are being recommended." In
addition, the company reported that "the Material Safety Data
Sheet [(MSDS)] developed for worker use wi th this R&D oroduct
will be revised to reflect the [GPMT] study results." Finally,
the company stated that copies of the revised MSDS and final
report of the skin sensitization study would be sent to EPA.
164
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8EHQ-0887-0690
Page 3 of 3
a)
The Chemical Screening Branch will request Atlantic
Richfield to ensure that EPA receives a full copy of
the final report (including the actual experimental
protocol, results of any gross or histopathological
examinations, results of any statistical analyses,
etc.) from the GPMT cited in the company's submission.
In addition, Atlantic Richfield will be asked to submit
full copies of the final reports from the company's
"previous animal studies" showing NPMI to be a severe
skin irritant. Finally, Atlantic Richfield will be
asked to describe in greater detail the "skin problems"
alleged by employees to be due to exposure to NPMI.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Atlantic Richfield
will be asked to describe the nature and results, if
available, of all studies (other than those reported
already to EPA or those cited in the open scientific
literature) about which Atlantic Richfield is aware or
that the company has conducted, is conducting or plans
to conduct to determine the toxicity of or the exposure
to NPMI.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screen i ng Branch wi 11 transmi t cop ies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies 0f this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
165
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
D"TE:
SEP , , 1981
:?age 1 of 5
SU8JECT:
Status Report*
Aoproved: ~
/ 0/ /r---
j~ 1 UatvL--
Darr, Section Head. .
Risk IdentificatioN Section/CSB
8EHQ-0887-0691 S
'1/1 ( I ~ 7
FROM:
James P.
Chemical
TO:
Prank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The submitting company (company identity claimed to be TSCA
Confidential Business Information (TSCA CBI» reported that "in
January 1986, due to a lack of published data regarding the
relationship between the severity of hydrotreatment and dermal
carcinogenicity of hydrotreated naphthenic oils, [the
company] initiated a [2-year] dermal carcinogenicity study in
mice." The submitter stated that the data from this study are
expected lito provide the scientific basis for assessing the
dermal carcinogenic potential of hydro treated naphthenic oils for
preparing precautionary labels and material safety data sheets."
The submitter provided the following information regarding the
conduct and preliminary results of the ongoing study:
"In the [2-year] carcinogenicity study, fifty (50) male
C3H/HEJ mice, 6-8 weeks of age when received, had 50 ul
of the test material applied topically three days per
week to the clipped interscapular region of the back.
This study was initiated in two phases; phase I started
in January, 1986, and Phase II started December, 1986.
The. . . [following] table summarizes the data obtained
to date. The tested materials, designated Ll to L5 and
L12 to L19 can be generically described as Hydrotreated
Light or Heavy Naphthenic Distillates (.Petroleum). The
tested materials designated L6 to L8 and L20 to L21 can
be generically described as Light or Heavy Naphthenic
Distillates (petroleum). The tested materials desig-
nated L9 to L10 can be generically described as
Severely Solvent-refined and Solvent-dewaxed Heavy
Paraffinic Distillates (Petroleum). These materials
are defined by the CAS Registry Numbers shown in the
table. The SUS viscosity at 1000p, a DMSO extractable
(I P 346) and an aromatic carbon content (ASTM D 2140)
level shown in the table further defines each of the
tested materials. II
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting orovision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
166
1:"" ~Oltlll 11" uuv. 1-111
-------
8EHQ-0887...0691 S
Page 2 of 5
"TWO- YEAR DERMAL CARCINOGENICITY TESTING - NAPHTHENIC OIL STUDya
Number of Mice
with Tumors
Viscosity Phase Phase
SUS at I II
L-No. C.A.S. No. 1000F DMSO CA ST ART WK 80 WK 36
12-01 64742-'3-6* " 1.' 7 12/86 0
13-01 64742-'2-'* 100 1.' 7 12/86 0
17-01 64742-.52-'* 100 2.0 8 12/86 0
is-OI 64742-.52-.5* 300 2.0 8 12/86 0
14-01 64742-.52-.5* 100 2..5 9 12/86 0
16-01 64742-.52-.5* 300 3.0 11 12/86 0
18-01 64742-.52-.5* 100 3.0 10 12/86 0
1-01 64742-.53-6* " 3.3 11 1/86 37
3-01 64742-.52-.5* 300 3.7 13 1/86 30
2-01 64742-.52-.5* 100 3.9 13 1/86 40
19-01 64742-.52-.5* 22.5 4.0 14 12/86 6
6-01 64741-.52-2* .5.5 .5.0 14 1/86 2.5d
20-01 64741-.53-3* 100 6.0 17 12/86 48d 0
7-01 64741-.53-3* 300 6.2 17 1/86 31d
21-01 64741-.53-3* 300 7.0 21 12/86
4-01 64742-.52-.5* 1200 2.2 12 1/86 0
.5-01 64742-.52-.5* 3000 2.0 12 1/86 Id
8-01 64741-.53-3* .5000 8.0 18 1/86 8
9-01 b 100 0 2 1/86 0
10-01 b 600 0 2 1/86 0
B(a)P (0.0196) 1&12/86 2ge 3e
B(a)P (0.0.596) 1&12/86 47e 44e
Toluene OnlyC 1&12/86 1 0
Shaved only 1&12/86 0 0
a Testing status as of August 6, 1987
b C.A.S. Numbers 64741-88-4* and 64742-6.5-0*
C Carrier Solvent for B(a)P
d Previously reported as carcinogenic (IARC Monograph No. 33, 1984)
e Previously reported as carcinogenic (IARC Monograph No. 32, 1983)
DMSO = DMSO Extractables (Ip 346)
CA = Aromatic Carbon Content (ASTM D 2140)"
167
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8EHQ~0887~0691 S
Page 3 of 5
In submitting these preliminary findings to EPA for processing
"in accordance with EPA's 'substantial risk' procedures," the
company reported that it "intends to pursue these preliminary
findings with quality assurance and a scientific assessment of
these specific findings." In addition, the company stated that
"when the studies end, and final evaluation of the study data has
been performed, such evaluation in addition to the final report,
will be made available to the Agency." The submitter noted that
the submission of this information should occur in about 2 years.
Submission Evaluation
As shown in the submitted table, several of the tested materials
have exhibited tumorigenic activity thus far in this ongoing
chronic mouse skin-painting study. The submitter should be asked
to ensure that EPA is apprised about any further significant
findings (e.g., from interim sacrifices) from this study. In
addi tion, the submi tter should be requested to ensure tha tEPA
receives a complete copy of the final report (including the
actual experimental protocol, results of gross/histopathologic
examinations, results of statistical analyses, etc.) from the
ongoing study.
Current production and Use
A review of the production range (includes importation volumes)
statistics for the tested petroleum process streams, which are
all listed in the initial TSCA Chemical Substance Inventory, has
shown that over 1 billion pounds of each of these materials were
reported as manufactured and/or imported in 1977. This produc-
tion range information does not include any information claimed
as TSCA Confidential Business Information (TSCA CBI) by the
person(s) reporting for the initial TSCA Inventory, nor does it
include any information that would compromise TSCA CBI. All of
the data reported for the i ni tial TSCA Inventory, i ncl uding the
production range data, are subject to the limitations that are
contained in the initial TSCA Inventory Reporting Regulations (40
CPR 710).
Appendix A ("Chemical Substance Definitions") of Volume I of the
pr i nted TSCA Chemical Substance Inventory (1985 Ed i t i on) gives
the following definitions for the CAS Registry Numbers cited in
this submission:
o
Light Naphthenic Distillates (Petroleum)
CAS No. 64741-52-2
"A complex combination of hydrocarbons produced by
vacuum distillation of the residuum from atmospheric
distillation of crude oil. It consists of hydrocarbons
having carbon numbers predominantly in the range of C15
through C30 and produces a finished oil with a vis-
cos i ty of less than 100 SUS at 1000p (19cST at 400C).
It contains relatively few normal paraffins."
168
-------
8EHQ-0887-0691 S
Page 4 of 5
o
Heavy Naphthenic Distillates (Petroleum)
CAS No. 64741-53-3
"A complex combination of hydrocarbons produced by
vacuum distillation of the residuum from atmospheric
distillation of crude oil. It consists of hydrocarbons
having carbon numbers predominantly in the range of C20
through C50 and produces a finished oil with a vis-
cosity of at least 100 SUS at l00~F (19cST at 40°C).
It contains relatively few normal paraffins."
o
Solvent-Refined Heavy paraffinic Distillates (petroleum)
CAS No. 64741-88-4
"A complex combination of hydrocarbons obtained as the
raffinate from a solvent extraction process. It con-
sists predominantly of saturated hydrocarbons having
carbon numbers predominantly in the range of C20
through C50 and produces a finished oil with a vis-
cosity of at least 100 SUS at l0~'F (19cSt at 40°C)."
o
Hydrotreated Heavy Naphthenic Distillates (Petroleum)
CAS No. 64742-52-5
"~ complex combination of hydrocarbons obtained by
treating a petroleum fraction with hydrogen in the
presence of a catalyst. It consists of hydrocarbons
having carbon numbers predominantly in the range of C20
through C50 and produces a finished oil [with a vis-
cosity] of at least 100 SUS at 100°F (19cSt at 40°C).
It contains relatively few normal paraffins."
o
Hydrotreated Light Naphthenic Distillates (Petroleum)
CAS No. 64742-53-6
"A complex combination of hydrocarbons obtained by
treating a petroleum fraction with hydrogen in the
presence of a catalyst. It consists of hydrocarbons
having carbon numbers predominantly in the range of C15
through C30 ~nd produces a finished oil with a vis-
cosity of less than 100 SUS at l00QF (19cSt at 40°,C).
It contains relatively few normal paraffins."
o
Solvent-Dewaxed Heavy Paraffinic Distillates (Petroleum)
CAS No. 64742-65-0
"A complex combination of hydrocarbons obtained by
removal of normal paraŁfins from a petroleum fraction
,by soivent crystallization. It consists predominantly
of hydrocarbons having carbon numbers predominantly in
the range of C20 through C50 and produces a finished
oil with a viscosity of not less than 100 SUS at l0QfF
(19cSt at 40°C)."
169
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8EHQ-0887-0691 S
Page 5 of 5
In its submission, the company stated that it "does not currently
market a product with the same description as those showing
positive tumorigenicity [in the ongoing 2-year skin-painting
study in mice] ."
Comments/Recommendations
The Agency has received numerous TSCA Section 8(e) and "For Your
Information" (FYI) submissions containing new toxicologic and
exposure data on a wide variety of petroleum process streams.
a)
The Chemical Screening Branch will ask the submitter to
ensure that the Agency is apprised about any further
significant findings from the company's ongoing 2-year
skin-painting study in mice. In addi tion, the company
will be asked to ensure that EPA receives a full copy
of the final report (including the actual experimental
protocol, results of gross and histopathologic examina-
tions, results of any statistical analyses, etc.) from
this ongoing chronic study.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the nature and res~lts, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which the company is aware or that the company
has conducted, is conducting or plans to. conduct to
determine the toxicity of or the exposure to the tested
materials.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the tested materials.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
170
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 4
DATE:
SEP 2 8 1987
SUIJECT,
Status Report* 8EHQ-0987-0692 Approved :~
James F. Darr, Section Head ~~~
Chemical Risk IdentificatioJ7~ection/CSB
9/:M/87
I ,
IIROM,
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAO/OTS/OPTS
Note
In its Section 8 (e) submission, the Monsanto Company reported
that the subject chemical ("acetic acid, oxo-, methyl es ter or
ethyl ester, homopolymer, reaction products with ethoxyethene and
reaction products with methoxyethene, sodium salts") was the sub-
ject of a "Premanufacture Notice" (PMN No. 84-535) submitted
previously to EPA under Section 5 of TSCA. According to the non-
confidential version of PMN No. 84-535, which was obtained from
the OTS Public Files, the name of the submitting company and the
exact identi ty of the subject chemical were claimed to be TSCA
Confidential Business Information (TSCA CBI); the chemical was
identified generically, however, as an "Alkali Metal Carboxylate"
in the non-confidential version of the PMN.
Submission Description
In its Section 8 (e) submiss ion, Monsanto provided the following
information regarding the conduct and results of chronic studies
of the PMN chemical in mice and rats:
"PMN substance No. 84-535 was administered to groups of
60 male and 60 female Sprague Dawley rats at target
levels of 0, 400, 2,000 or 10,000 ppm for approximately
two year s. Because of excessive mortali ty, the high
dose concentration was reduced to 5,000 ppm after 84
weeks into the study. Groups of 60 male and 60 female
mice were given 0, 600, 3,000 or 15,000 ppm PMN sub-
stance No. 84-535 in their drinking water for a period
of 18 months. Since the test material is the sodium
salt of a polycarboxylic acid, this would result in a
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
.'-A 1'0'" II" .".v. 1-,.,
171
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8EHQ-0987..0692
Page 2 of 4
high sodium load (approximately 2,000 ppm) to the test
animals. Therefore, sodium control groups cons i s t i ng
of 60 animals/sex were administered sodium hippurate at
levels such that the sodium load in each group was
equivalent to the sodium load in the high concentration
group for each species.
"The incidence of neoplasms was comparable among all
groups in mice of both sexes and male rats. In [the]
female rats, the incidence of neoplastic nodules in the
liver was I of 60, 5 of 60, 3 of 60, 8 of 58 and 6 of
59 in the drinking water control group (OWC), sodium
control (SC), low-, mid- and high-concentration groups,
respecti vely. The incidence of neoplastic nodules in
the mid-dose group was statistically significant (less
than or equal to .05) when compared to [the] pWC group
but not when compared to the SC group using the Fisher
Exact Test."
In submi tting the preceding information to EPA, Monsanto stated
that" the tox icolog ical s igni ficance of the sligh t increase in
neoplastic nodules in female rats is considered to be limited
because:
"The [observed] incidence of neoplastic nodules is not
significantly different from the sodium control group,
which was run concurrently and is the most appropriate
for comparison.
"The historical control incidence of neoplastic nodules
in female Sprague Oawley rats for 3 previous chronic
studies of equivalent length at the testing laboratory
where the study was conducted is 2 of 70, 14 of 60 and
4 of 70. Thus the highest incidence in this study is
within historical limits.
"with known hepatocarcinogens, neoplastic nodules are
generally thought to progress to hepatocellular car-
cinomas. In the present study, the incidence of
hepatocellular carcinoma was 0, 1, 1, 0 and 0 for the
OWC, SC, low-, mid- and high-dose group, respectively.
Thus, there was no progression to a malignant lesion.
"No sex-related differences in toxicity have been
observed with this compound previously. In the present
study, the incidence of neoplastic nodules among male
rats in treated groups was actually lower than in the
drinking water control group (neoplastic nodules - OWC
8 of 59, SC 3 of 60, low 7 of 60, mid 6 of 58, high 3
of 59).
"PMN substance No. 84-535 produced no increase in the
incidence of liver adenomas or carcinomas in mice a
. . ,
specIes WhIch has been shown to be extremely responsive
172
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8EHQ-0987-0692
Page 3 of 4
to other known hepato-oncogens even though the dosage
level of the test material in mice was 4-5 times that
in the rats. The dosage of the test material in the
low-, mid- and high-group on a mg/kg/day basis for
female rats was 54, 253 and 951, respectively, and for
female mice was 183, 923 and 4670, respectively.
"PMN substance No. 84-535 was not found to be mutagenic
in the Ames/Salmonella assay, CHO/HGPRT assay, in vivo
cytogenetics assay in rats, in vitro rat hepatocyte DNA
repair assay and [an] in vivc> - in vitro rat liver DNA
--
repair assay."
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported findings, Monsanto should be asked to submit complete
copi es of the final reports (incl udi ng the actual exper imental
protocols, results of gross a~d histopathologic examinations,
resul ts of stati stical analyses, etc.) from the chronic studies
of PMN substance No. 84-535 in mice and rats. In addi tion, the
company should be asked to submi t complete copies of the final
reports from any of the cited genotoxicity studies not submitted
already to EPA.
Immediately upon receipt of this TSCA Section 8 (e) submission,
the Chemical Screening Branch transmitted copies of the notice to
the Chemical Control Division (CCD/OTS) which is responsible for
administering the OTS "New Chemicals Program" (NCP).
Current Production and Use
In its Section 8 (e) submission, Monsanto reported that although
PMN No. 84-535 was commercialized initially, commercial activity
with the chemical has ceased. Monsanto also reported, however,
that "stores of this substance have been used in research and
development quantities and continue to be used for test panel
evaluation." According to the sanitized version of the PMN, the
subject chemical was intended for use as "component of industrial
and consumer products."
Comments/Recommendations
a)
The Chemical Screening Branch will request Monsanto to
submit complete copies of the final reports (including
the actual experimental protocols, data, results of any
statistical analyses, etc.) from all studies (including
the genotoxicity tests) cited in the TSCA Section 8(e)
notice that have not been submitted already to EPA.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Monsanto will be
asked to describe the nature and results, if available,
173
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8EHQ-0987...0692
Page 4 of 4
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which Monsanto is aware or that Monsanto has con-
ducted, is conducting or plans to conduct to determine
the toxicity of or exposure to the subject chemical.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
CCD/OTS/OPTS/EPA. In addi tion, copies of this sta tus
report will be provided to the TSCA Assistance Office
(TAO/OTS) for further distribution.
174
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATI:
SEP 2 3 t9ST
Status Report> 8EHQ-9987-9693 Approved: ~ 121/8'7
James F. Darr. Section Head ~._.. r. ~
Chemical Risk Identificatio~/;~~ion/CSB
Page 1 of 5
SUIJECT:
'ROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Union Carbide Corporation provided the following information
wi th regard to the conduct and results of a number of in vitro
and in vivo genotoxicity studies of tetraethy1ene glycol (CAS No.
112-613-7)':
"There were no dose-related or statistically signifi-
cant increases in gene mutations in a Salmonella
typhimurium assay using 5 strains of bacteria both in
the presence and absence of a metabolic activating
system.
"In a forward gene mutation test in Chinese Hamster
Ovary cells (HGPRT-10cus), there were no dose-related
or statistically significant increases in gene mutation
activity, either in the presence or absence of a meta-
bolic activating system.
"A sister chromatid exchange test, conducted using
Chinese Hamster Ovary cells, showed statistically
significant increases in the numbers of exchanges
compared wi th the controls, both in the presence and
absence of metabolic activation. The increases,
however, were not dose-related. In view of the weak
nature of the response, and because of no clear dose-
response relationship, a repeat test was conducted
using a second sample of tetraethy1ene glycol. This
repeat test produced essentially a similar weak
increase in sister chromatid exchanges but, again, was
not dose-related.
=======================================================:===============:==:==:======
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
175
.~A 1'0'" ..»8 '''IV. 10781
-------
8EHQ,..0987-0693
Page 2 of 5
"An in vitro evaluation of the potential to produce
clastogenic effects was undertaken using Chinese
Hamster Ovary cells. Overall, there was an increase in
the i nc idence of chromosome aberrations (most notably
simple breaks), but the biological significance of the
finding was uncertain because of the absence of any
clear dose-response relationship and inconsistencies
between duplicate cultures.
"Because of the increase, in vitro, of sister chromatid
exchanges and chromosome aberrations, but in an incon-
sistent manner, it was considered appropriate to
conduct a study to determine the in vivo clastogenic
potential of tetraethylene glycol. --The mouse micro-
nucleus test was chosen, using groups of 5 male and 5
female mice for each dose. The i ntraper i toneal doses
used were 2500, 4000 and 5000 mg/kg, and blood samples
were taken for counting of micronucleated polychromato-
ph i 1 i c erythrocytes (MN -PCE) at 30, 48 and 72 hours
postdosing. Based on a reading of 1000 PCE per animal,
there were increases in the incidence of MN-PCE for
males at the 30 hour sampling time only, as follows:
Dose
Sex
MN-PCE/1000 PCE
(Mean + SO)
2500 mg/kg M
F
4000 mg/kg M
F
5000 mg/kg M
F
Water Control M
(10 ml/kg) F
TEMb M
(0.3 mg/kg) F
4.8 +
2.4 +
3.8 +
2.2 +
5.6 +
3.7 +
2.8 +
1.8+
36.6 +
34.0 +"
3.42
1. 67
1. 30
2.28
2.6la
1. 92
2.59
0.84
11. 95
12.88
ap<0.0l
bTEM = Triethylenemelamine (positive control)
"As with the in vitro studies, there was no clear dose-
r~sponse relatIonship. In view of this, and because of
variability between animals, the number of PCEs counted
for male animals was increased to 2000. using this
larger sample, there was reasonably good agreement with
the first count. The incidence of MN-PCEs was in-
creased at all doses for the 2000 cell count, being
statistically significant at 2500 and 5000 mg/kg, as
follows:
176
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8EHQ-0987-0693
Page 3 of 5
Dose
Count
MN-PCE/1000' PCE
(Mean:!:.. SO)
p*
2500 mg/kg 1st 1000 4.8 + 3. 42}
2nd 1000 4.4 +" 2.97
4000 mg/kg 1st 1000 3.8 +" 1. 30
2nd 1000 4.0 + 0.71
5000 mg/kg 1st 1000 5.6 +" 2.6l}
2nd 1000 5.8 +" 2.59
Water Control 1st 1000 2.8 + 2.59
(10 ml/kg) 2nd 1000 2.4 +" 2.07
*Relative to water control
<0.05
<0.001
"These results confirm the clastogenic potential of
tetraethylene glycol, as exhibited by the micronucleus
test, with statistically significant increases for the
low and high, but not intermediate, dose. The absence
of a dose-response relationship is still evident.
"These findings indicate a clastogenic potential for
tetraethylene glycol by in vitro tests and confirmed by
a single in vivo method.-However, the absence of clear
dose-response-relationships, and inconsistency between
test data, do not allow a definition of the possible
biological significance of the findings with respect to
any adverse health effects."
In its Section 8 (e) submission, Union Carbide provided complete
copies of the final reports from the cited in vitro studies and
stated that the final reports for the ci ted ln vi vo studies are
being completed and would be sent to EPA as soon as th~se reports
are issued.
Submission Evaluation
The Agency's review of the reported genotoxicologic findings for
tetraethylene glycol will take place upon receipt of complete
copies of the final reports from the cited in vivo studies.
--
Current Production and Use
A review of the production range (includes importation volumes)
statistics for tetraethylene glycol (CAS No. 112-60-7), which is
listed in the initial TS8A Chemical Substance Inventory, shows
that approximately 103 million to 535 million pounds of this
chemical substance were reported as manufactured and/or imported
in 1977. This production range information does not include any
data claimed as TSCA Confidential Business Information (TSCA CBI)
177
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8EHQ-0987-0693
Page 4 of 5
by the person (s) reporting for the initial TSCA Inventory, nor
does it include any data that would compromise TSCA CBI. All of
the data reported for the initial TSCA Inventory, including the
production range data, are subject to the limitations contained
in the initial TSCA Inventory Reporting Regulations (4~ CFR 71~).
Accord i ng to the Condensed Chemical Dictionary (l~th Edi tion) ,
tetraethylene glycol uses include: "Solvent for nitrocellulose;
plasticizer; lacquers; coating compositions."
Comments/Recommendations
In its Section 8 (e) submission, Union Carbide stated that the
company is advising its customers and other U.S. manufacturers of
tetraethylene glycol about the reported genotoxicologic findings.
Although a positive in vitro genotoxicologic assay result, when
considered alone, maY-not be sufficient to reasonably support a
conclusion of substantial risk (as that term is defined in EPA's
TSCA Section 8 (e) policy document ("Statement of Interpretation
and Enforcement policy; Notification of Substantial Risk" 43 FR
llll~; March 16, 1978», EPA believes that such results are of
value in assess i ng poss ible risks posed by exposure to chemical
substances or mixtures. The Agency also believes that positive
genotoxicity findings, when considered in combination with other
pertinent information (e.g., knowledge of potential exposure to
and/or high production of the subject chemical or mixture), would
suggest the need, in many cases, to conduct further studies that
are designed to better define the toxicologic properties of or
exposure to the subject chemical(s). The results of such further
testing should be considered also for submission to EPA pursuant
to Section 8(e) of TSCA.
a)
The Chemical Screening Branch will ask Union Carbide to
ensure that EPA receives complete copies of the final
repor ts (i ncl udi ng the actual exper imental protocols,
results of statistical analyses, etc.) from the in vivo
studies cited in the company's Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Union Carbide will be
asked to describe the actions the company has taken or
plans to take to notify its workers about the reported
information. In addition, Union Carbide will be asked
to descr i be the nature and results, if ava i lable, of
all studies (other than those reported already to the
Agency or those published in the scientific literature)
about which Union Carbide is aware or that the company
has conducted, is conducting or plans to conduct to
determine the toxicity of or exposure to tetraethylene
glycol.
178
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8EHQ~0987~0693
Page 5 of 5
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of tetraethylene glycol.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
179
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGEtCy
OAT!:
ocr 2 6 1981
Page 1 of 2
SUBJECT:
status Report* 8EHQ-0987-0694 A ed ~
pprov :
James F. Darr, Section Head [l~b~ ~~
Chemical Risk Identificatiorl7;~~~ion/CSB
'ol')-(ft7
~ROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Westvaco Corporation reported that the company had recently
received a letter from a physician indicating that "exposure to
sodium lauryl sulfate (SLS) residues from a carpet shampoo caused
chronic respiratory effects in patients treated by her." In its
submission, Westvaco stated its belief that the physician had
sent the letter to Westvaco because it "formerly manufactured an
aqueous solution of SLS." Westvaco stated further that although
it does not currently produce SLS, the company purchases SLS for
use "as a raw material in two products which are manufactured by
Westvaco ." Westvaco noted, however, that nei ther of these two
products are used in carpet shampoo applications. In its TSCA
Section 8 (e) submission, Westvaco stated that 1) the company
considers the physician's statements to be allegations, and 2)
the company has placed the physician's letter in the company's
TSCA Section 8(c) files.
Comments/Recommendations
Although the information provided by Westvaco does not appear to
be of the type requi red for submi ssion under Sect ion 8 (e), the
"substantial risk" information reporting provision of TSCA, the
subject information does appear to be of the type required to be
recorded/maintained by Westvaco under Section 8(c), a mandatory
recordkeeping provision of TSCA. On August 22, 1983, the Agency
published (48 FR 38178) a final rule that requires chemical
manufacturers and certain chemical processors to maintain records
of significant adverse reactions alleged to have been caused by a
TSCA-covered chemical substance or mi xture. Thi s TSCA Sect i on
8(c) rule also requires that allegations that involve significant
adverse reactions in workers be maintained for 30 years and that
other recordable allegations be kept for 5 years. It should be
noted also that the Agency is empowered to inspect and/or require
submission of corporate TSCA Section 8(c) records and has done so
on a number of occasions to date.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete informatio~.
180
R~" 'OMI .... tI'II!V. ...,.,
-------
8EHQ-0987-0694
Page 2 of 2
a)
The Chemical Screening Branch will review the reported
information in more detail to determi ne the need for
and scope of further OTS assessment.
b)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
181
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATI:
tIN
4 1981
Page 1 of 4
SUIJECT:
Status Report* 8EHQ-le87-e695 APproved:.z;!Jt-
James F. Darr, Section Head ilNhl/1?:~
Chemical Risk Identificatio,r;~~~ion/CSB
l;)PfJf7
f '
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The CIBA-GEIGY Corporation provided final reports from mouse and
rat teratology studies of l-methy 1- 2-pyr r 0 1 i d i none (N-methyl-
pyrrolidone; CAS No. 872-513-4) conducted in 19713-1971 by BASF
Aktiengesellschaft in West Germany. The mouse study, which was
conducted in 1970, involved administration of the test material
intraperitoneally to pregnant NMRI mice at doses of 6113 and 1525
mm3/kg or orally at doses of 1026 and 2565 mm3/kg on the 11th
through the 15th day of gestation. (The provided report states
that previous studies in mice had shown the intraperitoneal and
oral LD50' s for N-methylpyrrolidone to be 3050 and 5130 mm3 /kg,
respect i vely.) According to the mouse study report, the higher
oral and intraper i toneal doses (which were in total 2 1/2 times
the respective LD50's) were tolerated well by the dams but not by
the developing offspring. The submitted study report states that
there was an "increased resorption rate as well as the increased
appearance of runts and reductions in the weight and lengths of
the fetuses." The study report also states that there was an
increase in the rate of birth defects with cleft palate being the
pr imary teratogenic effect observed. In the lower dose groups,
no embryotoxic effects were reportedly observed (i.e., lithe
resorption rate, number of runts, average weight and length of
fetuses were identical to normal values") nor was there any
increased incidence in birth defects found.
According to an English Summary of the rat study (the rat study
report itself is in German; the study was conducted in 1971), N-
methylpyrrolidone was administered orally at doses of 323 or 970
mm3/kg/day to pregnant Sprague-Dawley rats on days 6 through 15
of gestation. These daily doses were reported to correspond,
respectively, to 1/15 and 1/5 of the oral LD50 in rats. The sub-
mitted Summary states that the dams tolerated well the 10 low and
high oral doses of N-methylpyrrolidone (i.e., the mothers did not
show any "visible toxic symptoms or macroscopically recognizable
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Tox,c Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
182
III"A 'OMI U'" (I'lEV. 1-711
-------
8EHQ-I087-0695
Page 2 of 4
pathological changes"). In the developing offspring, however,
administration of the high dose reportedly produced 95% embryo-
lethal i ty and caused deformi ties in 8/15 survi vi ng fetuses. In
the lower dose group, administration of N-methylpyrrolidone was
reported not to have resulted in any embryotoxic or teratogenic
effects (i.e., "the observed deformities or anomalies in the
fetuses of this test group corresponded in type and number to
spontaneously occurring changes in Sprague-Dawley rats").
It should be noted that the submitted mouse study report contains
the following information wi th regard to BASF I S rationale for
conducting its teratologic studies of N-methylpyrrolidone:
"[The] testing of N-methylpyrrolidone for a possible
teratogenic action proved to be necessary after an
analgesic [(not identified in the report)] containing a
component with a pyrrolidone ring as [a] substituent
had proved to have a teratogenic action in rats which
was absent in the comparison product containing the
component without the pyrrolidone ring."
Finally, it should be noted that the submitted mouse study report
states that a teratology study (route and species not specified)
of pyrrolidone itself had been conducted and a report (dated May
29, 197~) prepared; no further information on this pyrrolidone
study was found in the mouse study report on N-methylpyrrolidone.
Submission Evaluation
The submitted information indicates that N-methylpyrrolidone
caused embryotoxic and teratogenic effects in rats and mice
following oral (mice and rats) or intraperitoneal administration
(mice) . Upon obtaining an English translation of the rat study
report, a more detailed review of the reported findings will be
undertaken. It should be noted in the interim, however, that EPA
has located a published article by Becci et al. (Fundamental and
Applied Toxicology; 2:73-76; 1982) concerning a study of the
teratogenic potential of N-methylpyrrolidone applied dermally to
pregnant Sprague-Dawley rats. The ABSTRACT section of this paper
contains the following information with regard to the conduct and
results of the study:
"Doses of 75, 237 and 750 mg of N-methylpyrrolidone/kg
body weight/day were administered dermally to groups of
25 pregnant Sprague-Dawley rats on days 6 through 15 of
gestation. Additionally, the study used a positive der-
mal control. Hexafluoroacetone was chosen based on its
dermal teratogenic activity. An oral positive control,
aspirin, was included in order to add significance to
the data generated in the experimental positive dermal
control group. All animals were killed and subjected
to uterine examination on day 20 of gestation. Maternal
toxicity was indicated at 75~ mg of N-methylpyrrolidone
/kg by reduced body weight gain during gestation. [The]
183
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8EHQ-I087-0695
Page 3 of 4
treatment with N-methylpyrrolidone resulted in a dose-
dependent brightly colored yellow urine and dry skin.
Treatment at the high dosage level resulted in fewer
live fetuses per darn, an increase in the percentage of
resorption sites and skeletal abnormalities. These
effects could be the result of maternal toxicity. There
was no evidence of teratogenic effects nor effects on
the darns at 75 and 237 mg/kg of body weight."
The INTRODUCTION section of the Becci et ale paper presents the
following information wi th regard to the conduct and results of
an earlier study performed by Schmitt (Biol. Rundsch.; 14:38-41;
1976) in which N-methylpyrrolidone was administered intraperi-
toneally (i.p.) to pregnant mice:
"Schmi tt (1976) found that N-methylpyrrolidone caused
dose-dependent embryotoxic and teratogenic effects in
AJ JENA and C57BL mice when given in single or repeated
i.p. doses on various days of gestation. The most pro-
nounced embryotoxic effect of N-methylpyrrolidone was
noted after a single i .p. administration of 166 mg/kg
was given on the 7th day post-conception. Twenty-three
percent of all implanted fetuses died. The same dose
level of N-methylpyrrol idone given [i. p.] on the 9 th
day [post-conception] caused the highest rate of fetal
malformations, (18.6%)."
The INTRODUCTION section of the Becci et ale paper states that
the dermal teratology study of N-methylpyrrolidone in rats was
conducted because of "the absence of teratogenicity information
[on the chemical] by a practical route of exposure for industrial
uses [ ( i . e., I as a sol vent used extensi vely in chemical
processing I)] ." Becci et ale stated further that the dermal
route of exposure for the study in rats was judged to be more
significant than the inhalation route because N-methylpyrrolidone
(which has a boiling point of 2020C) "is of limited volatility."
Becci et ale noted also that N-methylpyrrolidone is known to be
"capable of dermal penetration."
Current Production and Use
A review of the production range (includes importation volumes)
statistics for N-methylpyrrolidone (CAS No. 872-50-4), which is
listed in the initial TSCA Chemical Substance Inventory, has
shown that over 1 billion pounds of this chemical were reported
as manufactured and/or imported in 1977. This production range
information does not include any information claimed as TSCA
Confidential Business Information (TSCA CBI) by the person(s)
reporting for the initial TSCA Inventory, nor does it include any
information that would compromise TSCA CBI. All of the infor-
mation reported for the initial TSCA Inventory, including the
production range information, is subject to the limitations that
are contained in the initial TSCA Inventory Reporting Regulations
(40 CFR 710).
184
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8EHQ-I087-0695
Page 4 of 4
According to secondary literature sources, N-methylpyrrolidone is
used mainly as a solvent (e.g., for resins), as a chemical inter-
mediate, as a "spinning agent" for polyvinyl chloride (PVC), and
as a dispersant for pigments.
In its TSCA Section 8(e) submission, CIBA-GEIGY reported that the
company "processes N-methylpyrrolidone at one u. S. faci 1 i ty and
impor ts minor quanti ties in two of its products, both of which
are mixtures." (CIBA-GEIGY did not disclose the names of ei ther
of the two imported products.) According to information
contained in the provided mouse teratology study report, BASF
Aktiengesellschaft was manufacturing N-methylpyrrolidone for sale
as a solvent.
Comments/Recommendations
In its TSCA Section 8(e) submission, CIBA-GEIGY stated that the
company plans to revise its Material Safety Data Sheets (MSDSs)
and product labels to reflect the reported toxicologic findings.
It should be noted that the Agency has received TSCA Section 8(e)
submissions containing toxicologic and/or exposure information on
other pyrrolidone derivatives (N-vinylpyrrolidone, 8EHQ-0785-0561
S et seq. and N-(2-hydroxyethyl)pyrrolidone, 8EHQ-0682-0448 S et
seq.) .
a)
The Chemical Screening Branch will review the reported/
published information on N-methylpyrrolidone in order
to determine the need for further OTS assessment of
this chemical. In add i t i on, the Chemi ca 1 Screen i ng
Branch will contact BASF Aktiengesellschaft in an
attempt to obtain a full copy of the company's 1970
teratology study of pyrrolidone. Also, the Chemical
Screening Branch will ask the OTS Library to obtain a
copy of the 1976 paper by Schmitt.
b)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPAi copies of
this report will be sent also to the TSCA Ass i stance
Office (TAO/OTS) for further distribution.
185
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
OCT 3 0 1981
Page 1 of 3
SUIJECT:
Status Report* 8EHQ-1087-0696 APproved:~
James F. Darr, Section Head !lA_'''' c: ~
Chemical Risk Identificatiod7;;~;ion/CSB
1tJvj~7
'ROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Union Carbide Corporation provided the following information
with regard to the preliminary results of acute toxicity studies
conducted by union Carbide over the last year-and-a-half on a
series of 18 different alkoxylate nonionic surfactants:
"The acute lethal toxicity of these materials, as
expressed by peroral or 24-hour percutaneous LOS0,
varied between moderate to very low (i.e., LDS0 values
ranged between 0.4 to >16 ml/kg by peroral administra-
tion and between 0.8 to >16 ml/kg by percutaneous
application). An unusual pattern of toxicity, however,
was observed in the 24-hour occluded cutaneous
application in the rabbit portion of these studies.
The pattern was characterized by delayed deaths and
macroscopic evidence of lung injury. Microscopic
examination of lung tissue was recently conducted on
animals treated wi th the last 7 of the 18 of these
materials, these tissues being saved only after
recognizing that this pattern of toxicity had emerged.
Microscopic findings included bronchopneumonia,
pneumonitis, alveolar histiocytosis, edema, congestion
and necrosis. In almost all cases, the injury was
associated with the presence of foreign vegetable
matter in the lower respiratory tract and lung. The
foreign vegetable matter was presumably feed particles
which had been aspirated.
============================~=======================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
186
.~A ~OMl II'" IIUV. ..711
-------
8EHQ-I087-0696
Page 2 of 3
"No one of these studies by itself would trigger a
concern regarding substantial risk of adverse heal th
effects. However, when these results are considered
together, and taken across the entire family of these
sur factants, there appears to be a cons i stent pattern
of toxicity. A review of acute toxicity studies con-
ducted over the past 40 years on various alkoxylated
nonionic surfactants further substantiates a pattern of
delayed deaths and visual evidence of lung injury-
Based upon this review and the recent studies,
[Union Carbide believes] that not only do long chain
alcohol ethoxylates and ethoxy/propoxy copolymer
surfactants produce this pattern of toxicity, but that
nonylphenol ethoxylates may also exhibit a similar
pattern of toxici ty. However, the relevance of these
studies to human health is unknown."
In submitting this information to EPA under Section 8(e) of TSCA,
Union Carbide stated that copies of the final reports from the
recently conducted studies will be provided to EPA as soon as
those reports are issued. According to Union Carbide, these
final reports will "describe in detail the toxic response (days
to death), macroscopic and microscopic observations on the recent
surfactant acute toxicity and primary irritancy studies."
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon the Agency's receipt of complete
copies of the final reports of the performed studies.
Comments/Recommendations
In its Section 8(e) notice, Union Carbide stated that the company
is "advising employees and customers who handle, use or otherwise
may be potentially exposed to these types of surfactants" about
the results of these studies and the fact that the study findings
had been reported to EPA. In addition, Union Carbide stated that
"studies are currently being conducted and further information is
bei ng sought to clar i fy thi s tox ic response and better place it
in perspective to potential human health risks."
a)
The Chemical Screening Branch will ask Union Carbide to
ensure that EPA receives complete copies of the final
reports (including the actual experimental protocols,
the exact identity, including CAS Registry Number (if
known), of each of the test materials, etc.) from the
series of acute toxicity studies cited in the company's
TSCA Section 8(e) submission.
187
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8EHQ-I087-0696
Page 3 of 3
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Union Carbide will be
asked to describe the nature and results, if available,
of the company's ongoing studies designed to clarify
the reported toxicologic findings.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
188
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATI:
~251987
SUBJECT:
status Report* 8EHQ-1187-0697 Approved :~--- lI/t1
-------
"INITIATOR
PROMOTER
DMBA
Furnace Oil
DMBA
Low Boiling Fraction
DMBA
Aromatic Fraction
DMBA
Iso/Cyc10-paraffin
DMBA
n-Paraffin
DMBA
None (sham)
Acetone
Furnace Oil
Acetone
Low Boiling Fraction
Acetone
Aromatic Fraction
Acetone
Iso/Cyc10-paraffin
Acetone
n-Paraffin
8EHQ-1l87-0697
Page 2 of 3
SKIN MASSES
14
19
22
3
2
o
o
o
o
o
o
"Numbers of masses in the furnace oil, low boiling, and
aromatic groups were significantly increased above
control group numbers. No masses were present in the
acetone-initiated or sham control groups."
According to Amoco, the results obtained from this study 1) "can
be interpreted as supporting previous knowledge concerning the
tumorigenic and promoting potential of furnace oil" and 2)
"indicate that the [observed] promoting effects of furnace oil
are associated with two specific fractions of furnace oil."
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported findings, Amoco should be asked to ensure that EPA
receives full copies of the final reports from mouse bioassays
cited in the company's TSCA Section 8(e) submission.
Current Production and Use
Amoco Corporation reported non-confidentially (by phone on
November 23, 1987) that the tested furnace oil has the following
CAS Registry Number: 68476-30-2. According to Appendix A of the
1985 Edition of the printed version of the initial TSCA Chemical
Substance Inventory, CAS No. 68476-30-2 refers to Number 2 fuel
oil, a petroleum d i sti 1late oi 1 "having a mi nimum vi scos i ty of
32.6 SUS at 1000F to a maximum [viscosity] of 37.9 SUS at 1000F."
190
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8EHQ-1187 -0697
Page 3 of 3
A review of the production range (includes importation volumes)
statistics for CAS No. 68476-30-2, which is listed in the initial
TSCA Chemical Substance Inventory, has shown that over 1 billion
pounds of this chemical substance were reported as manufactured
and/or imported in 1977. This production range information does
not include any information claimed as TSCA Confidential Business
Information (TSCA CBI) by the person(s) reporting for the initial
TSCA Inventory, nor does it include any information that would
compromise TSCA CBl. All data reported for the initial TSCA
Inventory, including the production range data, are subject to
the limitations contained in the initial TSCA Inventory Reporting
Regulations (40 CFR 710).
Comments/Recommendations
It should be noted that EPA' s Office of Toxic Substances has
received a number of TSCA Section 8(e) and "For Your Information"
(FYI) submissions containing toxicologic and/or exposure data on
a wide variety of petroleum and synfuel process streams.
a)
The Chemical Screening Branch will request Amoco to
ensure that EPA rece i ves fu 11 cop i es 0 f the f i na 1
reports (including the actual experimental protocols,
the results of gross/histopathologic examinations, the
resul ts of statistical analyses, etc.) from the mouse
bioassays cited in the company's Section 8(e) notice.
In view of EPA's general interest in corporate actions
that are taken on a voluntary basis in response to
chemical toxicity or exposure information, Amoco will
be asked to describe the actions the company has taken
or plans to take 1) to notify workers and others about
the reported information, and 2) to reduce or eliminate
exposure to the tested material(s).
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the tested material(s).
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
191
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 4
DATE:
~301987
SUIJECT:
Status Report* 8EHQ-1187-0698 APproved:~
. dt:tt~
James F. Darr, SectIon Hea
Chemical Risk Identificatio Section/CSB
Ij~ 1$7
"ROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Union Carbide Corporation provided the following information
with regard to the conduct and preliminary findings of an ongoing
epidemiologic study:
"In 1979, epidemiologists from the Union Carbide
Corporation (Union Carbide) and the National Institute
for Occupational Safety and Health (NIOSH) began a
joint epidemiology study of Union ,Carbide's employees
at three facilities in the Kanawha valley of West
Virginia. As part of this study, Union Carbide
examined the mortality experience of a cohort of 2,174
men who were employed between 1940 and 1979 and were
assigned, for one day or more before December 31, 1978,
to a chemical production department that used or pro-
duced ethylene oxide (EO). Compared wi th the general
population, the standardized mortality ratio (SMR) for
all causes was 79 (95% Conf idence Interval (CI) = 70,
89) and for all malignant neoplasms was 81 (95% CI =
61, 104). There were no statistically significant
excesses of deaths due to any cause.
"Analyses by duration of exposure in EO departments
revealed positive trends in pancreatic cancer and
leukemia mortality, which were not present when
analyzed by estimated cumulative EO dose. Further
analyses by general work area indicated that the
excesses were largely conf i ned to employees who had
been first assigned before 1947 to the ethylene chloro-
hydrin [(CAS No. 107-07-3)] production department where
potential for EO exposure is thought to have been low.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
192
.~A '0"" .... 'R.V. 1-'11
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Page 2 of 4
"Analysis by duration of assignment to that department
demonstrated noteworthy trends for both causes wi th
increasing duration. Observed and expected deaths in
the 0, less than 1 year, 1 - 9 years, and 10 + years
duration categories are 53 observed (obs.)/63 expected
(exp.), 0 obs./0.22 exp., 2 obs./0.49, and 4 obs./0.28
exp., respectively, for pancreatic cancer. Analogous
stati stics for leukemia are 50 obs./ 48 exp., lobs. /
0.16 exp., 1 obs./0.35 exp., and 2 obs./0.l9 exp.,
respecti ve1y. Al though the number of observed dea ths
is small, the relative difference between the observed
and expected deaths clearly increases with duration for
both causes.
"Since any chemical production in the department before
1947, other than ethylene ch1orohydr in, is thought to
have been minor, these [epidemiological] findings cur-
rently appear to, be associated wi th the production of
ethylene ch1orohydr in. To [the best of the Un i on
Carbide Corporation's] knowledge, the association of
the production of ethylene ch1orohydrin with increased
risk of pancreatic cancer or leukemia represents new
information."
Submission Evaluation
In its submission, Union Carbide reported that the company has
more detailed analyses underway and tha t the resu1 ts of these
analyses will be provided to EPA as part of the final report of
the epidemiologic study. In order for EPA to evaluate the
overall significance of the obtained results, Union Carbide
should be asked to ensure that EPA receives a full copy of the
final report (including the protocols, data, results of all
st'atistica1 analyses, etc.) from the company's epidemiologic
study as soon as tha t report becomes avai 1ab1e. In addi tion,
Union Carbide should be requested to keep the Agency apprised of
any further significant findings from the company's ongoing
study/analyses.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for ethylene ch1orohydrin (CAS No. 107-07-3), which is
listed in the initial TSCA Chemical Substance Inventory, has
shown that approximately 10.3 million to 53 million pounds of
this chemical substance were reported as manufactured and/or
imported in 1977. This production range in forma t i on does not
include any information claimed as TSCA Confidential Business
Information (TSCA CBI) by the person(s) reporting for the initial
TSCA Inventory, nor does it include any information that would
compromise TSCA CBI. All of the informa t i on repor ted for the
i ni tial TSCA Inventory, including the production range informa-
tion, is subject to the 1 imi tations tha t are con ta i ned in the
initial TSCA Inventory Reporting Regulations (see 40 CFR 710).
193
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Page 3 of 4
Accord i ng to the Condensed Chemical Dictionary (10th Ed i tion) ,
the uses of ethylene chlorohydrin include: "solvent for cellulose
aceta te, ethylcell ulose; introduction of hydroxyethyl group in
organic synthesis; to activate sprouting of dormant potatoes;
mfg. of ethylene oxide and ethylene glycol; insecticides." It is
not known at the present time, which (if any) of the cited uses
are current uses of ethylene chlorohydrin. It should be noted,
however, that the union Carbide Corporation reported by phone on
November 24,1987, that the company 1) stopped manufacturing
ethylene oxide via a process using ethylene chlorohydrin in 1957,
and 2) has not, to the best of the company's knowledge, engaged
in manufacture/processing of ethylene chlorohydrin since 1957.
Comments/Recommendations
The discussion pertains to the TSCA Section 8(e)** reporting
obligation of a company that obtains "new" information that
reasonably supports a conclusion that a chemical substance or
mixture that the subject company did, but does not any longer,
manufacture, import, process or distribute presents a substantial
risk of injury to health or the environment. A company that finds
itself in this particular situation should be aware that although
it may not be required technically to submit such information to
EPA under Section 8(e) of TSCA, EPA believes that a timely formal
submission of such information would fall clearly within the
"spiri tIt of the Section 8 (e) reporting provision. EPA believes
also that, in many cases, such a report would be of great benefit
to other s who currently handle the subject chemical (s) and who
can then initiate any warranted actions to reduce or eliminate
health or environmental risks. Finally, the Agency believes that
the timely formal submission of such risk-related information
would be a demonstration of the reporting company's chemical
stewardship practices.
It should be noted that EPA' s Office of Toxic Substances has
received both TSCA Section 8 (e) and "For Your Information" (FYI)
submissions on ethylene chlorohydrin.
The Chemical Screening Branch will ask Union Carbide to
ensure that EPA receives a complete copy of the final
report (including all protocols, data, results of any
stati stical analyses, etc.) from the company's ongoing
epidemiologic study. In addition, Union Carbide will
be asked to keep EPA apprised of any further signifi-
cant findings from the ongoing study/analyses.
** Section 8(e) of TSCA states that "any person who manufactures,
[imports], processes, or distributes in commerce a chemical
substance or mixture and who obtains information which reasonably
supports the conclusion that such substance or mixture presents a
subs tan t i aIr i sk 0 f i nj ury to health or the envi ronment shall
immediately inform the [EPA] Administrator of such information
unless such person has actual knowledge that the Administrator
has been adequately informed of such information."
a)
194
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8EHQ-1187-0698
Page 4 of 4
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical
toxicity/exposure information, Union Carbide will be
asked to describe the actions the company has taken or
plans to take to notify workers and others about the
reported epidemiologic findings.
b}
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance(s).
c}
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
195
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 8
DATI!:
JAN - 5 1988
SUBJI!CT:
status Report* BEHQ-12B7-0699
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
Approved: L r ce:- / ~ IIf
d' t (j
Co or Ina or
'" It OM:
TA- James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The E. I. DuPont de Nemours & Company, Inc. provided the results
of a recently completed lung cancer case control mortality study
of workers at a DuPont plant in Belle, West Virginia. According
to DuPont, this epidemiologic study was started in 1984 when
excesses of lung cancer deaths among wage and salary roll workers
were found during the company's conduct of routine cancer sur-
veillance activities. The following information regarding the
results and conduct of the epidemiologic study is presented in
the "ABSTRACT" section of the submitted report:
"Routine cancer surveillance reports have identified
excesses of lung cancer deaths among wage and salary
roll Belle Plant employees. The present study was
begun in 19B4 to determine whether the Belle employee's
risk of dying from lung cancer was associated with any
particular work area or job. Special attention was to
be given to employment in work areas and jobs with
potential exposure to two known carcinogens: coke oven
emissions and asbestos.
"This was a case-control study of 107 male lung cancer
deaths that occurred among [the] Belle plant's active
and pensioned employees during the period 1957 through
1979. Work histories were developed by [Belle] plant
personnel. Smoking histories of cases and controls
were completed by proxies. For all work area and job
title categories, odds ratios were computed to measure
the lung cancer risk of having worked in a particular
area or job relati ve to not having worked there. Job
titles of mechanics and craftsmen other than machinists
and metal workers were g~ouped because of their
generally higher potential exposure to asbestos prior
to the 19505.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
196
..-A '0"" ..... II'IIV. .,..
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8EHQ-1287-0699
Page 2 of 8
"In summary, the study found elevated lung cancer risks
for Mycoban[**]-cata1yst area (odds ratio = 6.7) and
for craftsmen (odds ratio = 2.5) other than machinists
and metal workers. These elevations were statistically
significant after adjusting for birth date, pay class,
cigarette smoking, and employment in other areas and
jobs. Employment in the coke oven area showed little
association with lung ca11"cer risk. Lung cancer risks
among operators, laborers, and helpers were lower than
among other occupations. Lung cancer risk in smokers
was higher than in never smokers and increased with
amount smoked (heavy smokers showed risks 9 times
higher than never smokers).
"Although the numbers in any given craft group were
small, the jobs of pipefitter, pipecoverer, millwright,
painter, rigger, carpenter, auto mechanic, welder, and
instrument mechanic had elevated odds ratios. possible
explanations for these elevations included prior
asbestos exposure (either during or prior to DuPont
employment), greater potential for high-level acute
exposures to other materials, inadequate measurement
and control of lifestyle factors such as cigarette
smoking, and chance. ....
"During the course of this study, it became apparent
that Belle plant employees had also experienced
excesses of non-neoplastic, non-infectious respiratory
disease (e.g., chronic obstructive pulmonary disease)
as measured by Accident and Health (A&H) insurance
claims over the period 1956-1984. ...."
The "ABSTRACT" section also presents the following information on
the need and recommendations for further studies:
"The elevated odds ratios [that were] found for the
Mycoban-catalyst area and for craftsmen warrant a more
in-depth epidemiologic investigation into lung cancer
risks at [the] Belle Plant. The present study should
be updated to include deaths that occurred from 198(J
through 1986. The update will provide about 6(J more
1 ung cancer cases for analys is. For the more recent
cases, it should be possible to obtain more accurate
employment and smoking histories. The 198(J-1986 group
will be analyzed separately and in combination with the
1957-1979 group [in order] to confirm or modify the
present findings. Although [the excesses of
non-neoplastic, non-infectious respiratory disease] may
simply reflect geographic or lifestyle differences, it
is recommended that a case-control study of these
excesses also be initiated."
[**] According to the Condensed Chemical Dictionary (1(Jth Ed.),
Mycoban is a trademark for sodium and calcium propionates.
197
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8EHQ-1287-0699
Page 3 of 8
The submitted epidemiologic study report presents a list of the
chemical substances/materials used in the Mycoban-catalyst area.
The reader's attention is directed to the 2-page attachment
(Appendix A) to this status report.
Submission Evaluation
Dupont's routine occupational health surveillance of Belle plant
employees identified statistically significant elevations in lung
cancer mortality among male wage roll and salary roll workers
employed at the Belle plant dur i ng the per iod of 1957 to 1979.
One hundred fifty one (151) lung cancer deaths were observed
among the Belle employees whereas 102.6 deaths would have been
expected (SMR = 147, p< 0.001). The text of the report does not
state, however, on what population the expected number of deaths
is based. A similar trend was observed for nonneoplastic, non-
infectious respiratory disease claims (274 observed, 217.7
expec ted, p< 0.001) . Further, Table 2 of the submi tted report
provides an SMR; however, the report does not state whether this
represents the standardized morbidity ratio. For both endpoints,
the trend began in the 1960's and continued through the 1970's.
Based on these observations, Dupont employed a case-control study
design in order to investigate potential agents associated with
the apparent increased lung cancer risk. Of pr imary concern to
Dupont epidemiologists was exposure to asbestos and to coke oven
emissions (the Belle facility contains a coke plant). Each lung
cancer case was matched to a control individual by age (within 5
years), adjusted service date, and termination date. Dupont
obtained smoking histories for each case and its control by a
questionnaire completed some years earlier by proxies, Le.,
former supervisor, family member and coworkers. DuPont's study
report does not give the frequency distribution of respondents.
preliminary analyses were adjusted for age (birthdate), pay
class, and smoking habits using Mantel-Haensze1 stratified
methods. These analyses examined how lung cancer risk, as
defined by the odds ratio, varied with exposure, assessed by
process area, job title and craft. Exposures in which the
stratified analyses showed an elevated odds were evaluated
further using logistic regression methods. The Dupont epi-
demiolog i sts accounted for work in other areas wi th these later
analyses.
Exposure classification was based on a job and area coding scheme
used in a previous study (Fayerweather et al. 1982) that examined
lung cancer and potential formaldehyde exposure at certain Dupont
facilities. The Belle plant provided work histories for each
case and control and these histories were coded by Dupont using
the 1982 coding scheme. The present study report does not iden-
tify the source for the job histories, whether they were based on
personnel records, job rosters, or supervisor interviews nor
whether they were old interviews coded again or new interviews
198
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8EHQ-1287-0699
Page 4 of 8
coded by an earl ier scheme. In contrast to the 1982 study, the
present study is unable to identify potential exposure to
spec if i c chemicals for each job, and thi s inabi li ty limi ts the
interpretation of the results.
The results from DuPont's many data analyses are summarized in
Appendix B of this status report. Logistic regression analyses
showed that smoking, as would be expected, and salary pay class
are major risk factors for lung cancer. These data analyses also
show that work in the Mycoban process and in job titles such as
craftsmen are associated with increases in lung cancer that
cannot be attributed to smoking. (It should be noted that nickel
and chromate compounds are listed in Appendix A of this status
report and these agents have been shown in other studies to be
human lung carcinogens.)
According to the submitted information, Dupont is continuing to
investigate exposures in these categor ies. Contrary to previous
studies, work in the coke oven area was not related to increased
lung cancer risk. However, this study might have had sufficient
power to detec t only a high level of risk. Li kewi se, the in-
creased lung cancer risk associated with pipefitting/pipecovering
job titles may in fact be due to asbestos, an "a priori" hypo-
thesis.
Several inconsistencies appear in this study that are cause for
concern. First, the text is confusing regarding the total number
of lung cancer cases on which the data analyses are based. For
example, the report text cites a number of cases and controls
with exposures in a particular area; however, the total number of
lung cancer cases is difficult to determine. The cohort analyses
identified 151 lung cancer deaths. Tables III through VI of the
submitted report identify descriptive characteristics such as
smoking, pay class, and year of birth for only 94 cases. In
addition, DuPont's cover letter states that these analyses are
based on 107 lung cancer cases. It is very important to know the
reason for excluding 44 (151-107) cases or 57 (151-94) cases. The
excluded cases represent approximately one-third of the total
number of identified lung cancer deaths and their exclusion from
the analyses could seriously bias the results.
Second, a previous study of lung cancer mortality among Dupont
employees (Fayerweather et a1. 1982) identi f ied 17 lung cancer
cases at the Belle plant wi th potential formaldehyde exposure.
In the current analyses, however, no cases were identified as
having been exposed in the Belle plant's hexamine/formaldehyde/
thylox work areas. Therefore, the present findings appear to be
in conflict with the 1982 findings. It is very important to know
whether any of the l7 cases wi th formaldehyde exposure in the
1982 study were included in the present study. In addition, it
is important to know the number of cases and controls that are
common to the 1982 study and the current study.
199
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8EHQ-1287-0699
Page 5 of 8
In conclusion, although the present submission states that
exposures in the Mycob~n catalyst process and to craftsmen may be
ass 0 cia t e d wit h i n c rea sed 1 un g can c err i s k , the s u bm i s s ion
suffers from potentially biased case identification, recall bias
from the proxy smoking histories and lack of exposure specificity
(the inability to pinpoint specific exposures). At this time,
EPA is not able to support Dupont's statement that asbestos may
be the primary etiologic agent responsible for the increased lung
cancer mor tal i ty among Belle workers. In addi tion, thi s study
cannot exonerate any specific exposure encountered in the Belle
plant. DuPont should be asked to ensure that future analyses
def ine the i nclus ion cr iter ia for the cases and con tro 1 s, and
also, identify exclusion rules. The future analyses also need to
carefully evaluate job histories and relevant exposures in order
to draw more firm conclusions with regard to the increased lung
cancer mortality among the Belle plant employees.
Comments/Recommendations
In its Section 8 (e) notice, DuPont stated that the company has
informed its workers about the reported findings and is currently
"evaluating what additional studies, if any, should be undertaken
at the Belle plant." In addition, DuPont stated that the company
plans to "update the study to include deaths that occurred from
1980 to confirm or modify the present findings." Finally, DuPont
stated that the results of any further studies would be submitted
to EPA as soon as those results are available.
a)
The Chemical Screening Branch will request DuPont to
address the questions/concerns found in the Submission
Evaluation section of this status report. In addition,
Dupont will be asked to ensure that 1) EPA is apprised
of any significant findings from the planned update of
the company's epidemiologic study, and 2) EPA receives
a complete copy of the updated study report.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the findings.
c)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA;
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
Reference
Fayerweather, W. E. et ale (unpublished 1982 study entitled
"Case-Control Study of Cancer Deaths in DuPont Workers with
Potential Exposure to Formaldehyde" OPTS Docket No. 62033)
Attachments: Appendix A (2 pages) and Appendix B (1 page)
200
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8EHQ-1287-0699
Page 6 of 8
" APPENDIX A:
CHEMICALS AND MATEIlIALS IN THE KYCOBAN-CATALYST AREA
1946-1948 - ODerator - Catalv.t Plant
copper chroaite
zinc chroaite
copper sulfate
zinc sulfate
chroaic acid
...onia
...onium bicarbonate
soda a.h
.ulfuric acid
Iraphite
nickel chroaite
nickel pellets
nitric acid
copper nitrate
copper oxide (ail1 scale)
barium nitrate
"anesium oxide
..n,ane.e sulfate
aan,ane.e chromite
barium chromi te
fl1 ter aid
copper aetal
barium carbonate
iron molybdate
ferric chloride
hydrochloric acid
cobalt carbonate
cobalt ..tal
cobalt nitrate
...oniua carbonate
cobal t oxide
.terotex
powdered cobal t
sodium ..ta.ilicate
hydrolen
nickel carbonate
powdered nickel
boric acid
phosphoric acid
~nium molybdate
(stopped 1950)
(stopped 1948)
(stopped 1948)
(stopped 1953)
(stopped 1953)
(.topped 1953)
(.topped 1958)
(stopped 1958)
201
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Page 7 of 8
"APPENDIX A (CONTINUED):
CHEKICALS AND MATERIALS IN THE KYCOBAN-CATALYST A1lEA
tCycoban Plant
calcium propionate
.odium propionate
propionic acid
.oda a.h
lilDe
filter aid
Carbonate Plant
88IDonium carbonate
88IDonium bicarbonate
88IDonia carbon dioxide
Catalyst Plant
iron bar.
iron oxide
oxygen
a1 undWII
aagnedum oxide
pota..ium bichroaate
pota..iWII carbonate
d lica
raney alloy
nitric
hydrogen
.oda a.h
boric acid
pho.phoric acid
copper chroai te
copper _onia
chr08ic acid
araphi te
Dickel carbonate
powc:l8red nickel
nickel pellets
fl1 ter aid
zinc .u1fate
copper nitrate
copper oxide (ai11 .cale)
bariWII nitrate
nickel chroai te
88IDoniWII bicarbonate
.u1furic acid
.oda a.h
(aluminum-nickel)
cobal t carbonate
cobalt ..tal
cobalt nitrate
_onium carbonate
cobal t oxide
.ter~ex
..ng~e.. chroaite
zinc chroaite
copper .ulfate
aangane.. .u1fate
iron 8Olybdat.
ferric chloride
88IOnl WI 80 1 ybda te
hydrochloric acid"
202
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8EHQ-1287-0699
Page 8 of 8
APPENDIX B
Odds Ratios from Stratified Mantel-Haenszel
Regression Analyses for Individual Exposure Areas.
and
Logistic
Stratified Analyses:
No. of Cases
Odds Ratio
95% Conf. Int.
LOW HIGH
Work Area-
Mycoban-catalyst
9
4.7
0.9
25.3
Hexamine/formaldehyde/
thylox
o
Job Title-
Mechanical trades
57
2.0
1.1
3.7
Crafts-
All craftsmen and
mechanics
57
2.0
1.1
3.7
All craftsmen except
metal workers and
mechanics
52
2.7
1.4
4.3
Auto mechanic
3
*
Carpenter
2
*
Cement finisher/brick
mason
2
*
**
Logistic Regression Analyses:
Crafts-
Craftsmen other than metal
workers and machinists?
2.5
1.3
4.7
Pipecoverer/pipefitter
?
3.8
1.1
2.3
Process Area-
Mycoban-catalyst
?
6.7
1.2
36.3
*
Odds Ratio = Infinity
**
Referent group is Belle plant male wage roll employees born
prior to 1905 who never smoked, never worked as craftsman/
mechanic, and never worked in Mycoban-catalyst, coke oven,
or gas house areas.
203
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DA T E:
DEC 3 0 1987
Status Report* 8EHQ-1287-0700 Approved: /7Jt- /f;Jof7
(.../ I
James F. Darr, Section Head 11.._4- r tC..-
Chemical Risk Identificatiod/;::;ion/CSB
Page 1 of 3
SUBJECT:
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Shell Oil Company provided the following information with
regard to the conduct and resul ts of a 14-day derma 1 study 0 f
9,9-bis (4-hydroxyphenyl) fluorene (BPFLi CAS No. 3236-71-3) in
rabbits:
"Groups of ten rabbits, five males and five females,
were treated topically with 0.25, 1.0 or 2.0 g/kg body
weight of BPFL (moistened with saline) or saline (con-
trol) for 14 consecutive days. Two male rabbits in the
high dose group died dur i ng the study. Both male and
female rabbits in the 1.0 and 2.0 g/kg dosage groups
had decreased body weights relative to controls and
some animals showed clinical signs of toxicity (hunched
posture). Clinical pathology findings and relative
organ weights suggested renal effects in the 1.0 and
2.0 g/kg dosage group rabbits. Pathologist's report
indicated that bile duct hyperplasia and nephropathy
were observed in the 1.0 and 2.0 g/kg dose groups but
not in the 0.25 g/kg dose group or in the controls.
The no-effect level for the test article was 0.25 g/kg
for both males and females."
In its submission, Shell stated that, when completed, the final
report of the 14-day dermal study in rabbits would be provided to
EPA along wi th final reports of other stud ies (i. e., "nega ti ve"
acute and primary dermal irritation studies in rabbits and a
"negative" skin sensitization study in guinea pigs). Shell also
stated that "despite the lack of irritation effects in the test
animals, there have been occurrences of human skin irritation
associated with BPFL." Shell provided the following information
related to the observed human skin irritation:
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
204
.~A ~OMl .... I~EV. 1-71)
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8EHQ-1287-0700
Page 2 of 3
"This irritation is believed to be caused by direct
skin contact [with BPFL], often when protective
clothing is improperly removed following completion of
the operations. Irritation typically occurs on the
hands, arms or elbows of exposed persons as well as the
around the eyes and nose. This irritation is readily
reversible and has been treated by the application of
steroid cream. The current [BPFL] safety data sheet
describes the irritation effects." [Note: A copy of the
current BPFL safety data sheet was included in Shell's
TSCA Section 8(e) submission.]
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of full copies of
the final reports (including the actual experimental protocols,
results of gross and histopathologic examinations, etc.) from all
BPFL studies cited in Shell's submission. In the interim, it
should be noted that the "HEALTH INFORMATION" section of the
provided BPFL safety data sheet states that 1) "based on human
experience,. [BPFL] is moderately to severely irritating to
the eyes [and] the skin. . . [and] may cause skin sensiti-
zation." and 2) "based on similar product testing, [BPFL] dust is
presumed to be irritating to the nose, throat and respiratory
tract. [and] moderately toxic and may be harmful if swal-
lowed." In order to facilitate EPA's evaluation of the reported
tox i city of BPFL, Shell should be requested also to prov ide 1)
the exact identity of the "similar product" tested (including the
CAS Registry Number, if known), and 2) the final reports of the
studies of this similar product that formed the basis for the
ingestion and inhalation toxicity statements presented in the
BPFL safety data sheet.
Current Production and Use
In its Section 8 (e) submission, Shell stated that BPFL is a
research and development (R&D) chemical not listed on the TSCA
Chemical Substance I nven tory. She 11 a 1 so-- s ta ted tha t a TSCA
Section 5 Premanufacture Notification (PMN) has not been filed
for BPFL. Shell stated further that 1) the intended use of BPFL
"is strictly as a site-limited intermediate and feedstock for
other products" and 2) "BPFL would be consumed in downstream
reactions and would not be a component of final products."
Finally, Shell reported that the company "plans to continue
development of BPFL as an R&D substance."
205
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c)
8EHQ-1287-0700
Page 3 of 3
Comments/Recommendations
In its Section 8(e) submission, Shell stated that the company is
updating the BPFL safety data sheet in order to 1) reflect the
reported toxicologic findings, and 2) provide revised worker
Drotection recommendations. In addition, Shell reported that the
~ompany intends "to notify all persons who have come in contact
with this substance during research and development activities by
mea n s 0 f a le t ter a nd the rev i sed safety data sheet." Shell
noted that this notification "included about 15 Shell employees
and four companies outside Shell." Finally, Shell reported that
a copy of the updated BPFL safety data sheet would be transmitted
to EPA.
a)
The Chemical Screening Branch will request Shell to
ensure that EPA receives full copies of the final
reports (including the actual experimental protocols,
results of gross and histopathologic examination, etc.)
from all animal studies cited in the cover letter to
the company's Section 8(e) submission. In addition,
Shell will be requested to provide the exact chemical
identity (including CAS Registry Number, if known) of
the "similar product" the studies of which provided the
basis for the information presented in the "INHALATION"
and "INGESTION" subsections of the "HEALTH INFORMATION"
portion of the submitted BPFL safety data sheet. Shell
wi 11 be asked also to provide complete copies of the
final reports of the cited toxicologic studies of this
"similar" chemical substance.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
tox ic i ty or exposure i nformat ion, Shell wi 11 be as ked
to describe the nature and results, if available, of
all studies (other than those reported already to EPA)
about which Shell is aware or that Shell has conducted,
is conducting or plans to conduct to determine the
toxicity of or the exposure to BPFL.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of BPFL.
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA, OPP/OPTS/EPA and
CCO/OTS/OPTS/EPA. In addi tion, copies of this sta tus
report will be sent to the TSCA Assistance Office
(TAO/OTS/OPTS/EPA) for further distribution.
206
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATI:
DEC 3 0 1987
Page 1 of 3
SUIJICT: status Report* 8EHQ-1287-070l Approved:
,.~: James F. Darr, Section Head ~ ~~
Chemical Risk Identificatio~Se~tion/CSB
~ J~{f,on
TO. Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
As background information for this TSCA Section 8(e) submission,
the Union Carbide Corporation (UCC) reported that, in 1986,
epidemiologists from UCC and the National Institute for
Occupational Safety and Health (NIOSH) "completed an overall
cohort mortality epidemiology study of UCC employees at three
facilities in the Kanawha Valley (KV) of West Virginia.l" Union
Carbide provided the following information regarding the com-
pleted study as well as other ongoing studies:
"The findings of this r 1986] study included an excess
number of deaths due to four types of lymphatic and
hematopoietic tissue cancers. There were 120 deaths
due to non-Hodgkin's lymphoma, multiple myeloma, non-
lymphocytic leukemia and lymphocyt i c leukemi a and 99
deaths expected, based on comparisons to the U.S.
population. The observation period for this study was
1940 to 1978. In order to investigate whether the
occurrence of these excesses was work-related, nested
case/control studies were simultaneously undertaken for
each of these four causes of death. Exposure odds
ratios were examined in relation to 6 major work
activity groups, 111 work areas, 21 specific chemicals
and 52 chemical groups representing over 1000 distinct
chemical substances present in these manufacturing
facilities."
In its letter to EPA, union Carbide stated that
information concerning the preliminary findings of
studies is believed by the company to be reportable
under Section 8(e) of TSCA:
the followi ng
these ongoing
to the Agency
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
207
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8EHQ~128 7 ....0701
Page 2 of 3
"An association was observed between non-Hodgkin's
lymphoma and ass ignment to the South Char 1eston [Wes t
virginia] plant's ethanol and isopropanol production
units, which used the strong acid process (odds ratio =
8.3; 95% Confidence Interval: 2.3; 30.7). Six of 52
cases of this disease (12%) vs. 4 of 260 controls (2%)
held assignments in these work areas. The cases were
first ass igned to these uni ts in the following years:
1930, 1931, 1934, 1942, 1952, and 1960. These findings
were not supported by duration response trends. Three
of the six cases worked less than two months in these
units.
"At the South Charleston plant, the ethanol strong acid
process operated from 1930 to 1960, and isopropanol
strong acid process operated from 1928 to 1949. Strong
acid processes have been reported in the literature to
be associated with cancer of the upper respiratory
tract.2,3 [To the best of Union Carbide's]
knowledge, an association of increased risk of non-
Hodgki n' s lymphoma wi th ass ignment to the ethanol and
isopropanol strong acid process uni ts represents new
information."
In addition, Union Carbide pointed out that the company recently
notified EPA under Section 8(e) of TSCA (see 8EHQ-1187-0698 et
seq.) that "the non-lymphocytic leukemia case/control comparisons
revealed an association of this cause of death with assignment to
the chlorohydrin unit." The reader's attention is directed also
to the status report that was prepared by the Agency in response
to 8EHQ-1187-0698.
Submission Evaluation
In the present Section 8(e) submission, Union Carbide stated that
the case/control studies have not been completed and that further
details regarding the reported findings will appear in the final
report which wi 11 be submi t ted to EPA as soon as the report is
available. In order for EPA to evaluate the overall significance
of the reported findings, Union Carbide should be asked to ensure
that EPA receives a complete copy of the final report (including
the actual protocols, data, results of statistical analyses,
etc.) from the company's epidemiologic studies. In addition,
Union Carbide should be asked to ensure that EPA is kept apprised
of any further significant findings from the company's ongoing
studies.
Comments/Recommendations
The discussion pertains to the TSCA Section 8 (e) reporting
obligation of a company that obtains "new" information that
reasonably supports a conclusion that a chemical substance or
mi xture that the subj ect company did, but does not any longer,
manufacture, import, process or distribute presents a substantial
208
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8EHQ-1287-0701
Page 3 of 3
risk of injury to health or the environment. A company that finds
itself in this particular situation should be aware that although
it may not be required technically to submit such information to
EPA under Section 8(e) of TSCA, EPA believes that a timely formal
submission of such information would fall clearly within the
"spirit" of the Section 8(e) reporting provision. EPA believes
also that, in many cases, such a report would be of great benefit
to others who currently handle the subject chemical (s) and who
can then initiate any warranted actions to reduce or eliminate
health or environmental risks. Finally, the Agency believes that
the timely formal submission of such risk-related information
would be a demonstration of the reporting company's chemical
stewardship practices.
a)
The Chemical Screening Branch will ask Union Carbide
to ensure that EPA receives a full copy of the final
report (including the actual protocols, data, results
of statistical analyses, etc.) from the epidemiologic
studies/analyses cited in the company's Section 8(e)
submission. In addi tion, Union Carbide will be asked
to keep EPA apprised about any further significant
findings from the ongoing epidemiologic studies.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Union Carbide will be
asked to describe the actions the company has taken or
plans to take to notify affected workers and others
about the reported epidemiologic findings.
b)
The Chemical Screening Branch will review the reported
information to determine the need for further OTS
assessment of the submitted epidemiologic findings.
c)
The Chemical Screening Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
References
1
Rinsky, R.A. et ale "Study of Mortality Among Chemical
Workers in the Kanawha Valley of West Virginia"
Am J Ind Med (in press)
2
Weil, C.S. et al. "Quest for a Suspected Industrial
Carcinogen" Arch Ind Hyg and Occ Med 1952; 5:533-547
3
Lynch, J. et ale "An Association of Upper Respiratory
Cancer wi th Exposure to Diethyl Sulfate" J Occup Med
1979; 21:333-341
209
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
DEC 3 I 1987
Page 1 of 4
SUBJECT:
Status Report* 8EHQ-1287-0702 Aoproved: c?91/....
8EHQ-1287-0703 . ~
James F. Darr, Section Head a~~~~
Chemical Risk Identificatiowr~:~tion/CSB
1~f1
IIROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
This status report covers two separate Section 8(e) submissions
regarding the same chemical substance (N-isopropylaniline; N-IPA;
CAS No. 768-52-5). In Section 8 (e) submission 8EHQ-1287-0702,
the Monsanto Company provided preliminary findings from a 3-month
inhalation study of N-IPA in rats and in Section 8(e) submission
8EHQ-1287-0703, Monsanto provided the final report of a l-month
dermal study of N-IPA in rats.
Submission Description
In the cover letter to Section 8 (e) submission 8EHQ-1287-0703,
Monsanto presented the following summary information concerning
the conduct and results of a l-month dermal application study of
N-IPA in rats:
11 In this study. . N-isopropylaniline (N-IPA) was
applied to and left unoccluded on the shaved skin
(approximately 25 square centimeters; approximately 10%
of the total body surface area) of groups of 10 male
and 10 female Sprague-Dawley rats at targeted doses of
0, 25, HJ0 or 400 mi 11 igrams/k i logram (mg/kg) per day,
five days per week, for 4 weeks. Pla~tic collars were
used to prevent ingestion of the test material. Nega-
tive controls were handled identically to [the] treated
animals, except [that] nothing was applied to the skin.
Analyses were conducted to determine stabi li ty under
simulated in-use conditions. Over a 6-hour period under
simulated conditions, approximately one-third of the
test material apparently volatilized.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
210
.~A 1'0- II" uuv. ~'.I
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8EHQ-1287-0702/3
Page 2 of 4
"Cumulative body weight gains were statistically
signi f icantly reduced from that of controls for ma les
at the 400 mg/kg/day level. Food consumption was also
reduced for males at this exposure level [for] the
first week of testing. Clinical signs of redness,
dryness, abrasions and/or scabs were primarily seen in
females at the highest two levels.
"Anemia and methemoglobinemia, wi th associated spleni c
changes of increased weight and hemosiderin deposition
and hemosiderosis were present at the middle and/or
high [N-IPA] exposure levels in both sexes. Epidermal
thickening (acanthosis) was seen at all test levels in
males and at the two highest levels in females.
"Based on the above results, N-isopropylaniline
appeared to be absorbed through intact skin of rats and
produced a mild skin irritation and thickening as well
as anemia, methemoglobinemia, and associated splenic
changes. A no observed effect level (NOEL) was not
established in this study, although effects seen at the
25 mg/kg/day dosage level were minor in severity."
In the cover letter to Section 8 (e) submission 8EHQ-1287-0702,
Monsanto presented the fOllowing summary information concerning
the conduct and preliminary results of a 3-month inhalation study
of N-IPA in rats:
"Four groups of 15 male and 15 female Sprague-Dawley
rats per group were exposed to mean analytical con-
centrations of 0, 5.3, 20 or 100 mg N-isopropylaniline
per cubic meter of air in 10 m3 inhalation chambers. A
minimum of sixty-four 6-hour exposures were conducted
over an approximate 14-week period. All animals sur-
vived the scheduled exposures except for one non-study
related death of a high exposure level male. Notable
after-exposure observations included red/brown peri-
nasal encrustation (three occurrences) and focal loss
of hair (control animals only). Observations noted on
weekly weigh days were considered non-study related and
were focal loss of hair, malocclusion and piloerection.
A slight increase in body weight did occur in the high
exposure level animals from Week 2 to study's end.
Ophthalmic examination of the control and high level
animals showed no ocular changes that could be attri-
buted to test material exposure. Methemoglobinemia,
occurring in all exposure groups, was considered a
direct effect of N-isopropylani line exposure and di s-
played a definite dose response. Decreased hemoglobin
levels in the high exposure males and increased MCV
[(Mean Corpuscular Volume)] values in ,high exposure
males and females appeared to be related to [the] test
material exposure. However, the [obtained] values were
either within the historical control range (hemoglobin
211
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8EHQ-1287-0702/3
Page 3 of 4
and MCV - males) or very slightly above this range (MCV
- females) and therefore, these changes are 0 f ques-
tionable biological significance. The deviations in
clinical chemistry values observed in treated animals
were randomly distributed among the various exposure
groups and therefore not interpreted as effects of test
material exposure. The increase in both relative and
absolute kidney weights in the high level animals and
the dark di scolora t ion of the high level male kidneys
could be associated to test material exposure. These
changes were not accompanied by any obvious microscopic
abnormalities and therefore their biological signifi-
cance is unknown. Microscopically, [the] increased
hemosiderin in the spleens of all the high level
animals was considered [to be] a direct effect of N-
i sopropylani 1 ine exposure and may have contr ibu ted to
the slight increase in splenic weight for this group.
The increase in hemosiderin pigment in concert with the
aforementioned changes in hematology suggest that there
may be some alteration in red blood cells kinetics
leading to accelerated red blood cell destruction. The
mild increase in absolute spleen weight for mid ex-
posure females was not accompanied by any obvious
microscopic abnormali ty and therefore was probably of
no biological or toxicological significance. All other
microscopic changes were considered non-exposure
re 1 a ted . In conc 1 us ion, the occurrence of elevated
methemoglobin concentrations in all exposure groups
precludes the identification of a 'no-effect' level for
the i nhalat ion of N- i sopropylani 1 ine aerosol, as [the
chemical was] administered in this study."
According to Monsanto's TSCA Section 8(e) submissions, "dermal
contact and inhalation are expected to be the primary routes of
occupational exposure to N-isopropylaniline." In addition,
Monsanto reported that "man is known to be much more sensitive to
methemoglobinemia following exposure to aromatic nitro (and
amino) compounds than the rat or rabbit."
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible once the Agency receives a complete
copy of the final report (including the actual experimental
protocol, results of gross and histopathologic examinations,
etc.) from Monsanto's 3-month inhalation study of N-IPA in rats.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for N-isopropylaniline (CAS No. 768-52-5), which is
listed in the initial TSCA Chemical Substance Inventory, has
shown that approximately 1 million to 10.1 million pounds of this
chemical substance were reported as manufactured and/or imported
212
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8EHQ-1287..0702/3
Page 4 of 4
in 1977. This production range information does not include any
information claimed as TSCA Confidential Business Information
(TSCA CBI) by the person(s) reporting for the initial TSCA
Inventory, nor does it include any information that would
compromise TSCA CBI. All of the data reported for the ini tial
TSCA Inventory, including the production range data, are subject
to the limitations that are contained in the initial TSCA
Inventory Reporting Regulations (40 CFR 710).
In its TSCA Section 8(e) submissions, Monsanto provided the
following information wi th regard to the potential for exposure
to N-IPA:
"Appropriate personal protective measures and effective
engineering controls are utilized in order to control
workplace exposure to N-IPA at or below acceptable
levels (ACGIH TLV/TWA: 2 ppm, 10 mg/m3). The hazards
of N-isopropylaniline exposure and the protective
measures necessary to minimize exposure are detailed in
the Material Safety Data Sheet (MSDS) for N-IPA."
Accord i ng to the Condensed Chemical Dictionary (10th Ed i t ion) ,
N-isopropylaniline is a yellow liquid (boiling point 2060C) used
as a chemical intermediate and in the dyeing of acrylic fibers.
Comments/Recommendations
a)
The Chemical Screening Branch will request Monsanto to
ensure that EPA receives a complete copy of the final
report (incl ud i ng the actua 1 exper imental protocol,
results of gross and histopathologic examinations,
etc.) from the 3-month N-isopropy1ani1ine inhalation
study that was the subject of 8EHQ-1287-0702.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Monsanto will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which Monsanto is aware or that the company has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of N-isopropy1aniline.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of N-isopropylaniline.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
213
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
DEC 3 I 1987
SU8JECT:
Status Report*
Aoproved: ~
. d fL....- T~.
Darr, Sectlon Hea ~
Risk Identification Section/CSB
8EHQ-1287-0704
,1?1( 1~1
FROM:
James F.
Chemical
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
Texaco Inc. reported that the company recently learned that a
National Toxicology Program (NTP) bioassay of naphthalene (CAS
No. 91-20-3) in male and female B6C3Fl mice had been completed.
According to Texaco, the final report of the study is awaiting
qua 1 i ty assurance review and is not ready for distribution by
NTP. Texaco reported also that it was the impression of the NTP
investigator in charge of the study that "naphthalene caused lung
tumors in male mice." Texaco stated further that during recent
phone conversations with NTP, the company obtained the followirig
information with regard to the conduct and results of the study:
"Respiratory Response - Naphthalene
Adenomas* Carcinomas
ppm Males Females Males Females
o 7/70 5/69 0/70 0/69
10 17/69 5/66 2/69 0/66
30 16/67 14/68 2/67 0/68
30 11/68 14/67 4/68 1/67
* Lung alveolar-bronchial,
Exposure, 6 hrs/day, 5 days/week, 103 weeks"
According to Texaco, the obtained data "have not undergone review
by the pathology working group of NTP."
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
214
R~A 'OMI "... II'!V. ..711
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8EHQ-1287-0704
Page 2 of 3
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible when EPA receives from NTP a copy of
the draft technical report for peer review by Technical Report
Peer Review Subcommittee of NTP's Board of Scientific Counselors.
As in similar situations involving other previous TSCA Section
8 (e) submiss ions, EPA should contact NTP to find ou t when NTP
plans to release a formal report of this study.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for naphthalene (CAS No. 91-20-3), which is listed in
the initial TSCA Chemical Substance Inventory, has shown that
approximately 365 million to 1.55 billion pounds of this chemical
were reported as manufactured and/or imported in 1977. This
production range information does not include any information
claimed as TSCA Confidential Business Information (TSCA CBI) by
the person(s) reporting for the initial TSCA Inventory, nor does
it include any information that would compromise TSCA CBI. All
of the data reported for the ini tial TSCA Inventory, i nc 1 ud i ng
the production range data, are subject to the limitations that
are contained in the initial TSCA Inventory Reporting Regulations
(40 CFR 710).
In its TSCA section 8 (e) submission, Texaco reported that the
company manufactures naphthalene" as a high pur i ty, low su 1 fu r
naphthalene of petroleum extraction." In addition, Texaco stated
that the uses of naphthalene "may include insecticides, dyes,
moth repellents, surfactants and leather tanning chemicals."
Comments/Recommendations
It shou Id be noted that Part VII of EPA' s Sect ion 8 (e) pol i cy
sta tement (" Sta tement of Interpretation and Enforcement Po 1 icy;
Notification of Substantial Risk" 43 FR 11110; March 16, 1978)
provides a number of examples of the types of information that
need not be reported to EPA under Section 8 (e) of TSCA (i.e.,
information about which subject persons can automatically assume
the Agency to be "adequa te 1 y in formed") . In add i ti on to the
examples cited in Part VII, subject persons can automatically
assume, for the purposes of TSCA section 8(e) reporting, that EPA
has been adequately informed about substantial risk information
contained in a formal publication or report released to the
general public by an agency of the U.S. Government. It should be
noted also that EPA's position on the Section 8(e)-reportability
of resul ts of NTP bioassays has been descr ibed previ ously (see
EPA's "status report" prepared in response to TSCA Section 8(e)
submission number 8EHQ-1282-0467). In summary, EPA's position on
Section 8(e) as it relates to the results of NTP bioassays is as
follows:
215
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8EHQ-1287-0704
Page 3 of 3
A subject person can assume automatically that EPA has
been "adequately informed" about the results of an NTP
carcinogenesis bioassay once the NTP formally releases
copies of the draft technical report from that study
for peer review by the Technical Report Peer Review
Subcommittee of NTP's Board of Scientific Counselors.
This assumption can be made because EPA's Office of
Toxic Substances (OTS) routinely receives full copies
of all draft NTP carcinogenesis biosassay technical
reports formally released by NTP for peer review.
Therefore, if a subject company obtains (i.e., knows of
or possesses) toxicologic information concerning an NTP
bioassay and there has not been a formal public release
of those findings by NTP (e.g., formal release of the
draft technical report for peer review), the subject
company should immediately consider the need to report
the information to EPA under Section 8(e) of TSCA.
It should be noted that EPA has correctly received a number of
TSCA Section 8(e) submissions (usually comprised of 1 to 2 pages)
filed by companies that obtained toxicologic data from studies
conducted by or for agencies of the u.S. Government that have not
been published or released fonnally to the general publ ic. In
each of these cases, OTS has immediately initiated appropriate
followup activities directly with the other Federal agency in
order to minimize and, in most cases, eliminate further TSCA
Sect ion 8 (e) report i ng obI igat ions on the part of the submi tting
company to provide such items as complete copies of supporting
data or actual technical reports.
a)
The Chemical Screening Branch will contact NTP to
determine when the findings from NTP's bioassay on
naphthalene will be formally released.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Texaco will be asked
to describe the actions the company has taken or plans
to take 1) to notify workersjothers about the reported
information, and 2) to reduce or eliminate exposure to
naphthalene.
b)
upon EPA's receipt of the NTP report on naphthalene,
the Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWERjEPA, OWjEPA, OARjEPA, ORDjEPA and OPPjOPTSjEPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAOjOTSjOPTSjEPA) for
further distribution.
216
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UNITED STATES E~NIRONMENTAL PROTECTION AGENCY
DATE:
JAN 2 I 1988
Dage 1 of 4
David R..(illiams,
FROM: h . 1 S .
C emlca creenlng
Section 8 (e)
Branch/ECAD
Approved: L t ~ I kir?
Coordinator (/
SUBJECT:
Status Report*
8EHQ-1287-0705
TO: James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Monsanto Company provided a full copy of the final report of
a 1-month inhalation study of diisopropylamine (DIPA) in rats.
The cover letter to Monsanto's Section 8(e) submission presented
the following information with regard to the conduct and results
of the study:
"In this study. four groups of 15 males and 15
female Sprague-Dawley rats per group were exposed for 6
hours per day (excluding weekends and holidays) to
diisopropylamine (DIPA) at mean analytical concentra-
tions of 0.0, 0.10, 0.60, and 2.00 milligrams per liter
of air for a maximum of 23 exposures over a one-month
period. Three high exposure level animals died during
the study. Gross signs or irritation to [the] eyes and
respiratory tract occurred in the mid and high exposure
level animals. Ophthalmic examinations showed a dose-
related corneal keratopathy. Decreased body weights
were seen in both mid and high level animals. Increased
red blood cell counts, hemoglobin and hematocrit
measurements existed in the high level males and among
mid and high exposure level females. Significantly
lower white blood cell counts (due to reduced absolute
numbers of lymphocytes) were present in males from all
exposure levels.
"Occurrences of decreased mean corpuscular volume,
serum chlor ide, total protein, a 1 bumi nand i nc r ea sed
serum cholesterol all seemed to be directly associated
to compound exposure. Thymic atrophy and seminal
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
217
E~A FORM II'" (REV. 3-711
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8E~{Q-1287-0705
Page 2 of 4
vesicle atrophy were also observed in high exposure
animals. Pathology findings consistent with gross
signs of irritation were inflammatory lesions in the
nasal passages of all exposure groups and those in the
trachea, lung and corneas of high exposure groups.
Since lymphocytopenia in males and lesions in the
cornea and nasal passages of both sexes occurred at the
lowest exposure level (13.10 mg/l in air), a 'no-effect
level' for OIPA could not be determined in this study."
In its submi ss i on, Monsanto noted that the" pr imary hazard from
diisopropylamine is due to its marked irritancy to skin, eyes and
mucosae."
Submission Evaluation
According to a number of secondary scientific literature sources,
DIPA has been shown in acute animal studies to be irritating upon
contact with skin and mucous membranes and moderately toxic when
admi ni stered orally. Overall, however, the secondary 1 i terature
sources consul ted by EPA do not present any information on the
systemic toxicity of DIPA resulting from long term exposure.
In Monsanto's I-month inhalation study in male and female rats,
the DIPA concentrations of 0.10, 0.60 and 2.00 mg/l air for 6
hours a day for a maximum of 23 exposure days over a one month
period are equivalent to approximately 12, 72 and 240 mg/kg/day,
respectively. Gross signs of irritation to the respiratory tract
and eyes were observed in the animals in the mid and high DIP.A
dose groups; ophthalmic examinations revealed a dose-related
corneal keratopathy. In addition, decreased body weights were
observed at the mid and high OIPA dose levels. The adverse blood
effects seen included increased red blood cell counts, hemoglogin
and hematocr i ts in the high dose males and in the mid and high
dose females. A decrease in whi te blood cells was seen in male
rats at each OIPA exposure. The observed decrease in the mean
corpuscular volume, serum chlor ide, total pro te i n and a 1 bumi n ,
and the increase in serum cholesterol also appear to be directly
associated with exposure to DIPA. Further, thymic atrophy (males
and females) and seminal vesicle atrophy (males) were seen in the
high dose groups. Also, inflammatory lesions were found in the
nasal passages in animals from all exposure groups and in the
trachea, lung and corneas of the animals from the high exposure
group.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for di isopropylamine (CAS No. 108-18-9), which is
listed in the initial TSCA Chemical Substance Inventory, has
shown that 0 to 1,000 pounds of this chemical were reported as
manufactured and/or imported in 1977. This production range
information does not include any information claimed as TSCA
Confidential Business Information (TSCA CBI) by the person(s)
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Page 3 of 4
reporting for the initial TSCA Inventory, nor does it include any
information that would compromise TSCA CBI. All of the data
reported, for the initial TSCA Inventory, including the production
range data, are subject to the limitations that are contained in
the initial TSCA Inventory Reporting Regulations (40 CFR 710).
Accord i ng to the Condensed Chemical Dictionary (10th Edi tion) ,
diisopropylamine is a volatile (boiling point 84.l0C) colorless
liquid used as a catalyst and chemical intermediate.
In its Section 8(e) submission, Monsanto reported that the
"Material Safety Data Sheet (MSDS) for diisopropylamine details
the hazards of the chemical and the necessary protective measures
which must be taken to control workplace exposure at or below
acceptable levels (ACGIH/TLV: 5 ppm)." Finally, Monsanto stated
that the company "no longer manufactures diisopropylamine."
Comments/Recommendations
The discussion pertains to the TSCA Section 8 (e) reporting
obligation of a company that obtains "new" information that
reasonably supports a conclusion that a chemical substance or
mixture that the subject company did, but does not any longer,
manufacture, import, process or distribute presents a substantial
risk of injury to health or the environment. A company that finds
itself in this particular situation should be aware that although
it may not be required technically to submit such information to
EPA under Section 8(e) of TSCA, EPA believes that a timely formal
submission of such information would fall clearly within the
"spirit" of the Section 8 (e) reporting provision. EPA believes
also that, in many cases, such a report would be of great benefit
to other s who currently handle the subject chemical (s) and who
can then initiate any warranted actions to reduce or eliminate
health or environmental risks. Finally, the Agency believes that
the timely formal submission of such risk-related information
would be a demonstration of the reporting company's chemical
stewardship practices.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Monsanto will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
the Agency or those published in the open scientific
1 i terature) about which Monsanto is aware or that
Monsanto has conducted, is conducting or plans to
conduct to determine the toxicity of diisopropylamine.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of diisopropylamine.
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c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
220
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
FEB I 9 aI3
Page 1 of 12
SU8JECT:
Status Report* 8EHQ-1287-137136 ADproved:. ,;'?;~ - -/ ------
, ,~~--
James F. Darr, Section Head t1MILA f:~ {/~/ MAR I 5 1988
Chemical Risk Identificatiob('~~~tion/CSB/ECAD
FROM:
TO:
Joseph J. Merenda, Director
Existing Chemical Assessment Division/OTS/OPTS
Submission Description
Via pr i va te counsel, Borg-Warner Chemicals, Inc. submi tted the
final report from a 4-month oral toxicity study of Weston XR 1532
in dogs. According to the submission, "Weston XR 1532 was the
identification used by Borg-Warner in 19813 for a product now
known as Ul tranox 626 [(major component: bi s (2, 4-di -tert-butyl-
phenyl)pentaerythritol diphosphite, CAS No. 26741-53-7)]:" The
"ABSTRACT" section of the submitted final report contains the
following information regarding the conduct and results of this
subchronic dog study:
"This study. . . was designed to assess the toxici ty
of Weston XR 1532 when administered, via gelatin
capsules, to Beagle dogs (4/sex/group) at dose levels
of 13, 4, 12 and 413 mg/kg/day for 4 months.
"One high dose female (4686) exhibited progressive fore
and hind limb paralysis accompanied by decreasing body
weight and food consumption and was sacrificed on Test
Day 86. \ All of the other control and treated animals
survived the duration of the study. The physical and
neurological opservations of these animals did not
reveal any effects which could be attributed to the
administration of the test material.
"The mean body weights of the treated males were
slightly greater than control prior to the initiation
of dosing and throughout the 4 month treatment period.
Mean food consumption values in the treated males were
slightly lower than control during the treatment
per iod. Mean body weight and food consumption values
of the surviving treated females were unremarkable.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
221
.~A ..OMl ..... ,..lEV. ,.,.1
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Page 2 of 12
"A subacute, eosinophilic pneumonia was observed
microscopically in four of eight high-dose animals, one
of eight mid-dose animals and two of eight low-dose
animals. This condition was not observed in any of the
control animals. The etiology of these pulmonary
lesions could not be determined.
"Seven of [the] eight high-dose animals displayed
degenerative myelin lesions. These lesions were
confined to the high-dose group and were considered
related to the administration of the test material.
One animal (4686) di splayed cl i nical mani festa tions of
severe abnormalities of the axonal fibers and myelin.
"Ophthalmology, hematology, clinical chemistry, urin-
alysis, absolute and relative organ weights and gross
necropsy findings did not reveal any effects that could
be attributed to the administration of Weston XR 1532."
Borg-Warner also submitted a Material Safety Data Sheet (MSDS)
covering Ultranox 624 (the subject chemical alone), Ultranox 626
(the subject chemical containing approximately 3.1% by weight
triisopropanolamine (TIPA; CAS No. 122-23-3» and ultranox 626A
(a "compacted" form of Ultranox 6.26). With regard to acute
toxicity of the subject product(s), the submitted MSDS reports an
acute rat oral LD50 of 5.58 g/kg, an acute rat inhalation LC50 of
>2 mg/l, and an acute rabbit dermal LD53 of >200 mg/kg; the MSDS
reports also that an acute dermal study (species not given but is
assumed to be rabbits) showed the product(s) to be irritating
with some necrosis observed. In addition to citing the results
of the subchronic oral dog study, the MSDS states that "rats fed
for 93 days at 133, 300, or 1303 ppm showed no effects except
some very slight to slight extramedullary hematopoiesis in the
1 i ver and spleen of the animals fed at the highest dose." The
MSDS states also that "hens dosed from 0.8 to 6.8 g/kg once and
then again 21 days later showed no signs of neurotoxicity." In
addi tion, the MSDS states that no adverse behavioral, gross or
histologic effects were seen in rats in a two year feeding study
at dietary levels of 103 or 503 ppm. The MSDS states also that
the test material was not teratogenic in rabbits dosed (route not
specified; assumed to be oral) at 20, 53 or 200 mg/kg. Finally,
the MSDS presents the following statements about neurotoxicity:
"Animal studies have indicated in one test that the
material is a neurotoxin at the high dose in dogs.
Three other tests in other types of animals, including
a 2 year study in rats, did not produce neurotoxicity.
This material is considered to be a suspect neurotoxin
at high levels of exposure. Symptoms of neurotoxicity
can include weakness, staggered walk, tremors, or even
paralysis."
In its submission, Borg-Warner provided the following information
regarding the actions that the company took voluntarily to notify
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customers about the preliminary/final results of the company's
subchronic oral study in dogs:
"As the result of a 'Dear Customer' letter. . . dated
April 7, 1980, users were specifically advised of the
interim evidence of neurotoxicity of Ultranox 626.
This was followed by a second [Borg-Warner] letter
dated February 6, 19B1, which described the final
resul ts of the dog study as well as the results of a
study in hens where no neurotoxicity was observed.
Subsequently, all users received [Material Safety
Data Sheets] disclosing the final results of the four-
month feeding study in dogs. .... A neurotoxicity
warning also appears on the label of each package of
Ultranox 626. ."
It should be noted also that a submitted Ultranox 626 product
label carries the following precautionary statement:
WARNING
MAY CAUSE SKIN IRRITATION.
MAY AFFECT NERVOUS SYSTEM.
DO NOT GET IN EYES OR ON SKIN.
USE WITH ADEQUATE VENTILATION.
LABORATORY ANIMAL STUDIES INDICATED NEUROTOXIC EFFECT AT HIGH
DOSE LEVELS.
In its TSCA Section B(e) submission, Borg-Warner reported that 1)
"the sole use of Ultranox 626 is as a stabilizer for plastic
resins" and 2) "the product is compounded into mainly olefin
polymers where it becomes encapsulated by the plastic material."
The submission reports also that in order for this product to be
commercially successful, Borg-Warner recognized the need for
clearance by the U. s. Food and Drug Administration (FDA) for use
of the product in food packaging materials. The submission
presents the following background information with regard to
Borg-Warner's request for and ultimate receipt of clearance by
FDA for the product:
"On September 17, 1979, Borg-Warner filed a Food
Additive Petition (FAP) [with FDA] for the use of
Ul tranox 626 as a stabi 1 i zer in polymer systems. The
petition number OB3478 was assigned by FDA. 46 Fed.
Reg. 12332 (Feb. 13, 1981). As part of its review of
FAP OB3478, a three-month oral toxicity study in non-
rodent species was requested by FDA. Borg-Warner
responded by commissioning the study in beagle dogs
that is the subject of this submission. [According to
the final report of this subchronic dog study, dosing
223
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was begun on September 13, 1979.] The preliminary
data from that study noted fore and hind limb paralysis
accompanied by decreasing body weight loss in one
[female] dog at the high dose (40 mg/kg) level. Thi s
finding prompted Borg-Warner to send [to] all of its
customers a 'Dear Customer' letter dated April 7, 1980
advising them of the interim neurotoxicity
finding. Borg-Warner also decided at this time to
extend the study for an additional thirty days.
"At the conclusion of the study, the single high dose
female was the only animal to display clinical signs of
central nervous system disorders. Seven of the eight
high-dose animals were found to display degenerative
myelin lesions, the only group to exhibit such lesions.
The final report [of the 4-month study in dogs] was
received by the company shortly after May 28, 1980, and
submitted to FDA promptly. In granting the petition,
FDA found the substance to be safe for use in food
contact materials under Section 409 of the Federal
Food, Drug and Cosmetic Act. 21 U.S.C. 348. The [FDA]
regulation at 21 CFR section 178.2010 was amended on
November 20, 1981, to include U1tranox 626. 46 Fed.
Reg. 57034. ...."
Borg-Warner's submission also presents several arguments believed
by the company to support its contention that the subchronic oral
dog study results were not required to be reported to EPA under
Section 8(e) of TSCA. The following statements contained in the
submission outline Borg-Warner's position in this matter:
o
"The neurotoxicity data on U1tranox 626 would have long
since been submitted to EPA -- either as a Section 8(e)
notice or as an FYI [("For Your Information")] submis-
sion depending upon the decision of Borg-Warner's Risk
Review Group -- had not Borg-Warner been advised by
. . . [the EPA's TSCA Assistance Office (TAO)] in April
or May 1980, and again as recently as December 7, 1987,
that toxicology studies submi tted to FDA did not have
to be submitted to EPA under Section 8(e).
o
"Consistent with the intent of [TSCA] Section 8 (e),
Borg-Warner has not suppressed the. . . [4-month oral
toxicity study of U1tranox 626 in dogs]. Quite the
contrary, it has been submitted to regulatory agencies
in at least eight foreign countries, is in the public
domain by virtue of its submission to FDA and the
neurotoxic effect noted in the study are disclosed in
the Material Safety Data Sheet (MSDS) sent to every
purchaser when the product is sampled or sold.
o
"The neurotoxicity of organophosphorus compounds is
well-known and the data merely corroborate known
information about these materials.
224
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Page 5 of 12
o
"Given the general knowledge of the toxicity of these
compounds, there has never been any significant ex-
posure to ultranox 626 and, hence, no significant risk
to man or the environment."
Borg-Warner's submission also raises a number of issues related
to application of EPA's May 15, 1987 TSCA Sections 8, 12, and 13
"Enforcement Response Policy" (ERP) in this matter.
Submission Evaluation
In summary, Weston XR 1532 (now known as Ultranox 626), which
contains bis(2,4-di-tert-butylphenyl)pentaerythritol diphosphite,
was administered orally via gelatin capsules to Beagle dogs
(4/sex/group) at doses of 4, 12 and 40 mg/kg/day for four months.
The study assessed the potential neurotoxicity of the product by
way of behavioral and neuropathological examinations.
A minimal battery of behavioral procedures was used to assess the
effects of the test material. Behavioral signs of toxicity were
observed in only one female and only at the highest dose. These
signs included progressive forel imb and hindl imb paralys is, and
decreased body weight and food consumption; no clinical observa-
tions were reported for the other animals in the study.
The neuropathological assessment was conducted on the following
tissues: brain (3 sections), eye (with the optic nerve), sciatic
nerve and spinal chord. In general, tissues were fixed in 10%
neutral buffered formal in. Central nervous system tissues were
cut at 19 microns and stained with hematoxylin and eosin and with
luxol fast blue. Seven of the eight high dose animals displayed
degenerati ve myel in lesions. There were no reported lesions at
lower dose levels.
The study protocol used was adequate to assess the potential for
neurotoxicity. Neurotoxicity was clearly observed at the highest
dose level. However, the protocol was limited in its ability to
adequately assess the extent of the damage or to determi ne the
minimal effective dose. It is possible that effects would have
been observed if additional doses between 12 and 40 mg/kg had
also been tested. It is also possible that effects could have
been observed if a more complete neuropathological assessment had
been conducted. Phosphi tes can produce a different pattern of
neuropathological endpoints compared to agents that produce an
organophosphate induced delayed neuropathy (OPION; Veronesi et
al., 1986; Veronesi and Overgsten, 1987). For example, in the
rodent model of OPION, the fasciculus gracilis is the earliest
and most severely damaged tract; only after repea ted exposures
are the lateral and ventral columns of the cervical chord in-
volved. In contrast, with some phosphites, the most vulnerable
tracts are those located in the lateral and ventral columns with
a sparing of the large diameter ascending tracts of the dorsal
columns. If the neurological assessment of such a phosphite in
the rat was restricted to the fasciculus gracilis, the extent of
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the adverse effects would likely be lost. Similarly, it is
possible that the areas examined in Borg-Warner's subchronic dog
study did not adequately characterize the damage to the nervous
system. Furthermore, it is poss i ble that if more sophi sticated
neuropathological assessment procedures had been used (e.g.,
electron microscopy, use of plastic media or other spec i al i zed
stains), other effects might have been observed.
The neurobehavioral procedures used, although adequate to assess
neurotoxici ty, were also limi ted in nature. The description of
the procedures for behavioral assessment stated that they were
1 imi ted to "behav ior, movements, reacti vi ty to stimul i, muscle
tone." A clear description of these endpoints was not given.
For example, what behavior was observed? Were the movements
forced? What were the characteristics of the stimuli used? In
addition, the discussion of the examination of different reflexes
(e.g., righting, patellar) did not adequately describe how these
observations were made (e.g., order, time after dosing). The
autonomic signs exami ned were pupi 1 size and secret ions; other
autonomic signs that have proven to be reliable and sensitive in
other studies but were not included in the present dog study are
piloerection, respiration, urination and vocalization. Although
functional effects were observed in only one female in the high
dose group, it cannot be excluded that the absence of functional
effects in the other animals was due to the insensitivity of the
neurobehavioral measures used. Several other important questions
also arise with regard to the neurobehavioral examinations. For
example, were these neurobehavioral examinations conducted on a
"blind" basis? If different observers were used, was the inter-
observer reliability controlled? If so, how? If these factors
are not controlled appropriately, the power of the dog-study to
detect neurobehavioral problems could be adversely affected. The
ability to detect neurobehavioral effects has been shown to be
highly correlated to the test conditions employed (Reiter and
MacPhail, 1979).
In conclusion with regard to the submitted subchronic dog study,
neurotoxicity was observed at the high dose level and included
degenerative myelin lesions in seven of the eight animals tested.
Clinical symptoms of toxici ty, which were reported in only one
female at the highest dose level tested, included progressive
forelimb and hindlimb paralysis, and decreasing body weight and
food consumption; because more extensive neuropathological and
behavioral examinations were not conducted, the possibility that
other neurobehavioral/neuropathological effects occurred cannot
be excluded. Considering that there was such a large gap between
the 12 and 40 mg/kg/day dose levels, it is also possible that
neurotoxicologic effects could have occurred at doses lower than
40 mg/kg/day. It is concluded, therefore, that the test material
caused significant neurological effects at the highest dose level
tested in this subchronic oral study in dogs.
EPA should request Borg-Warner to submit full copies of the final
reports (including the actual experimental protocols, results of
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gross and histopathological examinations, etc.) from the hen
study, 90-day rat study and two-year rat study cited in the pro-
vided Ultranox 626 MSDS. The Agency may also want to request
Borg-Warner to submit complete copies of some or all of the other
studies cited in the MSDS.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for CAS No. 26741-53-7, which is listed in the initial
TSCA Chemical Substance Inventory, has shown that no 1977 manu-
facture or importation of the chemical was reported or that all
manufacturing and/or importation data submitted were claimed to
be TSCA Confidential Business Information (TSCA CBI) by the
per son ( s ) r e p 0 r tin g for the i nit i a 1 I n v e n tor y and can not be
disclosed (Section 14 (a) of TSCAi U.S.C. 2613 (a)). All of the
data submitted for the initial TSCA Inventory, including the pro-
duction range data, are subject to the limitations contained in
the initial TSCA Inventory Reporting Regulations (40 CFR 710).
According to the submission, during the time that Borg-Warner was
seeking FDA approval of Ultranox 626 under the food additive
regulations, Borg-Warner was working with prospective customers
in establishing appropriate applications of the chemical. The
submission states that "during this time, Borg-Warner sold
limited quantities of Ultranox 626 for those few applications
where customers did not demand an FDA clearance" and "sales in
1979 were about 10,000 pounds to only one customer." In addition,
the submission states that "by 1980, sales had increased to
60,500 pounds to five customers." The submission states further
that "traditionally, this product has been purchased by a rela-
tively few customers who are well aware of the hazards associated
with organophosphite materials."
In Appendix B of Borg-Warner's submission, the company provided
the following additional information regarding the manufacture of
and the potential for exposure to Ultranox 626:
"Borg-Warner Chemicals is the USA's only manufacturer
of the chemical substance identified as Ultranox 626
The product is currently manufactured at one
site in the United States. The sole commercial use of
Ultranox 626 is as a stabilizer in polymer systems.
Borg-Warner Chemicals exports approximately 30% of the
Ultranox 626 it manufactures. The remaining 713% is
used domestically by large resin manufacturers that
compound the Ul tranox 626 into ma i nly olefin polymer s
at which point the potential environmental and human
exposure to Ultranox 626 is reduced to near zero.
Accordingly, human and environmental exposure can be
extremely well-defined as involving relatively few
users, each sophisticated enough to be well aware of
the potential for neurotoxicity of organophosphorus
compounds. ....
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"The number of Borg-Warner employees involved on a
daily basis in [the] manufacturing [of] ultranox 626 is
approximately fourteen. Ultranox 626 is an essentially
dust-free solid and is not readily absorbed through the
skin; employees handling ultranox 626 even without
proper protection would not be expected to absorb a
significant amount of the substance. The airborne
concentration of Ultranox 626 to which employees might
be exposed over an 8 hour period is less than 2 parts
per million (ppm) (w/w). In order to inhale a quantity
of Ultranox equivalent to 40 mg/kg body weight (the
dose at which a neurotoxic effect was observed in the
canine feeding study), an employee would need to be
exposed to an airborne Ultranox 626 concentration of
210 ppm (w/w) over a period of 8 hours. ["Based on
assumptions that a 70 kg worker inhales 10 cubic meters
of air over 8 hours and that all inhaled Ultranox 626
would be retained."] [Note: The submitted
Ultranox 626 Material Safety Data Sheet, recommends
that exposure to Ultranox 626 be limited to 10 mg/m3
air as an 8-hour time weighted average (TWA).]
"Plastic resins manufactured with Ultranox 626 are sold
to molders for fabrication into articles. Ultranox 626
is typically encapsulated in such articles at a level
of 300-500 ppm. The Food and Drug Administration (FDA),
having reviewed the [dog] toxicity study that is the
subject of this submission, has cleared Ultranox 626
for use in food-contact plastic materials at a level of
up to 1000 ppm in olefin polymers and at levels up to
8600 ppm in polyvinyl chloride copolymers. .... In
doing so, FDA confirmed that the use of Ultranox 626 in
food packaging materials not only poses no significant
risk, but that such use is safe. ...."
Comments/Recommendations
Although EPA acknowledges the actions taken by Borg-Warner to
notify customers and others, it is EPA's initial position that
the neurotoxicologic effects from the subchronic oral dog study
should have been reported to EPA previously under Section 8 (e) ,
the substantial risk information reporting provision of TSCA.
The following discussion provides the basis for EPA's position:
Section 8(e) states that "any person who manufactures,
[imports,] processes or distributes in commerce a chem-
ical substance or mixture and who obtains [(i.e., Knows
of or possesses)] information which reasonably supports
the conclusion that such substance or mixture presents
a substantial risk of injury to health or the environ-
ment shall immediately inform the [EPA] Administrator
of such information unless such person has actual
knowledge that the Administrator has been adequately
informed of such information."
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The preface to Part V of EPA's TSCA Section 8(e) policy
statement ("Statement of Interpretation and Enforcement
Policy; Notification of Substantial Risk" 43 FR 11110;
March 16, 1978) explains that a "substantial risk of
i nj ury to heal th . is a risk of cons iderable con-
cern because of (a) the seriousness of the effect. . .
and (b) the fact or probabi 1 i ty of the occurrence [of
that serious effect]." with regard to the seriousness
of the effect, Part V expla i ns that EPA cons iders the
types of health effects for which substantial risk
information must be reported to include "any pattern of
effects or evidence that the chemical substance can
produce. . toxic effects resulting in. . serious
or prolonged incapacitation." Information regarding
these types of ser ious effects can be obta i ned ei ther
directly or inferred from designed studies (e.g.,
studies in animals) as described in Part VI of the
Section 8 (e) policy statement. Part VI explains also
that a subject "person is not to delay reporting until
he obtains conclusive information that a substantial
risk exists, but is to immediately report any evidence
that reasonably supports that conclusion."
with regard to the "fact or probability of its [(i.e.,
the serious effect's)] occurrence" criterion, Part V of
the Section 8(e) policy statement explains that certain
types of adverse health effects (e.g., neurotoxicologic
effects) are considered by EPA to be so serious that
relati vely li ttle or no weight should be attached to
the impl icated chemical's exposure in determining
whether a risk is substantial.
The following discussion addresses Borg-Warner's rationale
(described previously; see Submission Description section of this
status report) as to why the subchronic oral dog study resul ts
were not submitted previously to EPA under Section 8(e) of TSCA:
Borg-Warner stated ,that the company sought and received
(by phone from EPA's TSCA Assistance Office (TAO»
guidance regarding the TSCA Section 8(e)-reportability
of information submitted to FDA. Although it is not
possible to determine precisely the questions asked by
Borg-Warner, the responses (if any) given by TAO in
this matter or to whom Borg-Warner spoke, it is clear
that EPA's TSCA Section 8(e) policy statement does not
authorize reporting to other Federal agencies as a way
to satisfy EPA's Section 8 (e) reporting requirements.
Part VII of the Section 8(e) policy statement explains
that information need not be reported to EPA pursuant
to Section 8 (e) if the information has been reported
already to EPA under another mandatory reporting pro-
vision of TSCA or some other authority administered by
EPA. Further, EPA has made it clear that Part VI I of
the Section 8(e) policy statement does not exempt from
229
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Page 10 of 12
Section 8 (e) reporting information submitted elsewhere
under an authority administered by an agency other than
EPA (see EPA's response to Comment 21 in Appendix B of
the TSCA Section 8(e) policy statement which explains
that until successful information exchange systems are
in place between EPA and other Federal agencies and the
policy statement is amended to exempt certain reports
made to other specified Federal agencies, "substantial
risk information must be reported directly to EPA.")
(emphasis added)
Borg-Warner contends that the data from the company's
subchronic oral dog study merely corroborate known
information. While the Agency agrees that much is
known about the neurotoxic properties of many organo-
phosphorus compounds, the neurotoxicologic findings
from Borg-Warner' s dog study appear to be first and
only neurotoxicologic findings to date for the subject
plastic resin stabilizer. Further, Borg-Warner' s
understanding that Section 8(e) reporting is triggered
upon receipt of new serious toxic effects information
obtained from an animal study involving a different
route of exposure is reflected in Borg-Warner's past
TSCA Section 8(e) reporting practices. For example, on
June 23, 1982, Borg-Warner submitted data on triphenyl
phosphite "in accordance with Section 8(e) of the Toxic
Substances Control Act" (Section 8(e) submission number
8EHQ-0682-045l et seq). In this previous Section 8 (e)
notice, Borg-Warner stated that triphenyl phosphite (an
organophosphite used primarily as a stabilizer in
plastics) had been found to produce neurotoxic effects
in chickens exposed to the chemical via the skin. In
submitting these neurotoxicologic findings to EPA under
Section 8(e) of TSCA, Borg-Warner reported that "it has
been known for many years and reported in the open
literature that triphenyl phosphite can produce neuro-
toxic effects in animals when taken orally." It should
be noted, however, that Borg-Warner did not state nor
imply that the company considered the submitted data on
triphenyl phosphite to be merely corroborative and not
subject to reporting to EPA under Section 8(e) of TSCA.
In fact, Borg-Warner's triphenyl phosphite submission
ends with the following statement: ". [Borg-Warner
trusts] that this information fulfills [the Agency's
TSCA Section 8(e)] reporting requirements."
With regard to Borg-Warner's contention that "there has
never been any significant exposure to Ultranox 626
and, hence, no significant risk to man or the environ-
ment," Part V of the Section 8 (e) policy statement
makes it clear that in the case of new serious toxic
effects information, little or no weight is to be given
to exposure in deciding whether to submit new toxicity
information to EPA under Section 8(e) of TSCA.
230
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Page 11 of 12
Based on the preceding discussion, it is EPA' s ini tial posi tion
that the neurotoxicologic findings from Borg-Warner's subchronic
oral study of Weston XR 1532 in dogs should have been submitted
previously under Section 8(e) of TSCA; the fact that Borg-Warner
provided this dog study to FDA for review and ultimate approval
of Ultranox 626 for use in certain food packaging materials did
not in any way relieve Borg-Warner of its obligation to report
the observed neurotoxicologic effects to EPA under Section 8 (e)
of TSCA.
a)
The Existing Chemical Assessment Division (ECAD/OTS)
will ask Borg-Warner to submit any further information
regarding Borg-Warner's rationale for not submitting
the neurotox icologic find i ngs from the subchron i c dog
study at an earlier date under Section 8 (e) of TSCA.
Borg-Warner will be asked also to submit full copies of
the final reports (including the actual experimental
protocols, results of gross and histopathological
examinations, results of any statistical analyses,
etc.) from all stud ies (other than the subchronic oral
study in Beagle dogs) that were cited in the submitted
Ultranox 624/626/626A Material Safety Data Sheet.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Borg-Warner will be
asked to describe the nature and results, if available,
of all studies (other than those submi tted already to
EPA, those cited in the open scientific literature, or
those cited in the provided ultranox 624/626/626A MSDS)
about which Borg-Warner is aware or that the company
has conducted, is conducting or plans to conduct to
determine the toxicity of bis(2,4-di-tert-butylphenyl)-
pentaerythritol diphosphite or products that contain
the subject chemical substance.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assi stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
References
Veronesi, B., padilla, S. and Newland, D.; Biochemical and
neuropathological assessment of triphenyl phosphite in rats.
Toxicol. Appl. Pharmacol. 83:203-210, 1986.
231
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Page 12 of 12
Veronesi, B. and Dvergsten, C.; Triphenyl phosphite neuropathy
differs from organophosphorus-induced delayed neuropathy in rats.
Neuropathology and Appl. Neurobiol. 13:193-208, 1987.
Reiter, L.W. and MacPhail, R.C.; Motor activity: A survey of
methods with potential use in toxicity testing. Neurobehav.
Toxicol. 1: Supple 1, 53-66, 1979.
NOTE: The reader's attention is directed to the following status report
prepared by EPA in response to 8EHQ-0488-0706 Followup Response.
232
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
..uN 2 4 1988 ~gi 1 of 3
Status Report* 8EHQ-0488-0706 FLWP Approvedi( /:~A
, /'
. ~ r,r- -- / JUN 24 /988
James F. Darr, SectIon Head V,U().rvv- /
Chemical Risk Identificatio Section/CS~3/ECADj
SUBJECT:
FROM:
TO:
Joseph J. Merenda, Director
Existing Chemical Assessment Division/OTS/OPTS
Note
The reader's attention is directed first to the "Status Report"
prepared by EPA following receipt of initial TSCA Section 8(e)
submission number 8EHQ-1287-0706.
Submission Description
In 8EHQ-0488-0706 Followup Response, Borg-vlarner Chemicals, Inc.
submitted final reports from 16 toxicological studies conducted
by or for Borg-Narner on a product containing bis(2,4-di-tert-
butylphenyl)pentaerythritol diphosphite (CAS No. 26741-53-7")as
the major component. This product, known at one tilne as h'eston
XR 1532, Weston XR 1452, Weston MDH-6140 or CDP-1106, is known
presently as Ultranox 626. The following studies were contained
in Borg-Warner's followup response:
o
90-day oral toxicity study (rats);
o
two acute oral toxicity studies (chickens);
o
two primary dermal irritation studies (rabbits);
o
hypersensitivity study (guinea pigs);
o
two Ames Salmonella typhi~urium mutagenicity studies;
o
acute inhalation LC50 study (rats); acute dermal irritation
toxicity study (rabbits); skin corrosivity study (rabbits);
o
acute oral delayed neurotoxicity study (chickens);
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
lnformatlon submltted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
233
.~A 1'0- U" f...V. 1-7.'
-------
~EHQ~0488-07U6 FLWP
Page 2 of 3
o
8-week bioaccumulation study (fish);
o
2-year
oral toxicity study (rats);
o
oral teratology study (rabbits);
o
6-~onth oral toxicity study (rats);
o
oral (feeding) reproduction study (rats);
o
a cut e 0 r a 1 to xi c i t Y stud Y (r a t s) .
In its followup response, ~org-Harner reiterated its rationale as
to ''ihy the neurotoxicological findings from the company's sub-
chronic oral toxicity study of Weston XR 1532 in Beagle dogs were
not submi t ted under Sect i on 8 (e) of TSCA. A discuss i on of thi s
subchronic study and Borg-Warner's rationale can be found in the
Submission Description and Comments/Recommendations sections of
the status report prepared for 82HQ-1287-0706 Initial.
Submission Evaluation
In general, the mammalian studies contained in Borg-\varner's
followup response do not suggest that the subject product caused
neu ro 1 og i ca 1 cha ng e s . In eva 1 u at i ng these mammal i an toxici ty
studies, however, the Agency has found that there are a number of
problems associated with the design/interpretation of many of the
subrni tted studies that can reduce the strength of the find i ngs
for assessing neurological effects. For example, some of the
studies 1) did not utilize a positive control, 2) did not include
any neuropathological examinations, and/or 3) did not contain a
clear description of the neurobehavioral examination/assessment.
These "negative" neurotoxicological findings do not in any way,
however, alter the fact that clear, serious neurotoxicological
effects were observed in Borg-Warner's subchronic oral toxicity
study of the subject product in Beagle dogs. EPA's evaluation of
the results of this subchronic oral study can be found in the
Submission Evaluation section of the status report prepared for
8EHQ-1287-0706 Initial.
Based on a preliminary evaluation of the studies presented in
Borg-Warner's followup response for toxic effects other than
neurotox ic effects, the tested product does not appear to cause
mutagenic, oncogenic or teratogenic effects; further, the product
does not appear to bioaccumulate. With regard to the results of
the reproduction study in rats (in which Weston XR 1452 was ad-
ministered via the feed), Borg-vlarner should be asked to supply
the raw data from this study to EPA in order for the Agency to
attempt to determine if the 20% reduction in fertility observed
in the high dose (500 ppm) group is cause for concern.
234
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SEHQ-04eS-0706 FLw~
Page 3 of 3
Current Production and Use
Ultranox 626 is used as a stabilizer in poly~er systems. Further
information relating to production/use of this chemical can be
found in the Cu r r en t Product i on and Use sect ion of the sta tus
report prepared by EPA in response to 8EHQ-l287-0706 Initial.
Comments/Recommendations
~lthouJh the results of the studies included in 8EHQ-0488-0706
Followup Response do not indicate any overt neurotoxicological
effects for Borg-Warner's product known now as Ultranox 626, this
does not alter the fact that serious neurotoxicological effects
were observed in Borg-Warner's subchronic oral toxicity study in
Beagle dogs. EPA has determined, therefore, that the serious
neurotoxicological effects from 30rg-Warner's subchronic oral
study in Beagle dogs should have been sub~itted in a timely
manner under Section 8(e) of TSCA. The basis for EPA's position
on the Section 8(e)-applicability/reportability of the subject
findings as well as EPA's comments on Borg-Warner's rationale can
be found in the Comments/Recommendations section of the status
report prepared for 8EHQ-l287-0706 Initial.
a)
T~1e Existing Chemical Assessment Division ~'Jill inform
Borg-Warner about EPA' s determination that the neuro-
toxicological findings from the company's subchronic
oral toxicity study in Beagle dogs should have been
submitted to EPA in a timely manner under Section 8(e)
of TSCI\.
Borg-Warner will be asked to submit co~plete copies of
the raw data frolfl the company's reproduction study of
Weston XR 1452 in rats.
b)
The Chemical Screening Branch will continue its review
of the reported information in order to determine the
need for further OTS assessment.
c)
'rhe Chemical Screening BranC:1 will transmi t copies of
this status report to ~nO.sH, OSHA, CPSC, FDA, NTP,
OSAER/EPA, OW/EPA, OAR/EPA, ORO/EPA, OPP/OPTS/EPA and
OCM/OPTS/EPA; copies of this status reJort will be sent
a 1 so to the TSCA Ass i stance Of f ice (TAO/OTS/OPTS/EPA)
for further distribution.
235
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 2
DA TE:
JAN - 5 1988
SUBJECT:
Status Report*
Aoproved: ~t4
(j
TNi lli aens ,~ect i on 8 (e) Coord i na tor
Screening Eranch/ECAojOTS
8EHQ-1287-0707 S
7~ //1~f
FROM:
David R.
Chemical
TO:
Ja~es F. Darr, Section Head
Chemical Risk Identification Section/CSB
Note
The submitting company has claimed its company na~e and the exact
identity of the subject che~ical to be TSCA Confidential Business
Information (CEI); the Information Management Division (IMDjOTS)
wi 11 be requesting the sub.ni tting company to substantiate these
TSCA CHI claims. In the "sanitized" version of this Section 8 (e)
submission, the company identified the subject chemical substance
nonconfic1entially as a "pyridinecarboxylate."
Submission Description
The submitting c01npany provided the following information with
regard to the con.'1uct and preliminary results of an ongoing 2-
week pilot feeding study of t~is pyridinecarboxylate in mice:
"In this study, mice \.vere administered diets containing
0, 21313, 1000, or 501313 ppm [pyridinecarboxylate] for 2
weeks prior to sacrifice. At necropsy, liver foci were
observed in one of three males and one of three females
at both 1003 and 50013 ppm. Microscopic evaluation of
these foci is not yet complete but liver foci are not
comlllonly observed in animals of this age. The only
other evidence of toxicity in this study are decreased
weight gain and discolored livers at 5131313 ppm."
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a complete copy
of the fi.nal report (including the actual experimental protocol,
results of gross and histopathologic examinations, etc.) from the
ongoiWJ stu<1y citeJ in the company's Section 8 (e) submission.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
infor~ation submitted to EPA pursuant to Section 8(e), the substantial
risk information re~orting orovision of the Toxic Substances Control
~ct (TSCA). The statements made in this report should not be regarded
as exoressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
236
E:"A FORM 1320-6 (REV. 3-76)
-------
8EHQ-1287-0707 S
Page 2 of 2
Current Production and Use
In view of the submitter's TSCA CBI claims, no information with
regard to TSCA Chemical Substance Inventory status of the subject
chemical will appear in this status report.
Comments/Recommendations
In its Section 8 (e) notice, the submitting company stated that,
when completed, a copy of the final report from the company's
ongoing 2-week feeding study of pyridinecarboxylate in mice will
be forwarded to EPA.
a)
The Chemical Screening Branch will ask the submitter to
ensure that EPA receives a complete copy of the final
r epor t (i nc 1 ud i ng the ac tua 1 exper imental protoco ls,
results of gross/histopathologic examinations, etc.)
from the 2-week feeding study cited in the company's
Section 8(e) notice.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity/exposure information, the submitting company
wi 11 be asked to descr ibe the act ions the company has
taken or plans to take 1) to notify workers and others
about the reported information, and 2) to reduce or
eliminate exposure to this pyridinecarboxylate. In
addition, the submitting company will be requested to
descr i be the nature and resul ts, if ava i lable, of all
studies (other than those reported already to EPA or
those cited in the published scientific literature)
about which the company is aware or that the company
has conducted, is conducting or plans to conduct to
determine the toxicity of or the exposure to this
pyridinecarboxylate.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chelnical substance.
c)
The Chemical Screeni ng Branch wi 11 transmi t cop ies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
237
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
0,\ TE:
JAN - 5 1988
Page 1 of 2
SUBJECT:
Status Report*
8EHQ-1287-0708 S
Aoproved: ~ ~'~
U
Coordinator
/ h/;?
FROM:
Oavid R. Williams~ction 8(e)
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI) i the Information Management Division (IMD/OTS)
will be requesting the submitting company to substantiate these
TSCA CSI claims. In the "sanitized" version of this Section 8(e)
notice, the company reported non-confidentially that the subject
chemical is an "acetophenone oxime."
Submission Description
The submitting co.npany provided the following information with
regard to the conduct and preliminary results of an ongoing
chronic oncogenicity study of this acetophenone oxime in mice:
"Preliminary data from the 12 month sacrifice of 10
animals/sex from the mouse oncogenicity study with
[acetophenone oxime revealed] an increase in liver
tumors in the high dose males. No such tumors were
observed in the fema les. The tumor incidence in the
males was:
[Acetophenone Oxime Dose Levels]
o 0.2 1 5 15 50/75*
hepatocellular adenoma 0 0 0 1 0 4
hepatocellular carcinoma 0 1 0 0 1 1
* animals dosed [(route of administration not specified)]
at 50 ppm for 6 months then changed to 75 ppm."
In providing these preliminary toxicologic findings to EPA under
Section 8 (e) of TSCA, the submitting company stated that the
"results are not surprising since liver tumors have been reported
in mice administered commercial chemicals of similar structure."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting Drovision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
238
E~A '0'"" "'" (~EV. ..711
-------
8EHQ-1287-0708 S
Page 2 of 2
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a full copy of
the final report (including the actual experimental protocol,
resul ts of gross and hi stopa tholog ical exami nat ions, results 0 f
statistical analyses, etc.) from the mouse oncogenicity study
cited in the submission. In the interim, the submitting company
should be asked to keep EPA apprised of any further significant
findings from the ongoing chronic study.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information with
regard to the TSCA Chemical Substance Inventory status of the
subject chemical will appear in this status report.
Comments/Recommendations
In its submission, the company reported that, when completed, a
copy of the final report of the company's mouse oncogenicity
study of acetophenone oxime would be sent to EPA.
a)
The Chemical Screening Branch will ask the submitter to
ensure that EPA rece i ves a complete copy of the f i na 1
report (including the actual experimental protocol,
resul ts of gross/h i stopa tho log ic exami nations, resul ts
of statistical analyses, etc.) from the oncogenicity
study cited in the company's Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity/exposure information, the submitting company
wi 11 be asked to descr ibe the acti ons the company has
taken or plans to take 1) to notify workers and others
about the reported information, and 2) to reduce or
eliminate exposure to this acetophenone oxime. The
submi tting company will be asked also to describe the
nature and results, if available, of all studies (other
than those reported already to the Agency or those
cited in the open scientific literature) about which
the company is aware or that the company has conducted,
is conducting or plans to conduct to determine the
toxicity of or the exposure to this acetophenone oxime.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemica 1 Screen i ng Branch will transmi t cop ies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPAi
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
239
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JAN I 8 1988
Page 1 of 3
SU8JECT:
status Report*
8EHQ-1287-0709 S
Approved: fI-' r!5:v.-
Coordinator
;/;~ I Iy!
David R. Williams,~ection 8(e)
FR~: Chemical Screening Branch/ECAD
TO: James F. Darr, Section Head
Chemical Risk Identification Section/CSB
Note
(See Note on Page 3 of this Status Report)
The submitting company has claimed its company name and the trade
names of the tested chemicals to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will be requesting the submitting company to substantiate these
CBI claims. The exact identities and CAS Registry Numbers of the
tested chemicals were not claimed to be TSCA CBI.
Submission Description
The submitting company provided the following summary information
with regard to the cooduct and preliminary findings of in vitro
Ames Salmonella typhimuriu:n (bacteria) mutagenicity assays con-
ducted with and without exogenous metabolic activ3tion:
TEST RESULTS [**]
TEST STRAIN:
TA 100
TA 1535
CHEMICAL NAME
ACTIVA.TION:
WITHOUT WITH
wITHOUT WI'rH
Oxirane, 2,2'-(3,7,7,11-tetramethyl-
2,5,9,12-tetraoxatridecane-l,13-
diyl)bis- (CAS No. 87257-05-4)
3.4
12.4
6.2
107.6
Poly(oxy-l,2-ethanediyl) ,«-hydro-
w-(oxiranylmethoxy)-, ether with
2-ethyl-2-(hydroxy:net~yl)-1,3-
propanediol (3:1) (CAS No. 52495-71-3)
3.6
12. 1
2.8
125.6
[**] Fold Over Background
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting orovision of the Toxic Substances Control
j,ct (TSCA). The statements -~ in this report should not be regarded
as expressing final EPA Dol icy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
240
E~" FO- II" IRE". 3-711
-------
8EHQ-1287-0709 S
Page 2 of 3
In providing this information to EPA under Section 8(e) of TSCA,
the company stated that while bacterial strains TA 98, TA 1537
and TA 1538 were negative, "the primary source of concern is the
somewhat unusual resul ts showing responses> 103 [fold over back-
ground] in one TA test strain [(TA 1535)] with activation." In
addition, the submitter reported that "many other closely related
substances are present in lesser quantities (due to the nature of
the reaction process) as well as impurities." The submitter
noted also that "because these products are made wi th epichloro-
hydrin, [the company does] not know if the results are
influenced by impurities." The submitter reported further that
although epichlorohydrin may be present in the products at a
concentration of approximately 0.5%, the company has "not been
able to determine what effect would be expected if there were 50
ug of epichlorohydr i n in a 10,000 ug product sample." The sub-
mitter also reported that analyses of the epichlorohydrin content
of the tested products are underway. Finally, the company stated
that the company plans" to pur i fy the samples and rerun them to
determine if impurities are having a significant effect. "
Submission Evaluation
The provided data indicate that the subject chemicals are potent
inducers of reverse mutations in prokaryotes under the conditions
employed in the performed Ames assays. An EPA evaluation of the
overall significance of the reported findings should be possible
upon EPA's receipt of full copies of the final reports (including
the actual exper imental protocols, data, resul ts of sta ti sti ca 1
analyses, etc.) from all studies (including analytical studies)
that were cited in the company's TSCA Section 8(e) notice.
Current production and Use
The subject chemicals are not listed in the computerized version
of the non-confidential initial (1977) TSCA Chemical Substance
Inventory. According to the submitter, these chemicals are
currently in research and development (R&O). The company did not
provide any information on the actual or intended use of the
subject chemicals, nor was such use information located in the
secondary literature sources consulted by EPA:
wi th regard to the potential for worker exposure to the tested
chemicals, the submitter stated that although "people handling
these products in . [the submitting company's] laboratories
and other laboratories have been using suitable precautionary
measures," the company is conducting a review of the current
handling practices. The submitting company also reported that
"in addition to the specific precautions advised, the presence of
epichlorohydrin, reported on [the Material Safety Data
Sheets (MSDSs)] and risk assessment as an impurity but possible
carcinogen, should prompt appropriate caution among those
handling the material[s]." Finally, the submitter stated that
"potential risk would be based on improper handling."
241
-------
8EH~1287-0709 S
Page 3 of 3
Comments/Recommendations
Although a positive in vitro genotoxicologic assay result, when
considered alone, maY-not be sufficient to reasonably support a
conclusion of substantial risk (as that term is defined in EPA's
TSCA Section 8 (e) policy document ("Statement of Interpretation
and Enforcement policy; Notification of Substantial Risk" 43 FR
11110; March 16,1978)), EPA believes that such results are of
value in assessing possible risks posed by exposure to chemical
subs tances or mi xtures. The Agency also bel i eves that pos i t i ve
genotoxicity findings, when considered in combination with other
pertinent information (e.g., knowledge of potential exposure to
and/or high production of the subject chemical or mixture), would
suggest the need, in many cases, to conduct further studies that
are designed to better define the toxicologic properties of or
exposure to the subject chemical(s). The results of such further
testing should be considered also for submission to EPA pursuant
to Section 8(e) of TSCA.
b)
c)
Note
a)
The Chemical Screening Branch will ask the submitting
company to ensure that EPA receives complete copies of
the final reports (including the actual experimental
protocols, data, results of statistical analyses, etc.)
from all studies (including analytical studies) cited
in the company's TSCA Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity/exposure data, the submitter will be asked to
descr ibe the nature and resul ts, if ava i lable, of all
stud i es (othe r than those reported already to EPA or
those published in the open scientific literature)
about which the company is aware or that the company
has conducted, is conducting or plans to conduct to
determine the toxici ty of or the exposure to the sub-
ject chemical substances.
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemicals.
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
RAB/ECAD/OTS/OPTS. In addi tion, copies of this status
report wi 11 be prov ided to the TSCA Ass i stance Off ice
(TAO/OTS/OPTS/EPA) for further distribution.
As the result of a letter to the Agency dated
May 13, 1988, the Henkel Corporation withdrew
its TSCA CBI claim for the company's name.
J~ F. DarJ:-
jft11i,,J-J r.t~~
~42
7/21/88
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
JAN - 7 1988
Page 1 of LI
SU8JECT,
status Report*
8EHQ-1287-07l0
Approved: ~A r ({;;,
d. (I
Coor Inator
, hI iFF
.
David R. Williams,~ection 8(e)
FR~: Chemical Screening Branch/ECAD
TO: James F. Darr, Section Head
Chemical Risk Identification Section/CSB
Submission Description
Texaco Inc. provided summarized information regarding the conduct
and preliminary results of an ongoing chronic mouse skin painting
study of hydrodesul fur i zed 1 ight vacuum gas oi 1 (CAS No. 64742-
87-6) and hydrodesulfurized heavy vacuum gas oil (CAS No. 64742-
86-5). It should be noted that in a previous Section 8(e) notice
(8EHQ-0887-0687 et seq.), Texaco provided preliminary results of
this same study, but only for the hydrodesulfurized heavy vacuum
gas oil; the reader's attention is directed to the status report
prepared for 8EHQ-{3887-0687. Texaco's current Section 8(e) sub-
mission provides an update of the company's previously reported
findings on hydrodesulfurized heavy vacuum gas oil and presents
new data on hydrodesulfurized light vacuum gas oil. According to
Texaco, the ongoing chronic study involves application of 50 ul
of the test materials twice per week to the shaved backs of mice
(50/group) with no attempt to remove the test materials from the
skin at any time during the study. The following table reflects
the interim findings as of approximately the 10th month of the
ongoing study:
Test Group No. of Animals Alive pappillomas Advanced Tumors
A 47 {3 {3
B 47 {3 0
,.... 0 4 46
'--
0 16 12 34
E 41 4 10
A: Negative Control (no treatment)
B: Negative Control (USP Mineral Oil)
C: positive Control (Benzo(a)pyrene 0.05%
0: Hydrodesulfurized Heavy Vacuum Gas Oil
E: Hydrodesulfurized Light Vacuum Gas Oil
50(v)% USP Mineral oil
in Acetone)
( nea t)
cut back with
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
243
EPA FORM 1320-1 (REV. ..71)
-------
8EHQ-1287-0710
Page 2 of 4
According to Texaco, the results obtained to date in the study
show that there is a significant increase in the incidence of
pap ill omas and advanced tumor s in mice exposed via the sk in to
benzo(a)pyrene (positive control), hydrodesulfurized light vacuum
gas oil and hydrodesulfurized heavy vacuum gas oil when compared
to either control group. In its previous Section 8(e) submission
(8EHQ-0887-0687), Texaco reported that the latency of onset of
tumorigenicity for the hydrodesulfurized heavy vacuum gas oil was
cons idered to be short (i. e., 6 months). In the present not ice,
Texaco stated that the latency period (i.e., 10 months) observed
for the hydrodesulfurized light vacuum gas oil as a 50/50 mixture
with USP mineral oil was considered by the company to be short as
well.
Submission Evaluation
The submitted information indicates that hydrodesulfurized light
and heavy vacuum gas oils possess oncogenic activity toward the
skin of mice. An EPA evaluation of the overall significance of
the reported findings should be possible upon EPA's receipt of a
complete copy of the final report from this chronic mouse skin
application study.
Current Production and Use
A review of the production range (includes importation volumes)
sta t i st ics for hydrodesul fur i zed 1 ight vacuum gas 0 i 1 (CAS No.
64742-87-6) and hydrodesul fur i zed heavy vacuum gas oi 1 (CAS No.
64742-86-5), which are listed in EPA.' s initial TSCA Chemical
Substance Inventory, showed that over 1 billion pounds and over 9
billion pounds, respectively, were reported as being manufactured
and/or imported in 1977. This production range information does
not include any information claimed as TSCA Confidential Business
Information (TSCA CBI) by the person(s) reporting for the initial
TSCA Inventory, nor does it include any information that would
compromise TSCA CBI. All information reported for the initial
TSCA Inventory, including the production range information, is
subject to the limitations that are contained in the initial TSCA
Inventory Reporting Regulations (40 CPR 710).
Appendix A of the printed TSCA Chemical Substance Inventory (1985
Edition) gives the following definition for the hydrodesulfurized
light vacuum gas oil (CAS No. 64742-87-6):
"A complex combi na t ion of hydrocarbons obta i ned from a
catalytic hydrodesulfurization process. It consists of
hydrocarbons having carbon numbers predominantly in the
range of Cl3 through C30 and boiling in the range of
approximately 2300C to 4500C (446op to 842op)."
Appendix A of the printed TSCA Chemical Substance Inventory (1985
Edition) gives the following definition for the hydrodesulfurized
heavy vacuum gas oil (CAS No. 64742-86-5):
244
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8EHQ-1287 -071 0
Page 3 of 4
"A complex combination of hydrocarbons obtained from a
catalytic hydrodesulfurization process. It consists of
hydrocarbons having carbon numbers predominantly in the
range of C20 through C50 and boiling in the range of
approximately 3500C to 6000C (6620F to lll20F). This
stream is likely to contain 5 wt. % or more of 4- to 6-
membered condensed ring aromatic hydrocarbons."
In the present TSCA Section 8(e) submission, Texaco reported that
hydrodesul fur i zed light vacuum gas oi 1 "i s a non- i sola ted, site
limited refinery process stream which is used as a feed to the
catalytic cracking unit."
In the prior TSCA Section 8 (e) notice (8EHQ-0887-0687), Texaco
reported that hydrodesulfurized heavy vacuum gas oil "is a non-
isolated, site limited refinery process stream which is used as a
feed to the catalytic cracking unit or is recycled in the H-oil
process."
In addition, Texaco stated in both section 8(e) submissions that
"twelve shift personnel operate the [catalytic cracking] unit;
howeve r, exposure is 1 imi ted si nce the un i t is a closed system
and closed sampling procedures are used. ...."
Comments/Recommendations
Texaco reiterated in the present Section 8(e) submission that the
reported toxicologic findings will be included in the company's
"hazard communication program and workers will be warned again of
the potential for adverse health effects from skin contact from
certain oils and refinery streams." In addition, Texaco stated
that the company wi 11 1) keep EPA appr ised as fur ther resu 1 t s
from the mouse skin painting study are received, and 2) send a
copy of the final report to EPA when that report is completed.
a)
The Chemical Screening Branch has already asked Texaco
to ensure that EPA recei ves a full copy of the f i na 1
report (including the actual experimental protocol,
results of gross and histopathologic examinations,
results of any statistical analyses, etc.) from the
company's chronic mouse dermal application study.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to chemical
toxicity or exposure information, Texaco will be asked
to describe the nature and results, if available, of
all studies (other than those reported already to EPA
or those cited in the published scientific literature)
about which Texaco is aware or that the company has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of the hydrodesulfurized light vacuum
gas oil; Texaco was requested previously to respond to
similar questions regarding the hydrodesulfurized heavy
vacuum gas oil.
245
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8EHQ-1287 -071 0
Page 4 of 4
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of these petroleum process streams.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
246
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JAN I I 1988
Page 1 of 3
SU8JECT: Status Report* 8EHQ-l287-07ll
IIROM: David R. Williams~ection 8 (e)
Chemical Screening Branch/ECAD
APproved:~f ~
Coordinator
,1//;1'
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
On behalf of the Amoco Chemical Company, the Amoco Corporation
submi tted the following summary information wi th regard to the
conduct and preliminary results of animal studies designed to
determine the respiratory sensitizing potential of pyromellitic
dianhydride (PMDAi CAS No. 89-32-7) and the cross-reactivity
between PMDA and trimellitic anhydride (TMAi CAS No. 552-30-7):
"Two groups of ten male rats each were exposed to five
exposures of 500 micrograms [(ug)] PMDA per cubic meter
of air over a seven day period. [Note: The length of
the five exposures was not given in the submission.]
Following a two week rest per i od, one group was chal-
lenged with a single six hour dose of 500 ug/m3 PMDA
and the other group challenged wi th a single si x hour
dose of 500 ug/m3 TMA. Animals were sacrificed and
necropsied on the day after the challenge doses. Based
on earlier work with TMA, an evaluation of lung effects
was performed by removing the lungs at necropsy and
counting (gross observation) the number of hemorrhagic
foci on the lungs.
"These studies 1ndicate that PMDA, under the conditions
employed, produced numbers of lung foci strongly indi-
cative of respiratory sensitization. It was also found
that a TMA challenge of rats exposed to PMDA produced
lung foci similar to those produced following PMDA
challenge.
". . . [Amoco interprets] these results to indicate that
PMDA, at this concentration, produces a sensitizing
effect in male rats. . [Amoco also has] evidence,
from this work, that male rats exposed to PMDA react to
TMA in a manner [that is] indicative of a sensitization
reaction."
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
247
E~" ..0.... ".. (!!lEV. 3-711
-------
8EHQ-1287-0711
Page 2 of 3
In addition to reporting the preliminary experimental findings to
EPA under Section 8(e), Amoco provided a copy of a PMDA Material
Safety Data Sheet (MSDS) and product label that had been updated
to reflect the results of the performed animal studies.
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of full copies of
the final reports from all studies cited in the submission.
Current production and Use
A review of the production range (includes importation volumes)
statistics for trimellitic anhydride (CAS No. 552-3~-7), which is
listed in the initial TSCA Chemical Substance Inventory. showed
that ~ to l~~~ pounds of this chemical substance were reported as
manufactured and/or imported in 1977. A review of the production
range (includes importation volumes) statistics for pyromelli tic
dianhydride (CAS No. 89-32-7), which is listed in the initial
TSCA Chemical Substance Inventory, showed that ~ to 3,~~~ pounds
of this chemical substance were reported as manufactured and/or
imported in 1977.
The above production range information does not include any
information claimed as TSCA Confidential Business Information
(TSCA CBI) by the person (s) reporting for the initial TSCA
Inventory, nor does it include any information that would
compromise TSCA CBI. All of the data reported for the ini tial
TSCA Inventory, including the production range data, are subject
to the limitations contained in EPA's initial TSCA Inventory
Reporting Regulations (4~ CFR 71~).
Accord i ng to the Condensed Chemical Dictionary (l~th Edi tion) ,
PMDA has the following applications: "curing agent for epoxy
resins used in high temperature laminates, molds, and coatings;
cross-linking agent for epoxy plasticizers in vinyls; alkyd
resins; intermediate for pyromellitic acid. This publication
also states that TMA has the following applications: "plasticizer
for polyvinyl chloride; alkyd coating resins; high temperature
plastics; wire insulation; gaskets; automotive upholstery."
Comments/Recommendations
In add i tion to updating the PMDA MSDS and product label, Amoco
reported that the company plans to conduct studies designed to
determine PMDA dose-effect relationships.
It should be noted that EPA's Office of Toxic Substances (OTS)
has received other Section 8 (e) and "For Your Information" (FYI)
notices on TMA. prompted by a 1978 NIOSH "Current Intelligence
Bulletin" describing severe respiratory problems in workers
exposed to TMA, OTS prepared (in 1978) a draft Chemical Hazard
Information Profile (CHIP) on TMA.
248
-------
8EHQ-1287-0711
Page 3 of 3
a)
The Chemical Screening Branch will request Amoco to
ensure that EPA receives complete copies of the final
reports (including the actual experimental protocols,
results of gross/histopathologic examinations, etc.)
from all studies cited in the company's Section 8(e)
submission on TMA and PMDA. In addition, Amoco will be
asked to keep EPA apprised of significant findings from
the planned studies designed to determine PMDA dose-
effect relationships.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of TMA and/or PMDA.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
249
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
..IAN 2 I 1988
DATE:
?age 1 of 2
SU8JECT: Status Report* ~~~g=%i~~=:~i~ SUPP Approved:_[),/AM'A r. ~ IP7/;,
David R. Williams~ction 8(e) Coordinator (J'
FR~: Chemical Screening Branch/ECAD
James F. Darr, Section Head
TO: Chemical Risk Identification Section/CSB
Submission Description
In its initial Section 8(e) submission, the Koppers Company; Inc.
provided the following information with regard to the conduct and
preliminary results of a guinea pig dermal sensitization study of
Sapstain Control Chemical NP-l:
"Observations from the [performing] laboratory indicate
that Sapstain Control Chemical NP-l induced a skin sen-
sitization response in guinea pigs following repeated
topical exposure to a 0.6% aqueous solution. Challenge
applications of 0.5% elicited a sensitization response
in one of 20 test animals. No control animals developed
a comparable response. Upon rechallenge, 10 of 20 test
animals developed an enhanced response. Skin reactions
observed at lower challenge concentrations, 0.25% and
0.125%, were suggestive of a dose-response relationship
for sensi tization but are not sufficient evidence for
the induction of sensitization at dose concentrations.
"Other observations reported by the laboratory were
signs of marked to severe skin irritation following
con tact wi th [the] sl ightly di 1 uted or undi 1 uted test
material.
"Koppers is aware of the results of animal testing for
sensitization conducted on the major components of this
product by the manufacturers of these components. In
each case, the testing was nega ti ve for the induction
of sensitization."
In its ini tial submission, Koppers stated also that the company
"has not received any reports of dermal sensitization from. . .
[Koppers] employees engaged in the manufacture of Sapstain
Control Chemical NP-l or from. [Koppers] customers who use
it or the alternate brandname product LH-25 [Preservative]."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
250
E~A FO"",, II" (REV. 1-711
-------
8EHQ-0188-0712 INIT
8EHQ-0188-0712 sUPP
Page 2 of 2
In its supplemental Section 8(e) notice (8EHQ-0l88-07l2 SUPP),
Koppers reported that because the subject products are pesticides
registered with EPA under the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA) with Koppers as the "registrant" (EPA
Registration No. 453-297), all of the information contained in
the company's initial Section 8(e) notice had been submitted on
the same date to EPA's Office of Pesticide Programs (OPP/OPTS)
under Section 6(a) (2), a mandatory reporting provision of FIFRA.
In the initial TSCA Section 8(e) notice, Koppers stated that "the
results of acute oral and dermal lethality studies and primary
eye and skin irritation studies on Sapstain Control Chemical NP-l
." were submitted to the Agency under FIFRA in July, 1984.
Submission Evaluation
EPA's Office of Pesticide Programs will be evaluating the overall
significance of the reported dermal sensitization findings for
this registered pesticide.
Comments/Recommendations
Koppers reported that it "has initiated a review of the current
NP-l/LH-25 product labels and material safety data sheets" and
"these documents will be amended accordingly to afford warnings
to . [Koppers] workers and customers who manufacture and use
these products." In addition, Koppers stated that "in light of
the negative reports of sensitization potential existing on the
ingredients of Sapstain Control Chemical NP-l and the absence of
repor ts 0 f sens i ti za tion in the wo rk force exposed to th i s pro-
duct, Koppers Company will pursue additional investigations
concerning [the recent guinea pig dermal sensitization
study findings for NP-l]." Finally, Koppers stated that the
final report from this recent sensitization study would be
forwarded to EPA in March, 1988.
It should be noted that the toxicologic information on Sapstain
Control Chemical NP-l did not have to be submitted to EPA under
Section 8 (e), the substantial risk information reporting pro-
vision of TSCA. According to Part VII of EPA's Section 8(e)
policy statement ("Statement of Interpretation and Enforcement
Policy; Notification of Substantial Risk" March 16, 1978; 43 FR
11110), information does not need to be reported under Section
8 (e) if the information "has been submitted in writing to EPA
pursuant to mandatory reporting requirements under TSCA or any
other authority administered by EPA (including the Federal
Insecticide, Fungicide and Rodenti.cide Act [(FIFRA)] "
a)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
251
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
JAN 2 9 1988
SUBJECT:
Status Report*
8EHQ-0188-0713
ADPrDved:~ I(~
Coordinator
d-~~
FROM: Davi~ R.
ChemIcal
Williams~ction 8(e)
Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Dow Chemical Company provided summary information regarding
the results of a 2-year mouse inhalation study of ethyl chloride
(CAS No. 75-00-3) conducted by the National Toxicology Program
(NTP). According to Dow, "this inhalation study has a single
dose level, namely 15,000 ppm, of ethyl chloride, and
adenocarcinomas of the uterus have been observed in the exposed
animals." In addition, Dow reported that to the best of the
company's knowledge, "this study is currently under review within
NTP and a draft report has not been issued [formally by NTP]."
Submission Evaluation
An evaluation of the significance of the reported findings should
be possible upon EPA's receipt of further information from NTP
regarding the conduct and results of this chronic bioassay. EPA
should ask NTP when it plans to issue the draft technical report
of this study for peer review by the Technical Report Peer Review
Subcommittee of NTP's Board of Scientific Counselors.
Current Production and Use
A review of the prod,uction range (includes importation volumes)
statistics for ethyl chloride (CAS No. 75-00-3), which is listed
in the initial TSCA Chemical Substance Inventory, has shown that
411 million to 1.76 billion pounds of this chemical substance
were reported as manufactured and/or imported in 1977. This
production range information does not include any information
claimed as TSCA Confidential Business Information (TSCA CBI) by
the person (s) report i ng for the in i t i al TSCA Inventory, nor does
it include any information that would compromise TSCA CBL .l\ll
data reported for the initial TSCA Inventory, including the pro-
duction range data, are subject to the limitations contained in
the initial TSCA Inventory Reporting Regulations (40 CPR 710).
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
infor~ation submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting ~rovision of the Toxic Substances Control
~ct (TSCA). The statements made in this report should not be regarded
as expressing final EPA oolicy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
252
EFt,. FORM U20-6 IREI/. ]-76)
-------
8EHQ-0188-0713
Page 2 of 3
The Condensed Chemical Dictionary (10th Edition), contains the
following information pertaining to the uses of ethyl chloride:
"manufacture of tetraethyl lead and ethylcellulose; anesthetic;
organic synthesis; alkylating agent; refrigeration; analytical
reagent; solvent for phosphorus, sulfur, fats, oils, resins and
waxes; insecticides."
Comments/Recommendations
It should be noted that Part VII of EPA I S Section 8 (e) policy
statement ("Statement of Interpretation and Enforcement Pol icy;
Notification of Substantial Risk" 43 FR 11110; March 16, 1978)
provides a number of exa"mples of the types of informati on tha t
need not be reported to EPA under section 8(e) of TSCA (i.e.,
information about which subject persons can automatically assume
the Agency to be "adequately informed"). In addition to the
examples cited in Part VII, subject persons can automatically
assume, for the purposes of TSCA Section 8(e) reporting, that EPA
has been adequately informed about substantial risk information
contained in a formal publication or report released to the
general public by an agency of the u.S. Government. It should be
noted also that EPA's position on the Section 8(e)-reportability
of results of NTP bioassays has been described previously (see
EPA's "status report" prepared in response to TSCA Section 8(e)
submission number 8EHQ-1282-0467). In summary, EPA's position on
Section 8(e) as it relates to the results of NTP bioassays is as
follows:
A subject person can assume automatically that EPA has
been "adequately informed" about the results of an NTP
carcinogenesis bioassay once the NTP formally releases
copies of the draft technical report from that study
for peer review by the Technical Report Peer Review
Subcommittee of NTP's Board of Scientific Counselors.
This assumption can be made because EPA's Office of
Toxic Substances (OTS) routinely receives full copies
of all draft NTP carcinogenesis bioassay technical
reports formally released by NTP for peer review.
Therefore, if a subject company obtains (i.e., knows of
or possesses) toxicologic information concerning an NTP
bioassay and there has not been a formal public release
of those findings by NTP (e.g., formal release of the
draft technical report for peer review), the subject
company should immediately consider the need to report
the information to EPA under Section 8(e) of TSCA.
It should be noted that EPA has correctly received a number of
TSCA Section 8(e) submissions (usually comprised of 1 to 2 pages)
filed by companies that obtained toxicologic data from studies
conducted by or for agencies of the U.S. Government that have not
been published or released formally to the general public. In
each of these cases, OTS has immediately initiated appropriate
followup activities directly with the other Federal agency in
253
-------
8EHQ-0188-0713
Page 3 of 3
order to minimize and, in most cases, eliminate further TSCA
Section 8 (e) reporting obligations on the part of the submitting
company to provide such i terns as complete copies of supporting
data or actual technical reports.
It is important to note that ethyl chloride was listed in a TSCA
Section 8(d) health and safety data reporting rule (May 1, 1987;
52 FR 16022).
a)
The Chemical Screening Branch will contact NTP in order
to obtain further information regarding the conduct and
results of NTP's 2-year inhalation bioassay of ethyl
chloride in mice. In addition, the Chemical Screening
Branch will ask NTP when NTP plans to issue the draft
technical report from this study for peer review by the
Technical Report Peer Review Subcommittee of NTP's
Board of Scientific Counselors.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Dow will be asked to
describe the actions the company has taken or plans to
take 1) to notify workers and others about the reported
information, and 2) to reduce or eliminate exposure to
ethyl chloride.
b)
The Chemical Screening Branch will review the reported
and other available information on ethyl chloride in
order to determine the need for further OTS assessment
of the subject chemical substance.
c)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
254
-------
UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
SUBJECT:
Status Report*
8EHQ-0188-0714
Page 1 of 4
~f'~.e/-tV~~'~
Approved: James F. Darr
f'dAd ~ ~W
DATE:
MAA - I 1988
FROM:
David R. williams~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Eastman Kodak Company provided the following information with
regard to the conduct and results of a 4-week oral toxicity study
of 2-bromo-3-methylbutanoic acid (CAS No. 565-74-2) in rats:
"Groups of 5 male and 5 female rats were given daily
gavage doses of 80, 250, or 800 mg/kg of the test
compound dissolved in corn oi 1 for five days per week
over four weeks; a total of 22 doses were administered.
The high dose proved lethal to 2/10 animals. All males
in the 800 mg/kg dose group exhibited varying degrees
of motor impairment after one or more doses during the
first week of exposure. Abnormal clinical observations
in affected males included weakness in the hindlimbs,
decreased extension of the joints in the hindlimbs, and
weakness in the tail. In addition, a hypotonic gait
and waddling were observed. Spinal reflexes, super-
ficial pain pathways, and bowel and bladder functions
appeared to be unaffected. with continued dosing, the
affected males showed some recovery from the motor
impairment. Only very slight deficits were evident at
the end of the study. No motor impairment was observed
in females at any dose or in males at the two lower
doses.
"preliminary microscopic examination of nervous system
tissue from the high-dose males showed degeneration of
the cerebellar granule cells, symmetrical foci of
malacia or softening in the thalamus, and axonal
degeneration in the dorsolateral and ventral or
ventromedial funiculi."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
255
E.-A ..OMl II'" CI'EV. 1-711
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8EHQ-0188-0714
Page 2 of 4
Eastman Kodak also submi tted the final resul ts of a battery of
previously conducted acute animal toxicity studies of the subject
chemical. A provided internal corporate memorandum presents the
following information regarding the conduct and results of these
acute studies:
"The approximate acute oral L05e values for the rats
were 884 mg/kg for males (95% Confidence Interval
(C. I.) 669-1169 mg/kg) and 769 mg/kg for females (95%
C.I. 583-11315 mg/kg). [Being a solid, the test article
was liquified by warming to approximately 420C prior to
dosing.] Following oral gavage, the material was a
severe gastric irritant causing necrosis of the stomach
wall and damage to adj acent organs by leakage through
the gastric wall. Based on the dose level required to
produce toxicity, the material should be considered a
slight to moderate toxicant by the oral route. The
only apparent organ toxicity was to the stomach
following direct contact with the test article.
"Similarly, when the test article was placed in contact
with the skin of rats at doses of 13.5, 1, 2, and 213
ml/kg, it caused significant necrosis of the skin and
eschar formation. The test article is a solid, there-
fore prior to application to the skin, it was liquified
by warming to 413oC. It was held against the skin for
24 hours under an occlusive wrap. Doses of 2 or 213
ml/kg were lethal to rats while doses of 13.5 or 1 ml/kg
were not. A single male [rat] given a dose of 1 ml/kg
developed weakness, prostration, dehydration, and a
roughened hair coat, but gained a small amount of body
weight and survived the two week observation period.
In spite of skin necrosis at the application site,
clinical ~igns potentially due to percutaneous absorp-
tion of the test article were not observed in the
remaining rats (13.5 ml/kg and 1 ml/kg) and all rats
gained weight during the observation period. The
approximate dermal L0513 values were 1.41 ml/kg (95%
C.I. 1.137-1.87 ml/kg) for both males and females.
"To evaluate the irritant potency of the test article,
13.5 ml of the test article was placed against the skin
of gu i nea pig s and held in place for 24 hours by an
occlusive wrap. The test article was liquified by
warming prior to application. The exposure resulted in
necros i sand eros ion at the appl ication site after 24
hours and therefore the guinea pigs were euthanatized
for humane reasons without further observation.
"The test article was also tested for the potential to
produce skin sensitization or a skin hypersensitivity
reaction. Ten guinea pigs were induced wi th the test
article in complete Freund's adjuvant and an equal
number of animals received just the adjuvant. When the
256
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8EHQ-0188-0714
Page 3 of 4
animals were rechallenged two weeks later by dermal
application of the test article, 7 of the 10 animals
induced with the test article had a slight dermal
irritation reaction. Although the irritation response
did not meet the criteria for categorization as a posi-
tive response, the presence of slight erythema in a
majority of the induced animals indicates the test
material may have a slight potential to cause human
skin sensitization."
According to Eastman Kodak, 2-bromo-3-methylbutanoic acid exists
with two different purities (i.e., approximately 95% pure and
greater than 99% pure). Eastman Kodak stated that the lower
grade product was the one tested, and, in the absence of data on
the higher grade, the company assumes that the high grade has the
same toxicologic properties as the low grade. Eastman Kodak
stated also that both grades are considered to be "strong skin,
eye, and respiratory tract irritants." Eastman Kodak reported
further that both grades of the chemical are handled and labelled
in the same manner. Finally, Eastman Kodak stated that it is
"not aware of any adverse health effects associated with the
manufacture or use of these materials."
Submission Evaluation
An EPA eva 1 ua t i on 0 f the overall signi f icance {)f the reported
neurotoxicologic findings should be possible upon EPA' s receipt
of a complete copy of the final report of Eastman Kodak's 4-week
oral toxicity study of 2-bromo~3-methylbutanoic acid in rats.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for 2-bromo-3-methylbutanoic acid (CAS No. 565-74-2),
which is listed in the initial TSCA Chemical Substance Inventory,
shows that 0 to 1000 pounds of this chemical were reported as
manufactured and/or imported in 1977. This production range
information does not include any information claimed as TSCA
Confidential Business Information (TSCA CBI) by the person(s)
reporting for the initial TSCA Inventory, nor does it include any
i nforma t i on tha t would compromi se TSCA CBI. All of the data
reported for the initial TSCA Inventory, including the production
range data, are subject to the limitations that are contained in
the initial TSCA Inventory Reporting Regulations (40 CFR 710).
According to Eastman Kodak, the lower grade of 2-bromo-3-methyl-
butanoic acid "is produced in larger volume than the pure form,
and is used as a site-limited intermediate; none of it appears in
the final product." In addition, Eastman Kodak stated that "a
small quantity of the more pure form is sold as a reagent for
laboratory use." Eastman Kodak stated further that "potential
employee exposure during manufacturing has been minimized by the
use of company-supplied protective clothing, gloves, and
appropriate NIOSH-approved respirators."
257
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8EHQ-0188-0714
Page 4 of 4
Comments/Recommendations
In its Section 8 (e) notice, Eastman Kodak provided a copy of a
Material Safety Data Sheet (MSDS) that has been revised to
reflect the reported neurotoxicologic findings. In addition,
Eastman Kodak stated that the 2-bromo-3-methylbutanoic acid
product labels would be revised also to reflect the reported
findings. Finally, Eastman Kodak stated that the company is
"currently evaluating the need for further testing."
a)
The Chemical Screening Branch will ask Eastman Kodak to
ensure that EPA receives a complete copy of the final
report (including the actual experimental protocol,
results of gross/histopathologic examinations, results
of statistical analyses, etc.) from the 4-week oral
toxicity study cited in the company's submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Eastman Kodak will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which Eastman Kodak is aware or that the company
has conducted, is conducting or plans to conduct to
determine the toxici ty of or the exposure to the sub-
ject chemical substance.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of 2-bromo-3-methylbutanoic acid.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
258
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
FEB 2 5 1988
Page 1 of 5
SUBJECT:
Status Report*
8EHQ-0288-07l5
Approved: ~ r~ 3/J~
V
FROM' David R. Williams~:'ection 8 (e) Coordinator
, Chemical Screening Branch/ECAD
TO: James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The CIBA-GEIGY Corporation provided final reports from a battery
of in vitro genotoxicity assays of 2,2,6,6-tetramethylol cyclo-
hexanol polyglycidyl ether (TK-10854). According to CIBA-GEIGY,
positive results were obtained in an Ames Salmonella typhimuriu~
(bacteria) mutagenicity assay, a point mutation assay in cultured
V79 Chinese hamster cells and a chromosomal aberration assay in
cultured human lymphocytes; negative results were reportedly
obtained in Unscheduled DNA Synthesis (UDS) assays in cultured
rat hepatocytes and cultured human fibroblasts.
Submission Evaluation
The subject chemical (TK-113854) was evaluated in the Ames assay
in four Salmonella typhimuriu:n tester strains (TA1535, TA1537,
TA98 and TAl(30) using the standard plate incorporation assay
protocol. [The] tests were conducted wi th or wi thout exogenous
metabolic activation (S9 mix derived from livers of Aroclor 1254-
induced rats). At least 5 different concentrations of TK-113854
rang i ng from 213 to 5131313 ug/pla te were tested. The assay i tsel f
was conducted wi th ai;l acceptable protoco 1 and both the pos i t i ve
and negative controls responded appropriately during the study.
Using this procedure, TK-113854 was found to produce reproducible
dose-related responses in tester strains TA1535 and TA1013 in the
presence of the S9 mix. For example, in tester strain TA1535, a
doubli ng of the number of background revertants was observed at
78 ug/plate and a 26-fold increase in background revertants was
found at the highest concentration tested (i.e., 5131313 ug/plate).
Although a slight increase (i.e., lo6-fold increase over back-
ground) in the number of revertant colonies occurred in TA1535 at
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
259
EPA FO,", U20-. (REV. 5-711
-------
8EHQ-0288-0715
Page 2 of 5
5000 ug/plate in the absence of exogenous metabolic activation,
this result was neither reproducible nor dose-related, and thus,
is not cons idered to be bi olog ically signi f i cant. Based on the
resul ts of thi s bacter ial mutagen ic i ty study, TK-10854 produce s
primarily base-pair substitution mutations; the incorporation of
liver activation appears to be required in order for TK-10854 to
exert its mutagenic properties in this assay.
with regard to the gene mutation assay of TK-10854 in cultured
V79 Chinese hamster cells, the procedures used to maintain the
cultures for mutagenicity and the conditions for mutant selection
are reasonably consistent wi th those presented in the published
literature on this assay. However, there are departures in the
cytotoxicity test, the conditions and sample size for mutant
detec:tion, and, of the greatest significance, in the use of a
"de f a u 1 t " spon ta neou s m u ta n t frequency. I n the cytotox ic i ty
test, only 200 cells were exposed while lX106 cells were exposed
in the mutagenicity test. The recommended procedure is to
conduct the cytotoxicity test at the same cell density that is
used in the mutagenicity test. The procedure used in this assay
could result in the selection of concentrations that do not span
the full range of toxicity (i.e., low cell density results in
high test substance concentration on a per cell basis). In view
of the fact that the results of the toxicity determination on the
,11utagenicity portion were not reported, it is not possible to
verify that toxicity was or was not a function of cell density.
For mutant selection, 4 dishes at 2.5X106 cells/dish were incu-
bated with either thioguanine (TG) or azaguanine (AG); the AG
cells were supplemented with AG on the third day and split and
fresh AG was added on the fourth day. Although this is generally
a common procedure, it is usually recommended that 10' and 30
dishes be used for select ion wi th TG and AG, respect i vely. The
effect of this small sample size is apparent in the control data
presented in the submitted final report. In the total of 16
dishes (4 each for TG and AG with and without exogenous metabolic
activatio'1), there were only 3 inutant colonies observed, for an
average of 1 colony per five dishes. Assuming 100% cloning
efficiency, this is an observed mutant frequency of 0.75X10-6.
In the submitted report, however, the investigators state that
the limit of sensitivity of the test (4 dishes per group) is
4X10-6 and the investigators use this value as a default value
for any experimental frequency below this value. Because the
investigators' decision analysis is based on a fold increase over
controls, the effect of this procedure is that the factors shown
in Table 2 through Table 5 of the submitted final report are 4
times too low. A recalculation of the ratio of treated versus
~ontrol mutant frequency using the observed frequency value cited
above results in a conclusion that the conditions for a positive
r2sult (as defined in the protocol) are fulfilled in all cases
except for the group selected with AG without activation. This
is in conflict with the single case (TG without activation) cited
in the submitted report. It should be noted that even after
making a correction for actual spontaneous mutant frequency, the
magnitude of the response with treatment with TK-10854 is not
260
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8EHQ-0288-071S
Pag e 3 of 5
striking. Although the data relating to cloning efficiency were
not included in the report, EPA assumes that cloning efficiency
can be calculated because a "corrected" mutant count is provided
in the report. Overall, while the study as conducted is not
adequate to accurately characterize the potential of TK-10854 to
induce gene mutations in cultured V79 cells, the submitted data
do suggest that TK-10854 is capable of inducing gene mutations in
the assay. The deficiencies of small sample size and use of a
default spontaneous mutant frequency preclude a more definitive
conclu~ion regarding the results of this particular assay.
TK-10854 was also assayed for its ability to induce chromosomal
aberrations in cultured human peripheral blood lYillphocytes. The
cultures were treated both with and without exogenous metabolic
activation. Dose-related increases were observed for a variety
of aberration types including breaks, exchanges and fragments.
The submitted final report states that TK-10854 is clastogenic;
positive responses seen in cultures in the absence of metabolic
activation suggest that the liver microsomes may be involved in
detoxification of the parent compound. Basically, the assay was
performed well; the assay was preceded by a cytotoxicity study
and the highest doses tested were those that reduced the mitotic
index by 50%. The cytostatic studies confirm the observation of
increased toxicity in the absence of metabolic activation.
Although there are two criticisms of this particular assay,
neither criticism changes the overall conclusions. First, cells
were treated with TK-10854 48 hours after the commencement of the
culture period. At the 48 hour time point, the majority of the
dividing cells are in first division and this represents an
appropriate time for chemical treatment. Following the cessation
of chemical treatment, the cells were cultured for an additional
43.5 hours; in the absence of mitotic delay, this would represent
an additional 4 to 5 cell cycles. This protracted culture period
could lead to an underestimation of the clastogenic effects of
the tested chemical because most chromosomal aberrations are
cytotoxic and many of the damaged cells would be lost after 1 to
2 cell cycles. Thus, if a shorter post-exposure culture period
had been used, higher clastogenic responses may have been seen
and TK-10854 doses that were judged to be negative may have been
found to yield positive results. The second criticism relates to
the classification of certain aberrations as "minutes" or "double
minutes." It is not clear to EPA how these were distinguished
from chromatid and isochromatid fragments, respectively. Again,
neither of EPA's criticisms alter the qualitative evaluation that
TK-10854 is clastogenic in cultured human lymphocytes inducing a
variety of aberrations including breaks, fragments and exchanges.
Although TK-10854 was found to be inactive in the Unscheduled DNA
Synthesis (UDS) assays using cultured rat hepatocytes and human
fibroblasts, the study protocols may have been inadequate. In the
rat hepatocyte study, cells were exposed for 5 hours to TK-10854;
published recommendations (Mutation Research 123: 363-410; 1983)
suggest that for those UDS assays conducted with hepatocytes, the
exposure time should encompass 18 hours. In the human fibroblast
261
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8EHQ-0288-071S
Page 4 of 5
study, the cells were exposed to TK-10854 for 5 hours only in the
absence of exogenous metabo 1 ic act i va t ion; the ref ore, the st udy
is cons idered to be incomplete because it would fai 1 to detect
chemicals requiring metabolic activation to exert their activity.
Current production and Use
According to CIBA-G~IGY, the subject chemical "is a research and
development [(R&D)] material intended primarily for weatherable
liquid coatings." CIBA-GEIGY reported also that "only small
quantities have been distributed to a few potential customers."
In addition, CIBA-GEIGY reported that "once the product is used
in its intended application, it becomes a highly cross-linked,
high molecular weight, insoluble and inert material." CIBA-GEIGY
reported further that worker exposure "should be minimal or nil"
when the product is used by customers according to the following
handling warnings/recommendations given in the product Material
Safety Data Sheet (MSDS):
"Wear impervious gloves. Wear splash-proof chemical
goggles. Use NIOSH approved organi c vapor ca r t ridge
respirator 'I'lhen vapor/mist exposure is likely. Wear
appropriate protective equipment to avoid personal
contact and exposure. Avoid breathing vapor, mist or
spray. Wash thoroughly after handling."
Finally, CIBA-GEIGY reported that
to the product."
"there is no consumer exposure
Comments/Recommendations
CIBA-GEIGY reported that the company is 1) revising the MSDS to
reflect the reported positive and negative genotoxicity findings,
and 2) notifying in writing all customers who received samples of
this R&D material about the reported findings.
Although a positive in vitro genotoxicologic assay result, when
considered alone, maY-not be sufficient to reasonably support a
conclusion of substantial risk (as that term is defined in EPA's
TSCA Section 8 (e) policy document ("Statement of Interpretation
and Enforcement Policy; Notification of Substantial Risk" 43 FR
111113; March 16, 1978)), EPA believes that such results are of
value in assessing possible risks posed by exposure to chemical
substances or mixtures. The Agency also believes that posi tive
genotoxicity findings, when considered in combination with other
pertinent information (e.g., knowledge of potential exposure to
and/or high production of the subject chemical or mixture), would
suggest the need, in many cases, to conduct further studies that
are designed to better define the toxicologic properties of or
exposure to the subject chemical(s). The results of such further
testing should be considered also for submission to EPA pursuant
to Section 8(e) of TSCA.
262
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8EHQ-0288-0715
Page 5 of 5
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, CIBA-GEIGY will be
asked to describe the nature and results, if available,
of all stud i e s (other than those reported already to
EPA or those cited in the open scientific literature)
about which CIBA-GEIGY is aware or that CIBA-GEIGY has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of the subject chemical substance.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i s ta nce Off i ce (TAO/OTS/Op'rS/EPA) for
further distribution.
263
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
FEB I 6 1988
Page 1 of 2
SUBJECT:
Status Report' 8EHQ-0288-0716 S ADPrDved:~ r.~ ;;/'1f
-------
8EHQ-0288-0716 S
Page 2 of 2
Submission Evaluation
In its submission, the company reported that the final r2port of
this pilot rat teratology study would be provided to the Agency
when the report is completed. Upon EPA' s receipt of that final
report, EPA will evaluate the findings of this study as well as
those presented in the final pilot teratology study report which
is the subject of TSCA Section 8(e) submission 8EHQ-0288-0717 S.
The reader's att"?ntion is directed to the status reports that
have been prepared by EPA in response to 8EHQ-0288-0717 Sand
8EHQ-1287-0707 S.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information with
regard to the TSCA Chemical Substance In ven to ry s ta t us 0 f the
subject pyridinecarboxylate will appear in this status report.
In its submission, the company did report non-confidentially that
this pyridinecarboxylate "is currently manufactured and used for
[research and development (R&D)] purposes only."
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submitter to
ensure that the Agency receives a co~plete copy of the
final report (including the actual experimental proto-
col, results of gross/histopathological examinations,
results of statistical analyses, etc.) from the pilot
teratology study cited in this submission.
In view of EPA's general interest in corporate actions
that are taken on a voluntary basis in response to new-
found chemical toxicity or exposure information, the
submi tt ing company wi 11 be requested to de sc r i be the
ac t ion s the company has taken or plans to take 1) to
notify workers and others about the reported findings,
and 2) to reduce or el iminate exposure to the subject
pyridinecarboxylate. The submi tter wi 11 be requested
also to descr i be the nature and resul ts, if ava i lable,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which the company is aware or that the company
has conducted, is conducting or plans to conduct to
determine the toxicity of this pyridinecarboxylate.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPAi
copies of this status report will be sent to the TSCA
Assistance Office (TAO/OTS) for further distribution.
265
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 2
DATE:
FEB I 6 1988
SUBJECT:
Status Report*
8EHQ-0288-0717
1 «~
S Aoproved: (~;I
(/
Coordinator
;;./t 1IFr
FROM:
David R.
'2hemical
Williams,~ection 8(e)
Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The submitting cOTIpany has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will be requesting the submitter to substantiate these TSCA CSI
claims. Tn the "sanitized" version of this Section 8 (e) notice,
the submitting company identified the tested chemical substance
non-confidentially as a "pyridinecarboxy1ate." It should be
note" that Section 8 (e) submission numbers 8EHQ-1287-0707 Sand
8EHQ-0288-0716 S each contain information on a chemical substance
identified non-confidentially as a pyridinecarboxylate.
Submission Description
In this TSCA Section 8(e) notice, the company provided the final
report of a pilot teratology study of a pyridinecarboxylate in
rats. The submitter's cover letter presented the following
inEormation regarding the conduct and results of this study:
"In this [pilot] study, the subject pyridinecarboxylate
compound was administered by gavage to groups of six
mated female ra,ts during gestation days 6 through 15.
Dose levels [administered] were 0, 1013, 3013, 600, 101.30
and 2000 mg/kg/day. ~ll females in the 600 mg/kg group
and above died during the study. Maternal toxicity,
including the deaths of two dams, also occurred at 300
mg/kg; there were no 1i ve irnplants in [the] surv i v ing
females. At 100 mg/kg/day, clear maternal toxicity was
not observed. There were no external fetal abnormali-
ties at the 100 mg/kg/day dose, but the mean body
weight of fet"nale pups was significantly reduced. This
body we ight decrease is cons idered to be a border line
reproductive effect."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
266
EPA FORM UZO-I (REV. 3-711
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8EHQ-0288-0717 S
Page 2 of 2
Submission Evaluation
An EPA evaluation of the reported findings will take place upon
EPA's receipt of the final report of the pilot rat teratology
study which was the subject of TSCA Section 8(e) submission 8EHQ-
0288-0716 S. The submitter of this previous Section 8(e) notice
stated that a copy of that pilot teratology study report would be
provided to EPA when the report is completed. Upon EPA's receipt
of that final report, the findings of both pilot teratology
studies will be evaluated. The reader's attention is directed to
the status reports that have been prepared by EPA in response to
8EHQ-0288-0716 Sand 8EHQ-1287-0707 S.
Current Production and Use
In view of the submitter's TSCA CSI claims, no information with
regard to the TSCA Chemical Substance Inventory status of the
'subject pyridinecarboxylate will appear in this status report.
10 its submi ss i on, the company reported non-conf identi a lly tha t
this pyridinecarboxylate "is currently manufactured and used for
[research and development (R&D)] purposes only."
Comments/Recommendations
a)
In view of EPA's general interest in corporate actions
that are taken on a voluntary basis io response to new-
found chemical toxicity/exposure data, the submitter
wi 11 be asked to descr i be the act ions the company has
taken or plans to take 1) to notify workers and others
about the reported findings, and 2) to reduce or
eliminate exposure to the subject pyridinecarboxylate.
The submi t ti ng company wi 11 be asked also to descr i be
the nature and results, if available, of all studies
(other than those reported already to EPA or those
cited in the open scientific literature) about which
the company is aware or that the company has conducted,
is conducting or plans to conduct to determine the
toxicity of this pyridinecarboxylate.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this pyridinecarboxylate.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA;
copies of this status report will be transrnittej also
to the TSCA Assistance Office (TAO/OTS) for further
distribution.
267
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
FEB 2 5 1988
Page 1 of 3
O"'TE:
Status Report*
8EHQ-0'288-0718
APproved)'~ ~~ "?///;~
V
SUBJECT:
FROM:
David R.
Chemical
Williams~ection 8(e)
Screening Branch/ECAD
Coordinator
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Dow Corning Corporation provided the final results from a
recently conducted chronic Daphnia magna reproductive limit test
of a mixture of polyethylene glycol sorbitan monolaurate (CAS No.
90'135-64-5) and octamethylcyclotetrasiloxane (CAS No. 556-67-2).
The "ABSTRACT" section of the submitted final report presents the
following information regarding the conduct/results of the study:
"This test was conducted to determine whether octa-
methylcyclotetrasiloxane (OMCTS) elicits any adverse
response in Daphnia magna in the presence of an organic
solvent, polyethylene glycol sorbitan monolaurate
(PGSM), to prevent coalescence of the OMCTS. The test
vessels were glass jars with Teflon-lined caps to
reduce the loss of the volatile OMCTS. The test
organisms were transferred to fresh solutions on a
daily basis and once on the weekend.
"Survival of the Daphnia magna during the first 48
hours of the test was excellent. However, survival of
both test concentrations and the surfactant control
deteriorated through the course of the study. Due to
the differential survival between unamended controls
and the surfactant controls, this test does not con-
clusively demonstrate an adverse effect of OMCTS in the
absence of the surfactant.
"The following [test] results were determined to be
statistically significant. Day 7 survival of the
daphnia exposed to 10 ppm PGSM/1130 ppb OMCTS was sig-
nificantly less than either control group. Survival of
the daphnia exposed to 10 ppm PGSM/l13 ppb OMCTS was
reduced relative to controls by day 14. By the end of
the test, the mortality rate in the surfactant control
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting orovision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as exoressing final EPA oolicy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
268
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was significantly greater than that of [the] unamended
controls and mortalities in vessels exposed to either
level of OMCTS with PGSM were more than either control.
Since the mortalities [observed] in the surfactant con-
trol occurred so late in the study, the survival rate
as measured by total days survival was not significant-
ly different between the controls. However, both levels
of OMCTS with PGSM reduced survival by this measure.
IIReproduction, as measured by total number of young
produced, was reduced from both controls at 10 ppm
PGSM/100 ppb OMCTS. However, at 10 ppm PGSM/10 ppb
OMCTS, there was not a significant reduction in young
compared to surfactant controls.
IIStatistical analysis of the reproduction data was also
done to reduce the impact of premature death on total
young by examining total young/total days survival.
Only daphnia exposed to 10 ppm PGSM/100 .ppb OMCTS
showed reduced reproduction by this measure.
IIA no observable effect level cannot be determined from
this test, nor can the possibility of a synergistic
effect between PGSM and OMCTS be eliminated. This
study should be repeated with lower levels of PGSM and
OMCTS.II
Submission Evaluation
Immediately upon receipt of this TSCA Section 8 (e) notice, the
Chemical Screening Branch (CSB/ECAD) transmi tted a full copy of
the submission to the Test Rules Development Branch (TRDB/ECAD)
for inclusion in the ongoing review of available toxicologic and
exposure data on OMCTS. In 1984, OMCTS was designated by the
Interagency Testing Commi ttee (ITC; 15th List) for consideration
of test rule development under Section 4 of TSCA. The proposed
test rule on OMCTS was published by EPA on October 30, 1985 (50
FR 45123). OMCTS is also the subject of TSCA Section 8 (a) and
Section 8 (d) information reporting rules published by EPA on
November 28, 1984 (49 FR 46739 and 49 FR 46741, respectively).
Current Production and Use
Information on the manufacture and uses of OMCTS can be found in
EPA's October 30, 1985 proposed test rule (see 50 FR 45123).
Comments/Recommendations
In its TSCA Section 8(e) submission, Dow Corning stated that the
company had notified Dow Corning customers and silicone producers
worldwide about the reported findings. Dow Corning stated also
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Page 3 of 3
that additional studies were being conducted to determine the
reliability and importance of the submitted results. Dow Corning
stated further that EPA would be apprised of any additional per-
tinent information. Finally, Dow Corning stated that the final
report of the Daphnia magna reproduction limit test was also
being submitted to EPA under Section 8(d) of TSCA.
The following discussion pertains to the relationship between
TSCA Section 8(e) reporting and the reporting of studies "listed"
under Section 8 (d) of TSCA and those required to be conducted
under Section 4 of TSCA:
Part VI I of EPA' s TSCA Section 8 (e) policy statement
("Statement of Interpretation and Enforcement Policy;
Notification of Substantial Risk" March 16, 1978; 43 FR
11110) explains that substantial risk information does
not need to be submi tted to EPA under Section 8 (e) if
the subject information has been submitted to EPA under
another mandatory reporting requirement of TSCA or some
other authority (e.g., Federal Insecticide, Fungicide
and Rodenticide Act (FIFRA» administered by EPA. The
purpose of thi s part i cular exempt ion is not to change
substantially the Section 8 (e) reporting obligation,
but is designed merely to avoid requiring duplicative
reporting except in those cases where reporting under
the other authority does not or will not meet the time-
liness requirements of Section 8(e). Further, if other
mandatory reporting to EPA under an EPA-administered
authority is incurred coincidental with a Section 8(e)
reporting requirement and the subject information is
r epo r ted to EPA wi th i n no more than 15 work i ng days,
the filing of a separate Section 8(e) report with EPA's
Office of Toxic Substances would not be necessary-
Therefore, a section 8 (e) reporting requirement would
apply to any "substantial risk" information that is
obtained during the conduct of any study "listed" under
TSCA Section 8 (d) as being underway or required to be
conducted under Section 4 of TSCA unless the subject
information is otherwise required formally to be sub-
mitted to EPA under those or other sections of TSCA.
To date, a number of TSCA Section 8 (e) submitters have
correctly reported interim findings from studies
"listed" under Section 8 (d) of TSCA or those being
conducted under Sect ion 4 of TSCA. In such cases, the
TSCA Section 8 (e) reporting obligation was incurred
before the information was required to be reported to
the Agency under Section 8(d) or Section 4 of TSCA.
The Chemical Screening Branch will send copies of this status
report to NIOSH, OSHA, CPSC, FDA, NTP, OW/EPA, OAR/EPA, ORD/EPA,
OSWER/EPA, OPP/OPTS/EPA and TRDB/ECAD/OTS; copies of this status
report will be sent also to the TSCA Assistance Office (TAO/OTS)
for further distribution.
270
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DA TIE:
MAR 2 2 1988
Page 1 of 3
SUBJECT:
Status Report*
8EHQ-13288-137l9
APproved:-r
Coordinator
7 ~ 3b1/pp'
FROM:
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Olin Corporation provided a copy of the final report of an
Ames Salmonella typhimurium (bacteria) mutagenicity assay of a
chemi ca 1 product known as "Chemical 41313, Step 1" (2- [ethyl [3-
methyl-4-(phenylazo)phenyl] amino] ethanol; CAS No. 68214-81-3).
According to Olin, the tested material was mutagenic under both
oxidative and reductive conditions. Under oxidative conditions,
the product reportedly caused a positive response in bacterial
strains TA 98 and TA 1538 in the presence of induced rat liver
microsomes; under reductive conditions, the product reportedly
caused a positive response in strains TA 98 and TA 1538 in the
presence of uninduced hamster liver microsomes.
Submission Evaluation
The subject Ames assay was conducted wi th and wi thout exogenous
metabolic activation in the following bacterial strains: TA98,
TAl1313, TA1535, TA1537 and TA1538. The metabolic activation was
supplied by the S9 fraction of livers from rats treated before
sacrifice with Aroc1or 1254 for the nonspecific induction of
liver enzymes and from the S9 fraction of livers from hams ter s
receiving no treatment prior to sacrifice. The use of uninduced
hamster liver S9 in ,the Ames assay has been found in some cases
to facilitate the reduction of azo compounds. The hamster liver
activation is referred to in the submitted report as "reductive
conditions" while the use of induced rat liver activation is
referred to as "oxidative conditions."
The tests conducted wi thout metabol ic acti vation were uni formly
negative. In the presence of metabolic activation, however, the
subject chemical was found to be mutagenic for TA98 and TA1538
under both oxidative and reductive conditions. The test chemical
appears to be less toxic under reductive conditions than it is
under oxidative conditions. Under the reductive conditions, the
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
271
II~" "ORM ..... 'REV. ..,..
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8EHQ-0288-0719
Page 2 of 3
highest non-toxic dose was found to be 333 ug/plate while under
the oxidative conditions the highest non-toxic dose was found to
be 100 ug/plate. These are also the doses at which the maximum
mutagenic response was observed. Under the reductive conditions,
the maximum response was 2X background in strain TA98 and 2.3X
background in strain TA1538. Under the oxidative conditions, the
ma x im urn response in TA98 was 3X background. In strai n TA1538,
which was tested twice under oxidative conditions, the maximum
responses were 5. 3X background (first test) and 2. 5X background
(second test). The differences found in these two tests are not
considered to be outside the normal range of intra laboratory
variation for this assay. Further, there does not appear to be
any significant difference in response between the oxidative and
reductive conditions. In conclusion, the subject chemical is
considered to be mutagenic in the Ames assay when tested with
metabolic activation derived from either Aroclor 1254-induced rat
liver or uninduced hamster liver.
Current production and Use
A review of the production range (includes importation volumes)
statistics for CAS No. 68214-81-3, which is listed in the initial
TSCA Chemical Substance Inventory, shows that no 1977 manufacture
or importation of the chemical was reported or that all of the
manufacturing and/or importation data reported were claimed as
TSCA Confidential Business Information (CBI) by the person(s)
reporting for the initial Inventory and cannot be disclosed
( S e c t i on 14 (a) 0 f T S CA ; U. S . C . 2613 ( a» . All 0 f the d a tat hat
were submitted for the initial TSCA Inventory, including the
production range data, are subject to the limitations contained
in the initial TSCA Inventory Reporting Regulations (40 CFR 710).
In its submission, Olin reported that the subject chemical is "an
intermediate for the production of color developing agents used
in photographic products." Olin reported also that the chemical
"is used by Olin Hunt Specialty products, Inc. of Rhode Island, a
wholly owned subsidiary of Olin and is not sold to any other
company nor is it an ingredient in any other final product."
Comments/Recommendations
In its submission, Olin stated that the company has "conducted a
comprehensive review of employee work practices and engineering
controls and assessment of employee exposure in the manufacturing
area while employees (a) drum Chemical 400, Step 1, (b) isolate
Ch~mical 400, Step 1, and (c) conduct other manufacturing activi-
ties." Olin stated also that "industrial hygiene recommendations
were made, adopted and implemented for each of these manufac-
turing activities." Finally, Olin stated that "all management,
manufacturing and occupational health employees of Olin have been
informed of the. . . [reported mutagenicity findings as well as
the] engineering controls and monitoring programs are in place to
further control any possible exposure during manufacturing."
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Page 3 of 3
Although a positive in vitro genotoxicologic assay result, when
considered alone, maY-not be sufficient to reasonably support a
conclusion of substantial risk (as that term is defined in EPA's
TSCA Section 8 (e) policy document ("Statement of Interpretation
and Enforcement Policy; Notification of Substantial Risk" 43 FR
11110; March 16, 1978», EPA believes that such results are of
value in assessing possible risks posed by exposure to chemical
substances or mi xtures. The Agency also bel ieves that pos i ti ve
genotoxicity findings, when considered in combination with other
pertinent information (e.g., knowledge of potential exposure to
and/or high production of the subject chemical or mixture), would
suggest the need, in many cases, to conduct further studies that
are designed to better define the toxicologic properties of or
exposure to the subject chemical(s). The results of such further
testing should be considered also for submission to EPA pursuant
to Section 8(e) of TSCA.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Olin will be asked to
descr ibe the nature and results, if avai lable, of all
stud i es (other than those reported already to EPA or
those cited in the published scientific literature)
about which Olin is aware or that Olin has conducted,
is conducting or plans to conduct to determine the
toxicity of the subject chemical substance.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
273
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 4
DATE:
~-31988
SU8JECT:
Status Report*
8EHQ-0288-0720
Approved :h P. r:;;;:: ~ h/rr-
FROM:
David R. Williams~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The General Electric Company provided data (see Table 1 attached)
from a study conducted by the Institut Fresenius in West Germany
to determine if polybrominated dibenzofurans (PBrDF) and/or poly-
brominated dibenzodioxins (PBrDD) were formed as the result of
pyrolysis of a mixture containing polybutylene terephthalate
resin (85%; CAS No. 30965-26-5), decabromodiphenyl ether flame
retardant (11%; CAS No. 1163-19-5), antimony oxide synergist
(2.7%; CAS No. 1309-64-4) and other unspecified constituent(s)
( 3 %). Accord i ng to Gener al Electr ic, samples of thi s mixture
were heated for 10 minutes at temperatures ranging from 2000C to
9000C and then subjected to gas chromatography/mass spectroscopy
to quantify selected PBrDF and PBrDD isomer levels.
Submission Evaluation
The General Electr ic Company stated by phone on March 2, 1988,
that the company was in the process of preparing a supplemental
TSCA Section 8(e) notice containing further information regarding
the reported analytical findings. According to General Electric,
this supplemental Section 8 (e) submission will be sent to EPA
during the week of March 7-11, 1988.
It should be noted that on June 5, 1987 (52 FR 21412), the Agency
published a final PBrDF/PBrDD testing and reporting rule under
Sections 4 and 8 of TSCA; this rule was prepared by the Chemical
Regulation Branch (CRB)/Exposure Evaluation Division (EED)/Office
of Toxic Substances (OTS). In addition, it should be noted that
based on a Chemical Hazard Information Profile (CHIP) prepared in
1986 by the Chemical Screening Branch on a number of brominated
diphenyl ethers, the Risk Analysis Branch (RAB/ECAD/OTS) has been
reviewing available toxicologic/exposure data on this class of
chemical sub~tances.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
274
II~A "OMII .... ("EV. ..711
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8EHQ-0288-0720
Page 2 of 4
Comments/Recommendations
The following discussion pertains to the relationship between
TSCA Section 8(e) reporting and 1) mandatory reporting of studies
under Section 8(d) of TSCA, and 2) mandatory reporting of results
of studies required to be conducted under Section 4 of TSCA:
Part VII of EPA's TSCA Section 8(e) policy statement
(" Statement of Interpretation and Enforcemen t Po 1 icy;
Notification of Substantial Risk" March 16, 1978; 43 FR
11110) explains that substantial risk information must
be submi tted to EPA under Section 8 (e) of TSCA unless
the subject information has been submitted to EPA under
another mandatory reporting requirement of TSCA or some
other author i ty administered by EPA. The purpose of
this particular reporting exempti on is not to change
substantially the Section 8 (e) reporting obligation,
but is designed merely to avoid requi ring dupl icat i ve
reporting except in those cases where reporting under
the other authority does not or will not meet the time-
liness requirements of Section 8(e). Further, if other
mandatory reporting to EPA under an EPA-administered
authority is incurred coincidental with a Section 8(e)
reporting requirement and the subject information is
reported to EPA within 15 working days, the filing of a
separate Section 8(e) report with EPA is not necessary.
Therefore, a section 8 (e) reporting requirement would
apply for example to any "substantial risk" information
obtained during the conduct of any study "listed" under
TSCA Section 8 (d) as being underway or required to be
conducted under Section 4 of TSCA unless the subject
information is otherwise required formally to be sub-
m it ted to EPA under those or other sect ions of TSCA.
To date, a number of TSCA Section 8 (e) submitters have
correctly reported interim results of studies "listed"
under Section 8 (d) of TSCA or those being conducted
under section 4 of TSCA. In such cases, the TSCA
Section 8 (e) reporting obligation was incurred before
the information was required to be reported to the
Agency under Section 8(d) or Section 4 of TSCA.
Considering the preceding discussion and in view of the fact that
EPA's TSCA Sections 4 and 8 PBrOO/PBrOF testing and reporting
rule covers only manufacturers and importers of the chemical sub-
stances listed in that rule, General Electric, a processor but
not a manufacturer or importer of decabromodiphenyl ether (which
is a chemical listed in the rule), did not have any mandatory
obligation to report the analytical findings to EPA under that
rule. General Electric was correct, therefore, in making the
decision to submit the analytical findings to the Agency pursuant
to Section 8(e) of TSCA.
275
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8EHQ-0288-0720
Page 3 of 4
As was the case with General Electric's initial TSCA Section 8(e)
submission, the Chemical Screening Branch will immediately send
copies of General Electric's supplemental Section 8(e) submission
to the Chemical Regulation Branch/EEO/OTS, the Risk Analysis
Branch/ECAO/OTS, other appropriate EPA program Offices and other
appropriate Federal agencies.
The Chemical Screening Branch will send this status report to
NIOSH, OSHA, CPSC, FDA, NTP, OW/EPA, OAR/EPA, ORO/EPA, OSWER/EPA,
OPP/OPTS/EPA, CRB/EEO/OTS/OPTS/EPA and RAB/ECAD/OTS/OPTS/EPA. In
addition, this status report will be sent to the TSCA Assistance
Office (TAO/OTS/OPTS/EPA) for further distribution.
Attachment:
TABLE I
276
-------
TABLE I
"Effects of Pyrolysis TeMperatures
on
Polybutyleneterephthilite Resin Fli8e Retirded with Oecibr08Odiphenylether/Sb203*
All in .icrogri.s/ki1ogra. (ppb)
2000C 2500C 3000C 4000C 5000C 6000C 7000C 8000C goooC
Br - PBrOf n.d. 1,300,000 5,200,000 2,000,000 1,200,000 490,000 24,000 30 40
2,t 7,8-PBrOf n.d. 66,000 150,000 64,000 120,000 19.000 400 5 n.d.
Br - PBrOF n.d. 4.400.000 5,900,000 1,200,000 1,300.000 350,000 8,000 6 20
1 J,3, 7,8-PBrOF n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.
Br - PBrOf 36,000 2,600,000 2,200.000 900.000 670.000 100,000 3,400 n.d. n.d.
N 1,',3,4.7,8-PBrOF n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.
-...J
-...J Br7-PBrOf 140.000 140,000 n.d. n.d. 50,000 3,100 90 n.d. n.d.
Br - PBrDO 1 , 300 1,400 1.500 n.d. n.d. n.d. n.d.
2.!,7,8-PBrDO n.d. n.d. n.d. n.d. n.d. n.d. n.d.
Br - PBrDO 320 340 3.600 1,100 SO n.d. n.d.
l.t4,1,8-PBrDO n.d. n.d. 1,000 n.d. 6 n.d. n.d.
Br -PBrDO n.d. n.d. 5,200 900 10 n.d. n.d.
1,'.3,4,1,8-PBrOD n.d. n.d. n.d. 80 n.d. n.d. n.d.
Br7-PBrDO n.d. n.d. n.d. 40 n.d. n.d. n.d.
n.d. . not detectible
* Resin fOr8Ulition: P01ybuty1ene terephthi1ite, 851; Oecabr08Odipheny1ether 111; Ant 180ny oxide, 2.11; other, 31"
00
'1:ftr:l
PJ ::r::
OQ.o
(I) I
o
~N
00
o 00
Hli
o
~"
N
o
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 4
OAT!:
MAR 2 2 1988
SUBJECT:
Status Report*
8EHQ-0388-072l
~ ~~KMw'"i/-<-
ADprOved: James F. Darr
David R.
Chemical
Williams~ection 8(e)
Screening Branch/ECAD
MAR 2 4 /988
FROM:
Coordinator
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Eastman Kodak Company submitted the following summarized
i nforma t i on wi th regard to the conduct and results of a gui nea
pig skin sensitization study and an acute rat oral LD50 study of
4-methoxy-2-nitrophenylthiocyanate (CAS No. 59607-71-5):
"A group of 10 guinea pigs was tested for skin sensiti-
zation using the method described in the [Organization
for Economic Cooperation and Development (OECD)]
Guideline for Testing of Chemicals: Skin Sensitization
Guideline 406, Section 5. When animals which had been
induced with the test article in Freund's adjuvant were
challenged, strong erythema developed in nine of ten
animals. The strong erythema persisted to the 48-hour
o b s e r vat ion poi n tin six 0 f the n i n e ani ma 1 s . The
erythematous response was extensive. An area of necro-
sis was noted in one animal. No edema was seen in any
of the animals at challenge. The intensity of the
erythematous response and the area of skin over which
the reaction occurred at challenge resulted in a strong
positive classification.
"As part of an acute oral LD50 study, 5 male rats were
given a dose of 5000 mg/kg body weight of the test
compound by gavage. Groups of 5 female rats were dosed
at 1250, 2500, or 5000 mg/kg. At 5000 mg/kg, one male
and four females died on Day 2. Treatment-related
changes in rats dying within two days of treatment
i nc 1 uded hemor rhage of the glandular gastr ic mucosa,
presence of the test compound in the gastrointestinal
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
278
E"'" FORM U.' (REV. 3-711
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8EHQ-0388-0721
Pag e 2 of 4
tract, and yellow discoloration of the facial and
inguinal hair. Yellow discoloration of the inguinal
hair was the only abnormality noted at necropsy of the
one female surviving the 5000 mg/kg dose. No treatment-
related changes were seen at scheduled necropsy in
females at the two lower doses. The estimated LD50 in
females was 3536 mg/kg.
"Since four of five male rats survived a dose of 5000
mg/kg, the LD50 was estimated at greater than 5000
mg/kg. Treatment-related changes in male rats which
survived the 14-day observation period included small
testes (four of four animals) and yellow discoloration
of the inguinal hair (one of four animals). Treatment-
related testicular changes noted in tissue from all
four animals included decreased numbers of spermato-
gonia, spermatocytes, spermatids, and spermatozoa, and
degenerating spermatids and spermatozoa. Body weight
loss in males was significant during the first week
after dosing, and inadequate nutritional intake is a
confounding factor involved in interpretation of this
study. Additional testing is being conducted on groups
of male rats in order to determine the no-effect-1eve1
for the testicular changes. pre1 imi nary fi ndings from
these additional investigations indicate that the acute
oral LD50 in male rats may be lower than originally
estimated. The LD50 will be revised, if necessary, and
the no-effect-1eve1 for testicular effects will be
addressed in the final report on the acute toxicity of
this material. ...."
According to a submitted interim report on the acute toxicity of
4-methoxy-2-nitropheny1thiocyanate, the chemical was found to be
s 1 i gh t ly tox i c (LD 50 >2000 mg/kg) in an acute dermal study in
rats, slightly irritating in an acute dermal study in guinea
pigs, and slightly irritating in an acute eye study in rabbits.
Submission Evaluation
The provided acute toxicologic findings indicate that 4-methoxy-
2-nitropheny1thiocyanate is slightly to moderately toxic by the
oral route in rats. The treatment-related changes observed in
the surviving male rats in this acute oral study included small
testes, decreased spermatogonia, spermatocytes, spermatids, and
spermatozoa as well as degenerating spermatids and spermatozoa.
These changes suggest that the male reproductive system could be
a potential target in long term studies conducted at lower doses
of the subject chemical.
The submi tted data indicate also that the chemical is slightly
irritating to the skin of guinea pigs and slightly to moderately
irritating to rabbit eyes. The guinea pig sensitization study
results indicate that the chemical may have a high potential for
skin sensitization in humans.
279
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8EHQ-0388-0721
Page 3 of 4
Current Production and Use
A review of the production range (includes importation volumes)
statistics for 4-methoxy-2-nitrophenylthiocyanate (CAS No. 596~7-
71-5), which is listed in the initial TSCA Chemical Substance
Inventory, has shown that no 1977 manufacture/importation of the
chemical was reported or that all of the manufacturing and/or
importation data reported were claimed as TSCA Confidential
Business Information (TSCA CBI) by the person(s) reporting for
the initial TSCA Inventory and cannot be disclosed (Section l4(a)
of TSCA; U.S.C. 26l3(a». All data submitted for the initial
TSCA Inventory, including the production range data, are subject
to the limitations contained in the initial TSCA Inventory
Reporting Regulations (4~ CFR 7l~).
In its section 8(e) notice, Eastman Kodak provided the following
information regarding the production of and the potential for
exposure to 4-methoxy-2-nitrophenylthiocyanate:
"This chemical is used as a site-limited intermediate
in a photographic chemical. None of the intermediate is
present in the final chemical. The intermed iate was
not manufactured in 1987 and, at present, there are no
plans to manufacture it in 1988. [Eastman Kodak
is] not aware of any adverse health problems associated
with its manufacture or its use to make the final pro-
duct. After the initial synthesis, the chemical is
handled damp. Potential employee exposure has been
minimized during manufacture by the use of neoprene
gloves, safety glasses, full face air-supplied respira-
torsf safety shoes, and company supplied clothing.
During use, employees are protected by neoprene gloves,
disposable dust masks, safety glasses, company supplied
clothing, and general and local exhaust. In future
operations, employees will wear Tyvek coveralls over
their company supplied clothing."
Comments/Recommendations
In addition to conducting additional studies to determine the no-
observed-effect-level for the testicular toxicity found in rats,
Eastman Kodak updated the 4-methoxy-2-nitrophenylthiocyanate
Material Safety Data Sheet (MSDS) to reflect a potential for skin
sensitization and testicular toxicity; a copy of this updated
MSDS was included in the Eastman Kodak Company's Section B(e)
submission.
a)
The Chemical Screening Branch will ask Eastman Kodak to
ensure that EPA recei ves complete copies of the f i na 1
reports (including the actual experimental protocols,
results of gross and histopathological examinations,
e tc .) from the company's ongo i ng stud ies to determi ne
the no-observed-effect-level for adverse testicular
effects of 4-methoxy-2-nitrophenylthiocyanate.
280
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Page 4 of 4
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Eastman Kodak will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which Eastman Kodak is aware or that the company
has conducted, is conducting or plans to conduct to
determine the toxicity of 4-methoxy-2-nitrophenylthio-
cyanate.
b)
The Chemical Screening Branch will review the reported
information in order ~o determine the need for further
OTS assessment of 4-methoxy-2-nitrophenylthiocyanate.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
281
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
Ail -11988
Page 1 of 3
SU8JECT:
Status Report*
8EHQ-0288-0722
Aoproved: L r ~ 'I!(}IFJ>
(/ .
FROM:
David R. Williams~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB
Submission Description
The Boe i ng Company pr ov i ded the results of an epidemiolog ical
investigation conducted by the company as a result of employee
"concerns that women at Boeing's fabrication facility in Auburn,
Washington, were experiencing a rate of miscarriage that was
higher than expected." According to Boeing, the study "suggested
that the rate of miscarriage in a selected employee group may be
elevated; however, the small size of the study and the numerous
confounding factors identified in the study made the results
inconclusive." Boeing stated that "because this investigation
suggested that the rate of miscarriage in the selected employee
group may be elevated, . a further statistical analysis of
the data collected during the initial investigation [was per-
formed] to determine if [any] links to specific agents could be
established." According to Boeing, this "followup analysis
suggests a possible association between the rate of miscarriage
and potential exposure to agents in the workplace." Boeing also
s ta ted, however, tha t "because of the small si ze of the group
studied, and the multiple sources of potential bias that were
identified, this [followup] analysis also provides only sugges-
tive evidence of [an] association between the rate of miscarriage
and workplace agents."
The "CONCLUSIONS" section of the submitted followup analysis
presents the following information:
"The following conclusions can be drawn from the study:
1.
The study does not conclusively establish that the
overall rate of miscarriage in the organizations
investigated is higher than that in the general
population. However, the results do more to sup-
port than to refute the contention that [workers
in] these organizations experience higher rates of
mis~arriage than does the general population.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
282
E~'" '0'"" 1120... (REV. 1-7.)
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8EHQ-0288-0722
Page 2 of 3
2.
Exposure to [a polymeric resin parting com-
pound], to [an epoxy resin adhesive film],
and to heavy lifting are implicated by this study
as being associated with the rate of miscarriage.
3.
No single agent can be identified as the cause of
miscarriage in this study.
liThe 95% confidence interval [(CI)] for the rate of
miscarriage in the study cohort is 15%-43%. This is
inconsistent with those population-based studies in
which the normal rate of miscarriage was estimated to
be 10%-15%, but is consistent with those studies in
which a normal rate of 15%-20% was found. Had the 95%
confidence interval of this study included the entire
range of estimates of the normal range, one could
conclude that the rate of miscarriage in the target
population did not exceed the normal. If the lower
bound of the 95% confidence interval of the study
exceeded 20%, one could conclude that the rate of mis-
carriage in the target population exceeded the normal.
Since the results were intermediate, the conclusion
must be intermediate.
liThe question of cause and effect cannot be answered by
this study. Of the five [llgenerally accepted"] criteria
for inferring causality [i.e., strength of association,
temporality, consistency of results, dose-response
relationship, coherence]. . only two are satisfied--
a moderately strong association between the implicated
agents and miscarriage was found [(strength of associ-
ation criterion)] and the potential for exposure to
these agents preceded the miscarriages in all cases
[(temporality criterion)]. However, there are no other
reports concerning the reproductive effects of the im-
plicated agents and heavy lifting is generally thought
not to be associated with miscarriage [(consistency of
results criterion)]. There was no information collected
whereby the dose-response relationship could be evalu-
ated [(dose-response relationship criterion)], and the
biologic plausibility of the relationship was not
explored [(coherence criterion)].11
Submission Evaluation
Boeing's investigations demonstrate the difficulty involved in
studying reproductive hazards in the workplace. Al though it
cannot be determined that any particular chemical exposure or
process or workplace activity was the cause of miscarriages among
the employees at this Boeing facility, the studies do signal the
need for a more extensive examination of the rate of miscarriages
at the facility and suggest the need for a monitoring program for
workplace exposure to numerous chemicals. Considering that un-
diagnosed miscarriages may not have been reflected accurately by
283
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8EHQ-0288-0722
Page 3 of 3
employees' self-reported information, other indices of adverse
reproductive effects (e.g., low birth weight) could be used as
appropriate substitutes. Also, some emphasis in any further
studies that are conducted by the company should be placed on the
implicated polymeric resin parting compound and epoxy resin
adhesive film as well as the components of those products.
Comments/Recommendations
In its submission, Boeing stated that in spite of the uncertainty
of the reported epidemiologic findings, the company "is requiring
employees in the work areas included in the study to wear pro-
tective gloves. . ."
a)
In view of EPA's general interest in corporate actions
that are taken on a voluntary basis in response to new
chemical toxicity or exposure information, the Chemical
Screeni ng Branch wi 11 request Boei ng to des c r i be the
nature and results, if and when available, of all other
epidemiologic studies that Boeing has underway or plans
to conduct to investigate adverse reproductive outcomes
among employees at the Auburn, washington facility.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the reported findings.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
284
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
MAR I 4 1988
Pa8e 1 of 2
SUBJECT:
Status Report*
8EHQ-0388-0723
Aoproved: ~ ?:~ 3/;;/ /r,p-
(j
FROM:
David R. Willia~~ection 8(e) Coordinator
Chemical Screening Branch/BCAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Mo~santo Company reported that preliminary results from a
number of acute toxicity studies of 6-methylpurine (CAS No. 2004-
103-7) indicate that this chemical substance has an oral LD50 of
<50 mg/kg, a dermal LD50 of about 2010 mg/kg and is corrosive to
the eyes; the animal species tested in these studies were not
identified in the submission.
Submission Evaluation
It should be noted that chemicals having an oral LD50 value of
less than 50 mg/kg are typically classified as being "extremely"
toxic. An evaluation of the overall significance of the reported
toxicologic findings should be possible upon the Agency's receipt
of complete copies of the final reports from all of the studies
cited in this submission.
Current production and Use
6-Methylpurine was not found on the non-confidential computerized
initial TSCA Chemical Substance Inventory- According to Monsanto,
the company's "use of this purchased material is currently
1 imi ted to small quant i ties for research and deve 1 opmen t (R&D)
activities" and "as a result, Monsanto worker exposure to this
R&D mater i al (6-methylpur i ne) is extremely low, both in terms of
[the] existing quantity (120 grams) and number of research people
handling it «5)."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
EPA FORM IU.~'6 (REV. 30761
285
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8EHQ-0388-0723
Page 2 of 2
Comments/Recommendations
In its submission, Monsanto stated that the company has labelled
the subject chemical as a "Class B poison" and "Corrosive" to the
eyes. In addition, Monsanto stated that the company has advised
its potentially exposed workers and the supplier of the chemical
about the reported toxicologic findings.
a)
The Chemical Screening Branch will request Monsanto to
ensure that EPA recei ves complete copies of the final
reports (including the actual experimental protocols,
results of gross/histopathologic examinations, etc.)
from all acute toxicity studies cited in the company's
submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Monsanto will be
asked to describe the nature and results, if available,
of all stud i e s (other than those reported already to
EPA or those cited in the open scientific literature)
about which Monsanto is aware or that the company has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of 6-methylpurine.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemi ca 1 Screen i ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
286
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
APR I 2 1988
Page 1 of 4
SU8JECT:
Status Report*
8EHQ-13388-13724 S
APproved:r 't' Ł::.. 'IiF/Ft'
Coordinator
FROM:
David R. William~ection 8(e)
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The CIBA-GEIGY Corporation has claimed the exact identities of
the subject chemical substances as TSCA Confidential Business
Information (TSCA CBI); the Information Management Division
(IMD/OTS) will be requesting the company to substan t i a te these
confidentiality claims. In the "sanitized" version of this TSCA
Section 8 (e) submi ssion, CIBA-GEIGY reported non-confi dent i a 11y
that the tested material is a "mixture of sterically hindered
phenol derivatives." CIBA-GEIGY reported also that the major
component accounts for approximately 86% of the mixture and the
minor component accounts for approximately 8% of the mixture.
Submission Description
CIBA-GEIGY submitted the final report of a 28-day dietary feeding
study of the subject mixture in rats. CIBA-GEIGY's cover letter
presented the following information regarding the conduct and
major results of this study:
"A 28 -day d i eta ry admini stration study wi th rats was
performed at feed levels of 13, 11313, 51313, 251313 and
12,131313 ppm. ~mong other effects, signs of anemia
(2,51313 and 12,13013 ppm groups), liver toxicity (11313-
12,131313 ppm groups) and focal cell hypertrophy within
the adenohypophysis with parallel thyroid follicle
hypertrophy (51313 - 12,131313 ppm groups) were observed."
According to the "SUMMARY AND ASSESSMENT" portion of the provided
final report, administration of the test material in the diet for
28 days "did not result in any deaths and only caused a minor
disturbance in food intake and bodyweight gain of rats receiving
12,131313 ppm."
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
287
IE~A "OItM "" (REV. ,.,..
-------
8EHQ-0388-0724 S
Page 2 of 4
Submission Evaluation
The subject mixture was administered in the feed for 30 days to 5
rats/sex/group at doses of 0, 100, 500, 2500 and 12,000 ppm. This
correlated with doses of 0, 9.94, 49.0, 250 and 1211 mg/kg/day in
males and 0, 10.1, 47-1, 253 and 1102 mg/kg/day in females. Food
consumption, body weight, clinical observations, hematology, bio-
chemistry and pathology were examined.
No mortalities or adverse clinical findings were observed during
the study. Body weight was slightly decreased at 12,000 ppm for
both sexes, with the females showing a 4% decrease and the males
a 7% decrease by week 4. By weeks 3 and 4, the females at 2500
and 12,000 ppm showed a 7% and 9% decrease, respectively, in food
consumption from the controls. The males at the 12,000 ppm dose
level exhibited a statistically significant 13% reduction in food
consumption.
Hematology revealed a dose-related decrease in red blood cells
for both sexes which was not statistically significant and a
dose-related decrease in hemoglobin and hematocrit which was
statistically significant for both sexes at 2500 and 12,000 ppm.
The male rats showed a statistically significant decrease in
reticulocytes at the highest dose level. These data suggest that
the tested mixture may be adversely affecting the hematopoietic
system and producing anemia.
The clinical chemistry results for both sexes indicated a dose-
related increase in cholesterol, total protein and total globulin
levels and a dose-related decrease in the albumin/globulin ratio.
The values given for serum cholesterol, total protein, globulin
and albumin/globulin ratio were statistically significant at 2500
and 12,000 ppm in both sexes. These values were also much more
dramatically altered for females than for males. Although the
al terations in these parameters are suggesti ve of a cholestatic
type of liver injury, the remaining chemistry results do not
support this premise. Both sexes showed a decrease in alkaline
phosphatase levels instead of an increase as would be expected
with a cholestatic type injury. Serum bilirubin levels would
also be expected to be increased; however, none were examined.
In addition, males showed a significantly decreased blood urea
nitrogen at 12,000 ppm which may have been due, in part, to the
13% reduction in food consumption. Neither the alanine amino-
transferase (GPT) nor the aspartate aminotransferase (GOT) levels
were elevated at the highest doses. The GPT and GOT values were
statistically significantly elevated at 500 ppm in males, but
then proceeded to decrease with increasing dose.
Gross necropsy results showed a statistically significant dose-
related increase in relative liver weight for the males at 500,
2500 and 12,000 ppm and for the females at all dose levels.
Again, the values observed for females were markedly increased
over those of the males. The females also exhibi ted a dose-
related decrease in absolute and relative spleen weight.
288
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8EHQ-0388-0724 S
Page 3 of 4
The procedure section of the submitted final report listed a more
than adequate number of tissues to be preserved and examined
microscopically- However, the study results cover only a limited
number of these tissues (i.e., liver, kidney, uterus, bladder,
myocardi urn, adenohypophys is, thyroid and harder ian gland). The
primary treatment-related lesions that were presented appeared to
involve the liver, thyroid and pituitary. Hypertrophy of the
liver hepatocytes was present in all test animals at .2500 and
12,000 ppm. Minimal foci of liver cell necrosis was observed in
1/10 rats at 100 ppm, 2/10 at 500 ppm, 2/10 at 2500 ppm and 3/10
at 12,000 ppm. Electron microscopic examination of the hepato-
cytes from rats exposed to 12,000 ppm revealed some (no number
given in the report) with intracytoplasmic inclusions consisting
of lipid droplets and tubular elements of smooth endoplasmic
reticulum. These intracytoplasmic inclusions. may be associated
with the accumulation of lipids in the hepatocytes or the liver.
Histopathologic examination of the thyroid showed hypertrophy of
the thyroid follicles in 1/10 rats at 100 ppm, 9/10 at 500 ppm,
and 10/10 at 2500 and 12,000 ppm. Focal cell hypertrophy within
the adenohypophysis was observed in 1/10 rats at 500 ppm and 5/10
at 2500 and 12,000 ppm; only males were observed to have lesions
of the adenohypophysis.
Al though the data from thi s study adequately demonstrate the
toxicity of the subject mixture at the doses selected, the
pattern or type of toxicity produced is unclear. For example,
although the test material appears to be affecting the liver, the
lack of biologically significant increases in serum GOT or GPT
levels suggests that the const i tuents of the mi xture are not
producing direct toxicity to the liver. The markedly increased
cholesterol, total protein and globulin levels suggest a chole-
static type injury; however, the alkaline phosphatase levels are
notably decreased instead of increased and no bilirubin levels
were examined. The possibility of fat accumulation within the
liver may account for the hepatocellular hypertrophy but it is
unlikely that this would produce the biochemical aberrations ob-
served. Considering that elevated cholesterol levels have been
associated with hypothyroid states, the effects of the mixture
component(s) on the pituitary and thyroid may be as important as
the effects on the liver.
In conclusion, administration of the subject mixture to rats at
doses of from 9.94 to 1211 mg/kg/day in the feed for 30 days,
resulted in adverse effects to the liver, pituitary, thyroid,
and/or blood at each dose level tested.
Current production and Use
In view of CIBA-GEIGY's TSCA CBI claims, no information with
regard to the TSCA Chemical Substance Inventory status of the
cons tit uen ts 0 f the tested mixture wi 11 appear in thi s status
report.
289
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8EHQ-0388-0724 S
Page 4 of 4
C IBA-GE I GY pro v i ded the followi ng non-confidential information
concerning the company's acti vi ties wi th the subject mixture of
sterically hindered phenol derivatives:
"The company imported for research and development
purposes approximately 50 gms of the subject material,
all of which was used internally by [the] CIBA-GEIGY
Corporation for technical performance evaluations. No
material was distributed outside the company- The
substance has been subsequently dropped from further
consideration as a potential product. ....
". [The small amount of the mixture imported into
the U.S.] was handled using prudent laboratory prac-
tices. There is no remaining inventory of the material
in the U.S. . . ."
Comments/Recommendations
In addition to dropping from commercial consideration this
mixture of sterically hindered phenol derivatives, CIBA-GEIGY
reported that the company "will revise its Material Safety Data
Sheet and notify its employees who worked wi th or handled the
material of the new findings."
a}
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, CIBA-GEIGY will be
asked to describe the nature and results, if available,
of a 11 stud i es (other than those reported already to
EPA or those cited in the open scientific literature)
about which CIBA-GEIGY is aware or that CIBA-GEIGY has
conducted or is conducting to determine the toxicity of
the subject mixture or its constituents.
b}
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this mixture or its constituents.
c}
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
290
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
APR I 2 1988
Page 1 of 3
SU8JECT:
Status Report* 8EHQ-9388-9725
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
APproved:-!t"..r~ Jdtr
Coordinator
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB
Submission Description
The CIBA-GEIGY. Corporation submitted the following information
with regard to the conduct and preliminary results of a chronic
feeding study of the 1,2-ethanediyl-bis(oxy-2,1-ethanediyl) ester
of 3-(1,1-dimethylethyl)-4-hydroxy-5-methyl-benzenepropanoic acid
(CAS No. 36443-68-2) in rats:
"[At the CIBA-GEIGY's parent company (CIBA-GEIGY Ltd.
in Basel, Swi tzerland) ,] a 24-month feeding study was
conducted in rats which received targeted doses of 9,
5, 15, 59 and 199 mg/kg/day. The results [(as received
orally from the parent company)] apparently showed a
disturbance of lipid metabolism and liver enzyme acti-
vities, indicative of liver toxicity, and an increased
incidence of cystic dilatation or hyperplasia of the
thyroid follicles in the 15 (males only), 59 and 199
mg/kg groups. In addition, an increased incidence of
thyroid gland follicular adenomas and carcinomas were
observed in the 59 (males only) and 199 mg/kg/day
groups.
"Due to the limited data currently available and the
well known secQndary mechanisms of thyroid tumor in-
duction in the rat, . . . [CIBA-GEIGY is] not certain
at this time whether this information is relevant to
humans. ... [The] parent company is presently con-
sidering the etiology of the thyroid effects. Since
the [subject] chemical is not genotoxic, an epigenetic
mechanism may have been responsible for the thyroid
tumors. The company is consider ing investigating the
possibi 1 i ty that 1 i ver hypertrophy, which is known to
be an effect of this chemical, produced an imbalance of
thyroid hormone levels resulting in secondary tumor
development."
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
291
.~" ..OMl "'" '''''v. 1-781
-------
8EHQ-0388-0725
Page 2 of 3
Submission Evaluation
In order to evaluate the overall significance of the reported
toxicologic findings, CIBA-GEIGY should be asked to ensure that
EPA receives a complete copy of the final report of the subject
24-month feeding study in rats.
Current Production and Use
Al though the subject chemical substance was not located on the
non-confidential computerized version of the initial TSCA
Chemical Substance Inventory, the CAS Registry Number for this
chemical (followed by a "P") was found in volume I of the non-
confidential printed TSCA Inventory (1985 Edition). According to
introductory information given in Volume I, the "P" designation
i nd i ca tes tha t 1) the chemical substance was the subject of a
TSCA Section 5 "Pre-Manufacture Notification" (PMN), and 2) EPA
has received a "Notice of Commencement" (NOC) for the manufacture
and/or importation of that chemical.
In its Section 8(e) notice, CIBA-GEIGY reported that the subject
chemical substance, which is imported to the u.s. for use as a
stabilizer for a number of polymers, "is still at an early stage
of commercialization." CIBA-GEIGY also provided the following
information about the potential for exposure to this chemical:
"The current [Material Safety Data Sheet (MSDS)] and
label already warn against undue exposure through
swallowing, inhaling dust, eye contact, and repeated or
prolonged skin contact. Exposure of industrial workers
to CAS No. 36443-68-2 should, therefore, be minimal.
The subject material is present in very low concentra-
tions in the final polymer product(s), typically 9.25
percent by weight or less. Since the substance is
uniformly admixed throughout the polymer, the amount of
stabilizer at the surface of any article containing it
is extremely low. Dermal exposure to consumers is,
therefore, negligible."
Comments/Recommendations
CIBA-GEIGY reported in its Section 8 (e) submission that the
company was 1) revising the subject chemical's MSDS to reflect
the reported toxicologic findings, and 2) notifying all company
employees and customers about these findings.
a)
The Chemical Screening Branch will request CIBA-GEIGY
to ensure that EPA receives a complete copy of the
final report (including the actual experimental
protocol, results of gross/histopathologic
examinations, results of any statistical analyses,
etc.) from the 24-month feeding study cited in the
company's TSCA Section 8(e) submission.
292
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8EHQ-0388-0725
Page 3 of 3
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, CIBA-GEIGY will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which CIBA-GEIGY is aware or that CIBA-GEIGY has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of the subject chemical substance.
b)
As in the case of the initial submission, copies of all
additional reported information will be transmitted to
staff of the Chemical Control Division (CCDjOTS) which
is responsible for the OTS New Chemicals program. In
addition, the Chemical Screening Branch will review all
reported information in order to determine the need for
further OTS assessment of the subject chemical.
c)
The Chemical Screening Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWERjEPA, OWjEPA, OARjEPA, ORDjEPA, OPPjOPTSjEPA and
CCDjOTSjOPTSjEPA. In addi tion, copies of this sta tus
report will be sent to the TSCA Assistance Office
(TAOjOTSjOPTSjEPA) for further distribution.
293
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
OAT!:
Am I 4 1988
Page 1 of 3
SU8J!CT:
Status Report* 8EHQ-~388-~726
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
ADPrDved:~"- Ł:: 'rlrr
FRO":
Coordinator
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Hoechst Celanese Corporation provided the final report of a
subchronic fert i Ii ty study of p-tert-butyl ben zo i c ac id (PTBBA;
CAS No. 98-73-7) in male rats. The "Summary and Evaluation"
section of the submitted final report presents the following
information regarding the conduct and results of this study:
" . . . p-t-Butylbenzoic acid was given to groups of l~
male wistar rats each for 7~ days prior to mating in
concentrations of 2~, l~~ or 5~~ ppm mixed with the
da i ly food. These concentra ti ons corresponded to a
daily substance intake of about 1.6, 7.9 or 41.~ mg/kg
body weight. This was followed by mating attempts
extending over a period of 7 days with two females each
per male - The females were expected to produce off-
spring. The males were considered fertile when at
least one of the two females became pregnant. Males
which failed to prove their fertility were mated again
7~ days after the end of the treatment. At the end of
the test, the sex organs of the male animals were sub-
jected to a histological examination.
"The investig'tions have shown that the repeated
administration of 2~ ppm p-t-butylbenzoic acid did not
lead to an impairment of the general state of heal th
and of the fertility of the male animals.
"After feeding l~~ ppm, .the fertility of a single male
animal was impaired. Beyond that, the animals of this
group were without pathological findings.
"5~~ ppm led in all males to a slowing down of the
weight gain and to an interfeience with the fertility.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
294
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"The fertility impairment observed in the animals
treated with 100 and 500 ppm, however, [was] reversible
within 70 days after the end of the treatment, although
after 500 ppm, the weights of the testicles were still
reduced and histological damage could be detected in
some tubulus sections of the germinal epithelium.
"The concluding autopsy produced, except for the
slightly reduced testicular weights, no conspicuous
findings in the animals treated with 500 ppm.
"On the basis of these resu1 ts, the "no effect level"
for p-t-buty1benzoic acid with respect to its effect on
the fertility of male rats is about 20 ppm. 100 ppm
lies in the borderline area of tolerance."
In its submission, Hoechst Celanese stated that the subject study
had been commissioned by the German Berufsgenossenschaft Chemie
in Heidelberg, West Germany.
Submission Evaluation
Immediately upon receipt of this TSCA Section 8(e) notice, the
Chemical Screening Branch transmi tted a complete copy of the
submission to the Risk Analysis Branch/ECAD for review in con-
junction with other available PTBBA toxicity/exposure information
including data received by EPA under TSCA Sections 8(a), 8(d) and
8(e) as well as on a "For Your Information" (FYI) basis. The
TSCA Sections 8 (a) and 8 (d) data reporting rules for PTBBA (as
well as p-tert-butylbenzaldehyde and p-tert-butyltoluene) were
published by EPA on May 12, 1986 (51 FR 17336). In addition, the
Chemical Screening Branch prepared (in 1982) "Chemical Hazard
Information Profiles" (CHIPs) on PTBBA, p-tert-butylbenzaldehyde
and p-tert-butyltoluene. Finally, it should be noted that EPA
published (in 1985) a "Chemical Advisory" covering PTBBA, p-tert-
butyl toluene and p-tert-butylbenzaldehyde.
Comments/Recommendations
In its Section 8(e) submission, Hoechst Celanese stated that the
final report of this PTBBA study had been submi tted already to
EPA under Section 8(d) of TSCA; the following discussion pertains
to the relationship between reporting under TSCA Section 8(e) and
other reporting under TSCA or other authorities administered by
the Agency:
Part VII of EPA's TSCA Section 8(e) policy statement
("Statement of Interpretation and Enforcement Policy;
Notification of Substantial Risk" March 16, 1978; 43 FR
11110) explains that substantial risk information does
not need to be submitted to EPA under Section 8(e) if
the subject information has been submitted to EPA under
another mandatory reporting requirement of TSCA or some
other authority (e.g., Federal Insecticide, Fungicide
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Page 3 of 3
and Rodenticide Act (FIFRA» administered by EPA. The
purpose of this particular exemption is not to change
substantially the Section 8(e) reporting obligation,
but is designed merely to avoid requiring duplicative
reporting except in those cases where reporting under
the other authority does not or will not meet the time-
liness requirements of Section 8(e). Further, if other
mandatory reporting to EPA under an EPA-administered
authority is incurred coincidental with a Section 8(e)
reporting requirement and the subject information is
reported to EPA within no more than 15 working days,
the filing of a separate Section 8(e) report with EPA's
Office of Toxic Substances would not be necessary.
The Chemical Screening Branch will transmit copies of this status
report to NIOSH, OSHA, CPSC, FDA, NTP, OWjEPA, OARjEPA, OROjEPA,
OSWERjEPA, OPPjOPTSjEPA and RABjECAOjOTSjOPTSjEPA. In addition,
copies of this status report will be sent to the TSCA Assistance
Office (TAOjOTSjOPTSjEPA) for further distribution.
296
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
~ 241988
Page 1 of 3
SU8JECT:
Status Report*
8EHQ-0488-0727
Approved: LTC ~b
(j .
Coordinator
!"ROM:
David R. Williams~ction 8(e)
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB
Submission Description
The Amoco Corporation submitted the following summarized
information regarding the conduct and preliminary resul ts of a
28-day dermal toxicity study of intermediate catalytic cracked
petroleum distillate (ICCD; CAS No. 64741-60-2) in rats:
"The study was a 28-day dermal toxici ty test wi th the
following experimental design:
"Four groups of ten collared rats per sex
were dosed dermal1y with 9.0,0.2,0.8, or
1.5 m1 of ICCD per kilogram body weight.
Dosing was [for] five days per week for four
weeks. Following the exposure phase, the rats
were killed and subjected to gross necropsy.
Organ weights were [then] determined and a
number of tissues were collected for histo-
logic evaluation.
"The following effects were observed:
"1.
Dose-depenqent body weight decreases
time in both sexes;
over
"2.
Dose-dependent increases in absolute and
relative liver weight in both sexes;
"3.
Dose-dependent decreases
relative ovary weights;
in absolute and
"4.
Thymic atrophy in both sexes at all dose
levels;
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
297
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"5.
Small ovaries in the 0.8 ml/kg and 1.5 ml/kg
dose groups; [and]
"6.
Small uterus in [the] 1.5 ml/kg group rats."
In submi tting this information to EPA, Amoco reported that the
findings from the 28-day dermal study "indicate that ICCD can
produce toxic effects at 0.2 ml/kg and above, that these toxic
effects include general or systemic toxicity (body weight loss),
and that the thymus, liver, ovaries and uterus appear to be tar-
get organs for thi s substance." Amoco reported also that the
observed toxic effects "appear to be similar to those observed
following repeated dermal application of catalytic cracked
clarified oil (CAS No. 64741-62-4)." In addition, Amoco stated
that because "the boiling ranges of these two streams overlap,
they will contain many of the same components including carbazole
derivatives."
Submission Evaluation
Although no information was submitted regarding any clinical
signs of toxicity or histopathological findings, the provided
information does indicate that dermal exposure to ICCD may result
in a wide variety of toxic effects including general toxicity,
hepatotoxicity, immunotoxicity and reproductive system toxicity.
Amoco should be asked to ensure that EPA receives a full copy of
the f i na 1 repor t (i nc 1 ud i ng the actual exper imental protocol,
results of gross and histopathological examinations, etc.) from
the 28-day ICCD rat dermal toxicity study cited in the company's
TSCA Section 8(e) submission.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for ICCD (CAS No. 64741-60-2), which is listed in the
initial TSCA Chemical Substance' Inventory, has shown that over 1
billion pounds were reported as manufactured and/or imported in
1977. This production range information does not include any
data claimed as TSCA Confidential Business Information (TSCA CBI)
by the person(s) reporting for the initial TSCA Inventory, nor
does it include any data that would compromise TSCA CBI. All of
the data reported for the initial TSCA Inventory, including the
production range data, are subject to the limitations contained
in the initial TSCA Inventory Reporting Regulations (40 CFR 710).
In its TSCA Section 8 (e) submission, Amoco reported that "both
ICCD and catalytic cracked clarified oils can be used as com-
ponents in heavy fuels."
298
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Page 3 of 3
CommentS/Recommendations
Amoco reported that because 1) the Material Safety Data Sheets
(MSDSs) for ICCD and catalytic cracked clarified oil reflect the
toxicity of the clarified oil, and 2) the toxic effects of these
petroleum streams appear to be similar, "only minor modification
to the MSDSs for these products appears necessary at this time."
In addition, Amoco reported that copies of the updated MSDSs for
these streams would be sent to EPA when the final report from the
28-day ICCD rat dermal study is submitted.
It should be noted that EPA's Office of Toxic Substances (OTS)
has received many TSCA Section See) and "For Your Information"
(FYI) submissions on various petroleum process streams, including
catalytic cracked clar i fied oil. It should be noted al so tha t
the Risk Analysis Branch (RAB/ECAD/OTS) staff is evaluating
available toxicologic/exposure information on catalytic cracked
clarified oil.
a)
The Chemical Screening Branch will ask Amoco to ensure
that EPA receives a complete copy of the final report
(including the actual experimental protocol, results of
gross and histopathological exam! na t ions, etc.) from
the 2S-day rat dermal toxicity study that was cited in
the company's TSCA Section See) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Amoco will be asked
to describe the nature and results, if available, of
all studies (other than those reported already to EPA
or those cited in the open scientific literature) about
which Amoco is aware or that Amoco has conducted, is
conducting or is planning to conduct to determine the
toxicity of or the exposure to ICCD.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of ICCD.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
RAB/ECAD/OTS/OPTS/EPA. In addition, copies of this
status report will be sent to the TSCA Assistance
Office (TAO/OTS/OPTS/EPA) for further distribution.
299
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DAfE:
Am 2 8 1988
Page 1 of 2
SU8JECT:
Status Report* 8EHQ-@488-@728
David R. Williams~ction 8(~)
Chemical Screening Branch/ECAD
APproved:rA ro:;. 'l/.1h
FROM:
Coordinator
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Union Carbide Corporation provided the following information
regarding a possible human anaphylactic reaction to polyethylene
glycol-8@@@ (CAS No. 25322-68-3) "when taken orally in a complex
pharmaceutical preparation."
"The subject suffered a potentially life-threatening
apparent anaphylactic reaction within a few minutes of
taking a commercially available throat lozenge called
Imposit. He was hospitalized in a state of circulatory
shock with hypotension, but responded to standard
treatment. He was subsequently subjected to intra-
dermal sensitivity challenge testing with each of the
individual constituents of Imposit (14 in all).
"He exhibited a severe local reaction only to . . .
[polyethylene glycol-8@@@]. It was also determined
that 3 months before his apparent anaphylactic reaction
he had a mild reaction to a dental paste (Ledermix)
con ta i n i ng po lyethylene glycols 4@@ and 3@@@ and [a]
local anaesthetic. The patient has no other known
allergies and has been well since the apparent episode
of anaphylaxis.
"The European manufacturer of Imposit (Maddaus) notes
that it has sold over l@ million Imposit lozenges, but
has received no other reports of [human] hypersensi-
tivity reactions to the preparation. Additionally,
extensive literature searches by Union Carbide has
revealed a few cases of allergic contact dermatitis due
to polyethylene glycols, but no reports of anaphylactic
(Type I) hypersensitivity reactions."
===================================================================================:
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
300
II~" '0"'" U'" (.-EV. ~7')
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8EHQ-0488-0728
Page 2 Qf 2
In providing this information under Section 8 (e), Union Carbide
stated that "in the nearly S" years of worldwide sales of
hundreds of millions of pounds of polyethylene glycol products,
this is the first report of an anaphylactic reaction. . . [to
Union Carbide's knowledge]." Union Carbide reported also that
its TSCA Section 8(e} filing was "collated" from letters from the
patient and [European] physician involved as well as a direct
phone conversation between Union Carbide and that doctor.
Submission Evaluation
As stated in C..arett and Doull'. Toxicology (3rd Edition, 1986),
"Type I or anaphylactic reactions are mediated by homocytotropic
antibodies .(lgE in man). The Fc portion of IgE antibodies can
bind to receptors on mast cells and basophils. If the antibody
molecule then binds antigen, pharmacologically active amines such
as slow-reacting substance of anaphylaxis and histamine are
released from the mediator cell (e.g -, mast cell, basophil).
These agents result in vasodilation, edema, and generation of an
inflammatory response. The main targets of this type of reaction
are, the gastrointestinal tract (food allergies), the skin (urti-
caria. and atopic dermatitis), the respiratory system (rhinitis
and asthma), and the vasculature (anaphylactic shock). These
responses tend to occur quickly after rechallenge with an antigen
to which the individual has been sensitized and are termed
immediate hyper-sensitivity."
According to the information provided by Union Carbide, the
affected individual exhibited a state of circulatory shock with
hypotension; hospitalization and treatment reportedly resulted in
recovery. Further, the patient's subsequent exposure to poly-
ethylene glycol-8""" by intradermal sensitivity challenge testing
confirmed this chemical substance as the causative agent. In view
of the fact that no information concerning such serious reactions
to polyethylene glycol-8SSS has been located by Union Carbide or
EPA, this particular occurrence of a Type I sensitivity reaction
in a human appears to represent a truly idiosyncratic response.
Comments/Recommendations
a)
The Chemical Screening Branch will ask Union Carbide to
ensure that EPA is apprised of any further significant
information regarding the reported case of anaphylaxis.
The Chemical Screening Branch will include the reported
information in its ongoing review of other toxicologic
and exposure data on a number of polyalkylene glycols.
b)
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA;
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
301
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DA TE:
MAY - 4 1988
Page 1 of 4
SU8JECT:
Status Report> 88HQ-3488-0729 S Approved: ~ T,~ '/1/""-
David R. Williams~ection B(e) Coordinator
Chemical Screening Branch/ECAD
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The submitting company claimed its name and the exact identity of
the subject chemical substance to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
wi 11 be requesting the submi tting company to substantiate these
TSCA CBr claims. By phone, the submitting company identified the
subject chemical non-confidentially as "ethyl sulfluramid."
Submission Description
The submitting company provided the following summary information
with regard to the conduct and results of two 13-week studies of
ethyl sulfluramid in beagle dogs:
"A preliminary l3-week toxicity study. . was con-
ducted in beagle dogs with ethyl sulfluramid. ['Three
groups of 4 male and 4 female dogs were initially
exposed by either capsule or dietary admixture to dose
levels of 190, 300 and 1909 mg/kg/day on a five day per
week basis. An additional group of 4 male and 4 female
beagles served as a control group.'] The doses [that
were] selected for this test elicited unexpected toxi-
city and dose levels were reduced ['starting on day 9
of the study as follows: 199 to 59 mg/kg/day, 390 to
100 mg/kg/day, and 1990 to 300 mg/kg/day.'] Histopath-
ological evaluations revealed an absence of sperm in
the seminiferous tubules and ,epididymis for all treated
ma led og s (except one from the mid dose). Sperm
production for control males was deemed normal for dogs
of this age (approximately 7 to B months of age). This
effect in treated dogs was considered as a maturational
arrest of spermatogonia.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
302
a~" "0""" II" {REV. 1-711
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8EHQ.,.0488...0729 S
Page 2 6Ł 4
"Valid interpretation of this study was confounded by
several factors. The test chemical was more toxic than
[was] expected from earlier range-finding results and
necessi tated dose level reduct ions. The hea 1 th and
husbandry of the dogs may have added to the toxic
stress exhibited by the animals. The male dogs were
juveniles and the differences in sperm production may
have been a reflection of the animals' age.
"A second study was conducted. . . to verify these
results and to determine if these effects, if treatment
related, were reversible. Mature (1.5 to 2 years of
age) and maturing (6 months of age) dogs were repeated-
ly dosed wi th ethyl suI fluramid. [' Ten mature and ten
maturing dogs were initially exposed via capsule to
daily doses of 100 mg ethyl sulfluramid/kg body weight
on a five day per week bas is. Two ma ture and two
ma tur i ng dog s served as controls. Cli nical signs of
toxicity were seen in both the mature and maturing dogs
receiving ethyl sulfluramid. One mature dog was found
dead on day 20 of the study. As a resul t of these
observations, the dosing regimens for the mature and
maturing dogs was modified. . . [as follows]:
Weeks
Weeks
Weeks
Weeks
Week
Weeks
1-3
4-8
9-13
14-16
17
18-32
Weeks
Week
Weeks
Weeks
1-3
4
5-15
16-32
Mature dogs
Dosed with 100 mg/kg/day
Dosing suspended
Dosing with 50 mg/kg/day*
Dosing suspended
Dosing with 50 mg/kg/day
Non-dosing recovery period*
* one dog was dosed Weeks 9-21;
recovery was Weeks 22-33
Maturing dogs
Dosed with 100 mg/kg/day
Dosing suspended
Dosed with 50 mg/kg/day
Non-dosing recovery period
'During the first period in which dosing was suspended,
mature dogs continued to show signs of toxicity. Two
dogs were sacrificed in extremis on days 32 and 39,
respectively. Another mature dog was found dead during
week 13. No mortalities occurred in the maturing dogs
treated with ethyl sulfluramid.'] A clearcut time-
related decrease in sperm production was seen in the
mature dogs with the effect occurring approximately 3
303
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8EHQ-0488~0729 S
Page 3 of 4
weeks after the first dose. Upon suspension of dosing,
sperm production was essentially normal. These findings
could not be verified in the maturing dogs due to the
variabi1i ty in sperm production for male dogs of this
age.
"Unilateral castration was performed on all dogs at
termination of the dosing period. Histological assess-
ment of the testis and epididymis revealed reduced
sperm production for the mature dogs and some of the
maturing dogs. The remaining testis was removed and
evaluated upon completion of the non-dosing recovery
period. A general increase in sperm production was
noted for both the mature and maturing dogs."
Submission Evaluation
The provided summary information indicates that sexually mature
male dogs are more sensitive than sexually immature male dogs
with regard to the adverse reproductive system effects of ethyl
sulfluramid. In order for EPA to evaluate the overall signifi-
cance of the reported findings, however, the submitting company
should be requested to ensure that EPA receives full copies of
th"e final reports (including the actual exper imental protocols,
results of gross and histopathologic examinations, etc.) from the
two l3-week oral/feeding toxicity studies cited in the company's
TSCA Section B(e) notice.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information with
regard to the TSCA Chemical Substance Inventory status of the
subject chemical will appear in this status report. In its TSCA
Section B(e) notice, the submitting company reported that "no
quantities [of ethyl sulfluramid] have been distributed. . . for
any purpose other than research and development, although an
application for registration as a pesticide will be filed. . .
[shortly with EPA's Office of Pesticide Programs (OPP/EPA) under
the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA)]."
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submitting
company to ensure that EPA receives complete copies of
the final reports (including the actual experimental
protocols, results of gross/histopathologic examina-
tions, etc.) from the two 13-week oral/feeding studies
cited in the company's TSCA Section B(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the actions the company has taken or
plans to take 1) to notify workers and others about the
304
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8EHQ~0488~0729 S
Page 4 of 4
reported information, and 2) to reduce or eliminate
exposure to ethyl sulfluramid. In addi tion, the sub-
mitter will be requested to describe the nature and
results, if available, of all studies (other than those
reported already to EPA or those cited in the published
scientific literature) about which the company is aware
or that the company has conducted (including the com-
pany's "earlier range-finding" studies), is conducting
or plans to conduct to determine the toxicity of or the
exposure to ethyl sulfluramid.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
305
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
MAY I I 1988
Page 1 of 3
APprOVed:~ l....o:::. ')'#f
Coordinator
SUIJECT:
Status Report* 8EHQ-0588-0730
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
FRO,.:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The BASF Corporation submitted the following summary information
regarding the conduct and preliminary results of 9-month feeding
studies in rats with ethyl auramine, nitrate salt (C.I. Basic
Yellow 37; CAS No. 43130-12-7) and auramine, hydrochloride salt
(C.r. Basic Yellow 2; CAS No. 2465-27-2) performed by BASF's
parent company (BASF AG in West Germany):
"Groups of rats were administered 0, 1000 or 2000 ppm
of ethyl auramine, nitrate salt in the feed for nine
months. Animals were sacr i ficed at 3, 6 and 9 months
for histopathological examination. Mean body weights
and food intake were lower in the treated animals and
increased activity of gamma-glutamyl transpeptidase was
observed in liver homogenate. In addition, higher inci-
dences of foci and al tered hepatocytes were noted in
the treated animals after 6 months and 9 months. At
nine months, hyperplastic nodules were noted in two of
5 high dose males.
II In the. . . [auramine hydrochlor ide] study, rats were
administered 0,'300, 500, 1000, 1500 or 2000 ppm of the
compound in the feed for nine months. [The] mean body
weights and food intake were lower at all concentra-
tions and a dose-related increased activity of gamma-
glutamyl transpeptidase was noted in liver homogenate.
Histopathology indicated increased incidences of foci
and altered hepatocytes among treated animals. After
nine months, hyperplastic nodules were seen in males at
1000 and 2000 ppm and hepatocellular carcinomas were
observed in the high dose of 2000 ppm."
=======================~============================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
306
.18A "OM! .... (ftEV. ..711
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8EHQ-0588 -0730
Page 2 of 3
In submitting these preliminary findings under Section 8(e), BASF
stated that the results of these 9-month studies "indicate that
[the nitrate salt of] ethyl auramine appears to exhibit the same
pattern of effects on enzymes and li ver pathology as aurami ne;
however, . . . [the nitrate salt of ethyl auramine] appears to be
quantitatively less potent than auramine." BASF reported also
that the International Agency for Research on Cancer (I ARC) "has
concluded that commercial auramine is carcinogenic to mice and
rats after oral administration and that there is sufficient evi-
dence that the manufacture of auramine is associated with [an]
increased risk of bladder cancer in humans."
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon the Agency's receipt of full
copies of the final reports of the cited 9-month feeding studies
of auramine hydrochloride and the nitrate salt of ethyl auramine.
For further information with regard to the IARC deliberations on
auramine, the reader's attention is directed to the following
IARC Monographs: Volume 1 (pages 69-73; 1972) and Supplement 7
(pages 118-119; 1987).
Current Production and Use
The nitrate salt of ethyl auramine (CAS No. 43130-12-7) is not
listed in the non-confidential computerized version of the
initial (1977) TSCA Chemical Substance Inventory.
A review of the production range (includes importation volumes)
statistics for the hydrochloride salt of auramine (CAS No. 2465-
27-2), which is listed in the initial TSCA Chemical Substance
Inventory, showed that 149 thousand to 1.4 million pounds of this
chemical substance were reported as manufactured and/or imported
in 1977. This production range information does not include any
data claimed as TSCA Confidential Business Information (CBI) by
the person(s) reporting for the initial TSCA Inventory, nor does
it include any data that would compromise TSCA CBI. All of the
information reported for the initial TSCA Inventory, including
the production range information, is subject to the limi tations
contained in the initial TSCA Inventory Reporting Regulations (40
CFR 719).
In its TSCA Section 8(e) notice, the BASF Corporation stated that
it "does not handle or market the nitrate salt of ethyl auramine;
however, it does import or has imported the hydrochloride and
acetate salts of ethyl auramine as well as the hydrochloride salt
of auramine."
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8EHQ-0588-0730
Page 3 of 3
Accord i ng to the Condensed Chemical Dictionary (10th Ed.), the
uses of auramine hydrochloride are listed as follows: "Yellow dye
for paper, textiles, leather; also an antiseptic; fungicide." No
information on the use(s) of ethyl auramine or any of its salts
was located in the secondary literature sources consulted by EPA.
Comments/Recommendations
BASF stated that although the company does not handle the nitrate
salt of ethyl auramine, the reported results will be distributed
to all employees and customers who handle/purchase products that
contain other salts of ethyl auramine. In addition, BASF stated
the company is updating the Material Safety Data Sheets (MSDSs)
for these products.
a)
The Chemical Screening Branch will ask BASF to ensure
that EPA receives complete copies of the final reports
(including the actual experimental protocols, results
of gross and histopathological examinations, etc.) from
the two 9-month feeding studies cited in the company's
TSCA Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, BASF will be asked to
describe the actions the company has taken or plans to
take to reduce or eliminate exposure to the various
salts of auramine and ethyl aurarnine. In addition, BASF
will be asked to describe the nature and results, if
available, of all studies (other than those reported
already to EPA or those cited in the open scientific
literature) about which BASF is aware or that BASF has
conducted, is conducting or plans to conduct to deter-
mine the toxicity of or the exposure to such compounds.
b)
In 1981~ the Chemical Screening Branch prepared a
Chemical Hazard Information Profile (CHIP) on auramine
and its hydrochloride salt. Following a review of the
final reports from the BASF 9-month feeding studies,
the Chemical Screening Branch will consider updating
and/or expanding the CHIP.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i s ta nce Off ice (TAO/OTS/OPTS/EPA) for
further distribution.
308
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DA TI!,
.311988
Page 1 o,f 3
SUIJECT,
Status Report* 8EHQ-0588-073l S
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
Approved f I tC (.b#r
Coordinator
,,,0.1,
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The Dow Chemical Company has claimed the exact identi ty of the
subject chemical to be TSCA Confidential Business Information
(CBI); staff of the Information Management Division (IMD/OTS)
will be requesting Dow to substantiate this CBI claim. In the
"sanitized" version of the Section See) submission, Dow reported
non-confidentially that the subject chemical is a "substituted
diphenyl ether."
Submission Description
Dow provided the following summarized information with regard to
the conduct and preliminary results of an oral teratology study
of a substituted diphenyl ether in rats:
"Groups of 30 bred Fischer 344 rats were administered
the substituted diphenyl ether in corn oil solution by
oral gavage on days 6 through 15 of gestation at dose
levels of 0, 0.25, 0.50, 1.0 or 7.5 mg/kg body weight/
day. Each fetus was examined externally and at least
50% of the fetuses from each li tter were examined for
visceral alterations by the Staples technique. Results
summarized below do not include skeletal examination of
fetuses which is in progress.
"Indications of maternal toxicity were evidenced by an
increase in liver weights in high dose (7.5 mg/kg/day)
females. Accompanying the maternal toxicity at the
high dose was a significant decrease in fetal body
weight. In addition, visceral examination revealed an
increased incidence (not statistically significant) of
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
309
.~" ..0.... ..... '''IV. ..,.,
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8EHQ-0588-0731 S
Page 2 of 3
a great vessel malformation in the high dose group.
This [fetal] malformation involved a displacement of
the ascending aortic arch which occurred in one fetus
in the 1.0 mg/kg/day dose group and 3 fetuses in the
7.5 mg/kg/day dose group. Although the increased
incidences of great vessel malformation were not
statistically significant, the clustering of 3 fetuses
from 3 different litters at the top dose level suggests
a possible teratogenic response. ...."
Submission Evaluation
In order for EPA to evaluate the overall significance of the
reported developmental toxici ty, Dow should be asked to ensure
that the Agency receives a complete copy of the final report from
the oral teratology study cited in Dow's Section 8(e) submission.
It should be noted that the reported developmental toxicity
information is quite similar to that reported to EPA previously
under Section 8 (e) on a chemical identified generically as a
substituted diphenyl ether; the reader's attention is directed to
the "status report" prepared by EPA in response to initial TSCA
Section 8 (e) submission number 8EHQ-0986-0623 S. It should be
noted further that EPA has also received "For Your Information"
(FYI) submissions on chemical substances identified generically
as substituted diphenyl ethers (FYI-OTS-0286-0483 S et seq. and
FYI-OTS-l087-0580 S et seq.). In addition, EPA has received
Section 8 (e) and FYI notices on brominated diphenyl ethers and
the Chemical Screening Branch prepared (in late 1986) a "Chemical
Hazard Information Profile" (CHIP) on a number of brominated
diphenyl ethers; the Risk Analysis Branch (RAB/ECAD) is reviewing
available toxicity/exposure data on brominated diphenyl ethers.
Current Production and Use
According to Dow, the subject sub.stituted diphenyl ether
the research stage and is being evaluated as a pesticide."
"is at
Comments/Recommendations
In its Section 8 (e) submission, Dow stated that in accordance
with Dow's longstanding policy, the company is notifying relevant
employees about the reported toxicologic findings.
a)
The Chemical Screening Branch will ask Dow to ensure
that EPA receives a complete copy of the final report
(including the actual experimental protocol, results of
gross and histopathologic examinations, results of any
statistical analyses, etc.) from the oral teratology
study cited in the company's TSCA Section 8(e) notice.
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8EHQ...0588...0731 S
Page 3 of 3
In addition, Dow will be asked to submit final reports
(if available) from any pilot teratology studies of the
subject chemical if such studies were conducted.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Dow will be asked to
describe the nature and results, if available, of all
studies (other than those reported already to EPA or
those cited in the open scientific literature) about
which Dow is aware or that the company has conducted,
is conducting or plans to conduct to determine the
toxicity of this substituted diphenyl ether.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
311
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
D4TI!:
J.t4 - 9 1988
Page 1 of 5
SU8JECT:
Status Report* BEHQ-05BB-0732
David R. Williams~ection B(e)
Chemical Screening Branch/ECAD
APprovedr r ~ thlr{-
Coordinator
I'ROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
(See Note on Page 5 of this Status Report)
The submi tting .company has claimed its company name to be TSCA
Confidential Business Information (TSCA CBI); the Information
Management Division (IMD/OTS) will be requesting the submitting
company to substantiate this TSCA CBI claim. In the "sanitized"
version of this Section 8 (e) notice, the submitter stated that
the TSCA CBI claim involving company name is consistent with the
claim associated with a TSCA section 5 "Low Volume Exemption"
(LVE-B8-0020) . submi tted previously to the Agency on the subject
chemical substance.
Submission Description
In its Section B(e) notice, the submitting company provided the
final results of an acute male guinea pig dermal toxicity study
and an acute male and female rat oral toxicity study of 2-amino-
5,6-dimethoxybenzothiazole (CAS No. 6294-52-6).
The "REMARKS" section of the submitted report on the guinea pig
study provides the following information regard i ng the conduct
and results of this acute study:
"The test article was a slight skin irritant. A dose
of 0.5 g was applied to the guinea pig abdomen, and an
occ 1 us i ve wr ap was used to hold the mater i a 1 aga i nst
the skin for 24 hours. Signs of irritation were
restricted to slight erythema in three of five animals
at the site of application. By 24 hours after termina-
tion of exposure, all animals appeared normal. All
animals gained weight normally and no evidence of
percutaneous absorption was noted."
The submitter's cover letter provides the following information
regarding the conduct and results of the acute oral toxicity
study in rats:
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
lnformatlon submltted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
.~4 1'0" II" I".". 1-111
312
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8EHQ-0588-0732
Page 2 of 5
.. In the acute oral toxici ty study [( in which 2-amino-
5,6-dimethoxybenzothiazole was administered at single
dose levels of 312, 625, 1250, 2500 and 5000 mg/kg body
weight)], an estimated oral LD50 of 1165 mg/kg was
obtained in both male and female rats. All animals
receiving doses of 2500 mg/kg or more died before
scheduled study termination. Doses of 625 or 1250
mg/kg were also lethal to a portion of the treated
animals. Some animals from the latter two dose groups
which survived developed swellings of the neck and face
d ur i ng the second week of the study. The swell i ngs
were located in the cervical lymph nodes and appeared
to be abscesses. Materials obtained from three of the
abscesses were cultured for anaerobes and aerobes.
Bacteria that were isolated consisted predominantly of
bet'a hemolytic streptococci (non-group A) which are
normally found in the oral cavity of rats.
"The test article adversely affected the thymus and may
have decreased the immune response of the test animals,
but the precise nature of the toxic effect and the
cause of [the] deaths following test article admini-
stration are not clear. Atrophy of the thymic cortex
was observed in a majority of the rats that survived
for at least twenty-four hours after exposure to doses
> 625 mg/kg. Atrophy of the thymus commonly occurs in
animals given near lethal doses of many materials
because of stress induced during the toxic response-
Thus, [the] thymic atrophy is not totally unexpected.
However, the occurrence of streptococcal abscesses in
these animals is unusual. There are two possible
explanat ions for the seemi ngly high rate of infect i on
found in this study. I The first is that near lethal
doses of the test article severely stressed the animals
resulting in lowered immune function and therefore
infection. The second [explanation] is that the test
article directly interfered with immune function
resulting in infection. In either case, the test
article was associated with infection only at doses
which were lethal to some of the rats.
"At a dose level of 312 mg/kg, lethality and infection
were not seen, even though [the] animals were housed on
the same rack with infected animals."
Submission Evaluation
In the skin irritation study, 2-amino-5,6-dimethoxybenzothiazole
(0.5 g moistened with water) was applied to presumably unabraded
skin of the abdomen of 5 male Crl: (HA)BR Hartley guinea pigs. An
occlusive wrap was used to hold the test material in place for 24
hours. According to a table in the final report, slight erythema
at the appl ication site was seen in 3/5 an imals at 24/48 hou r s
post-exposure; no skin reactions were seen 2 weeks post-exposure.
313
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8EHQ-0588-0732
Page 3 of 5
In the acute oral toxicity study, groups of 5 male and 5 female
specific pathogen free (SPF) Crl:CD(SD)BR rats were administered
by gavage a single dose of 2-amino-5,6-dimethoxybenzothiazole in
0.5% solution/suspension in guar gum at 312, 625, 1250, 2500 or
5000 mg/kg body weight. The animals were then observed daily for
14 days at which time surviving animals were sacrificed and sub-
jected to necropsy. Dose-related clinical effects suggestive of
neurotoxicity \Jlere most notable. The clinical signs included
slight to severe weakness in animals from all 5 dose groups,
prostration in most animals at the highest doses, vasodilation in
all animals in the 3 highest dose groups, convulsions in 1 female
at 1250 mg/kg and tremors in 1 male at 625 mg/kg. At the highest
dose level, death occurred between a few hours and one day after
dosing; at the lower doses, death occurred between 1 and 12 days
post-exposure. The estimated oral LD50 is 1165 mg/kg for both
males and females.
The treatment-related gross morphological changes observed in the
animals that died shortly after dosing (Le., within 24 hours)
included one or more of the following effects: small spleens, red
discoloration of the facial hair, red discoloration of the urine
in the bladder, necrosis of the glandular/non-glandular gastric
mucosa, and yellow discoloration of the inguinal hair. Although
the cause of death is not known, the findings suggest that kidney
damage, hemorrhage and erosion of the stomach are the poss i ble
causes.
Necropsy and histological examination of selected animals \",ith
delayed deaths or animals that survived the l4-day observation
period showed one or more of the following treatment-related
changes: atrophy of the thymic cortex, enlarged livers, enlarged
spleens, pale kidneys, abscessation and enlargement of cervical
lymph nodes, and adipose t issue a trophy. Ag a in, the ca u se 0 f
death was not determined but was most likely due to impairment of
organ systems such as the immune system, liver and kidney. No
treatment related histopathological changes were observed in the
animals from the lowest dose group (312 mg/kg).
It should be pointed out that the most notable and consistent
effects observed in the animals that survived for at least 24
hours after oral exposure to 2-amino-5,6-dimethoxybenzothiazole
at doses of greater than 625 mg/kg involved the immune system.
In these an ima 1 s, the thymus, spleen and lymph nodes were all
affected; streptococcal abscesses were also found in most of
these animals. These findings suggest that the observed
infection was most likely due to impaired immune function.
In conclusion, based on the submitted toxicological information,
2-amino-5,6-dimethoxybenzothiazole may be classified as slightly
irritating following acute dermal exposure and moderately toxic
following acute oral exposure. It would be of interest to know
if the submi tting company plans to conduct a repeated exposure
study (e.g., a 28-day study) in order to characterize better the
toxicity profile of the subject chemical substance.
314
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8EHQ-0588-0732
Page 4 of 5
Immediately upon receipt of this TSCA Section 8(e) submission,
the Chemical Screening Branch informed the Chemical Control
Division (CCD/OTS); CCD is responsible for the administration of
EPA's TSCA Section 5 "New Chemicals Program" (NCP).
Current Production and Use
In its TSCA Section 8(e) notice, the submitting company provided
the following information regarding the use of and the potential
for exposure to 2-amino-S,6-dimethoxybenzothiazole:
"This chemical is used as a low volume site-limited
intermediate. ... [The company] is not aware of any
adverse health problems associated with its manufacture
or use to make the f i na I product. The chemical was
originally evaluated as health hazards unknown - avoid
all con tac t. Based on the acu te tox ic i ty test.i ng,
employees will be required to wear company supplied
clothing and gloves. In addition, employees working
with the damp material will wear disposable dust masks
while those working with the dry material will wear
cartridge dust respirators or air-line respirators."
A .sanitized" (Le., non-confidential) November 2, 1987 letter
attached to the sanitized version of LVE-88-0020 (obtained from
EPA's public TSCA files) presents the following information with
regard to the general use of and the potential for exposure to 2-
amino-S,6-dimethoxybenzothiazole as well as other chemicals for
which LVEs were submitted (LVE-88-0019 and LVE-88-0021):
"The [LVE] substances will be manufactured/used as
site-limited intermediates in a new synthesis for
chemicals already on the TSCA Inventory. All wastes
containing the LVE substances will be collected and
disposed of by incineration; therefore, [the
company expects] no releases to receiving bodies of
water. Additionally, products distributed in commerce
will not contain any of the LVE substances; therefore,
there will be no consumer exposure to the substances."
Comments/Recommendations
In addition to the previously described actions taken to reduce
or eliminate exposure to 2-amino-S,6-dimethoxybenzothiazole, the
submitter reported that the Material Safety Data Sheet (MSDS) for
this chemical has been updated to warn workers and others about
possible immunotoxicity; a copy of this updated MSDS was provided
by the company as part of its TSCA Section a(e) notice. Finally,
the company reported that it is considering the need for further
toxicologic testing of 2-amino-S,6-dimethoxybenzothiazole.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
315
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Note
8EHQ-0588...0732
Page 5 of 5
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which the company is aware or that the company
has conducted, is conducting or plans to conduct to
determine the toxici ty of or the exposure to 2-amino-
S,6-dimethoxybenzothiazole. The submitter will be
informed that EPA would be especially interested in the
results of a multiple exposure toxicity study (e.g., a
28-day study) of 2-amino-S,6-dimethoxybenzothiazole.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of 2-amino-S,6-dimethoxybenzothiazole.
As was the case for the submitter's initial TSCA
Section 8(e) notice, the Chemical Screening Branch will
immediately inform appropriate staff of the Chemical
Control Division (CCD/OTS) about all incoming TSCA
Section 8(e) data pertaining to the subject chemical.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
CCD/OTS/OPTS/EPA. In addition, copies of this status
report will be provided to the TSCA Assistance Office
(TAO/OTS/OPTS/EPA) for further distribution.
In a letter to EPA dated July 11, 1988, the
Eastman Kodak Company wi thdrew its TSCA CB I
claim for company name.
~f,,~~~i«~ /'-
James F. Darr
7/11/88
316
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
OA TI! :
~ 221988
Page 1 of 5
APprOVedr T~ C(n/Fp
SUBJECT:
Status Report* 8EHQ-0588-0733
FYI-OTS-0288-0599
David R. ~illiams~ction 3(e) Coordinator
Chemical Screening Dranch/ECAD
I'ROM:
TO:
James F. Darr, section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
Under. Section 8(e) of TSCA, the American Telephone ana Telegraph
Company (AT&T) provided a complete copy of the final report from
a delayed dermal contact hypersensitivity study of "PO Makeup'! (a
palladiu!T\ plating compound) in guinea pigs. According to AT&T,
PO Makeup was the subject of a TSCA Section 5 "Pre-Manufacture
Notification" (PMN No. P-88-445) filed previously by AT&T. It
should be noted that in PMN No. P-88-445, AT&T has asserted TSCA
Confidential Business Information (CBI) claims for 1) the exact
chemical composition of PO Makeup, 2) information concerning
portions of a mixture, and 3) certain process information.
The "SUMMARY" section of the final report submitted by AT&T under
Section 8(e) presents the following information with regard to
the conduct and results of the sensitization study as well as
other studies designed to determine appropriate dose levels for
that sensitization study.
"In a preliminary dose-range-finding study, four
animals, two per sex, were exposed to four concentra-
tions of 1.0, 5.0, 10 and 20% of the test material in
80% ethanol. In two Secondary Irr i tat i on Sc reens, a
total of four animals (one per sex per study) \'lere
exposed to concentrations of 30, 40, 50, 60, 70, 80, 90
and 100% of the test article in 80% ethanol. Based on
the results of the dose-range-finding studies, the dose
concentration chosen for induction and challenge [in
the dermal sensitization study] was 100%.
"[In the sensitization study,] PD :1akeup. . was
dermally applied to twenty guinea pigs (ten males and
ten females) for a total of three six-hour insult
periods at a 100% concentration. An additional group
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
1~fo~atl0n s~bmltted t~ EPA pursuant to Section 8(e), the substantial
rlsk lnformatlon reportlng provision of the Toxic Substances Control
Act (TSCA): Th~ statements , made i~ this report should not be regarded
as expresslng flnal EPA POllCY or lntent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
317
a~A 1'0'" II" ,,,avo ..,.,
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Page 2 of 5
of five gui nea pig s (three males and two females) was
treated with l-chloro-2,4-dinitrobenzene [(DCNB)] at a
0.3% concentration. The positive control group was
treated for a total of three six-hour periods. A group
of ten guinea pigs (five males and five females) was
treated with 80% ethanol for a total of three six-hour
insult periods. This group served as the negative
control. Four naive guinea pigs (two males and two
females) r2mained untreated until the challenge period.
"Thirteen days after the last induction period, the
animals were challenged in the same manner at a naive
site. positive responses were elicited in all animals
receiving the positive control article, l-chloro-2,4-
din i trobenzene (DCNB). No responses were observed at
24 or 48 hours after challenge in the animals in the
negative control group. One response was observed at
24 and 48 hours after challenge in the naive animals
receiving the test article at a 100% concentration.
Three positive responses were observed in the experi-
mental animals at 24 hours after challenge. Six
positive responses were observed in the experimental
animals at 48 hours after challenge. Seven days after
the pri~ary challenge, the experimental animals and an
additional group of four naive guinea pigs (two males
and two females) were rechallenged at a naive site.
Responses were observed at 24 and 48 hours after
rechallenge in the naive animals receiving the test
article at a 100% concentration. Four positive
responses were observed in the experimental animals at
24 hours after rechallenge. Seven pos i ti ve respon ses
were observed in the experimental animals at 48 hours
after rechallenge.
"Ba sed upon the observa t ions [that were] made in the
Delayed Contact Hypersensitivity Study in Guinea pigs,
PO Makeup when induced, challenged and re-
challenged at a 100% concentration, caused delayed
contact hypersensitivity in .guinea pigs."
In providing the above toxicologic findings to EPA, AT&T directed
the Agency's attention specifically to the symptomology and death
of one of the guinea pigs in the sensitization study:
"Animal # 6455 showed decreased activity, decreased
body tone, abnormal stance, abnormal gait, and dyspnea
on April 23 and 24, and died on April 25, 1988. The
animal had an initial weight of 323 grams but upon
death weighed 243 grams. Death occurred during the
rest period, after initial exposure but prior to the
challenge phase of the study. Gross necropsy of this
one animal - the only animal to die out of the twenty
used in the study - showed multiple lesions throughout
the cecum. This may have been due to exposure to . .
318
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8EHQ-OS~8,..0733
Page 3 of 5
[PO Makeup], and/or stress on the animal resulting from
the experimental conditions. The animal may have licked
the area when the protective bandage was removed during
~he rest period and thus ingested some of the [test]
material. Cecum lesions were not noted in the Acute
Exposure Dermal Toxici ty Study wi th PO Makeup
previously submitted to EPA [in conjuntion with PMN No.
P-88-445]. No other animal showed this symptom complex
during the study. It is therefore plausible that inad-
vertent exposure via the oral route occurred in this
instance. Because of the small amount of material
applied, the lack of similar pathological findings in
other assays of this material (previously submi tted to
the Agency), and the fact that the physical symptoms
displayed by the animal occurred shortly before death,
this symptom complex is not considered to represent a
neurotoxicity response."
It shou ld be noted that in a recent (February 1988) "For Your
Information" (FYI) submission (FYI-OTS-0288-0599), AT&T provided
a complete copy of the final report from an acute rabbit dermal
toxicity study of a palladium plating compound identified non-
confidentially as "PO Replenisher." In submitting this final
report, AT&T noted that PD Replenisher was the subject of PMN No.
P-88-444. (At the time of EPA's receipt of this particular FYI
submission, EPA' s 90-day review per iod for PMN No. P-88-444 had
not ended.) The" SUMMARY" sect i on of the subm i t ted f i na 1 repor t
presented the following information wi th regard to the conduct
and results of this acute rabbit dermal toxicity study of PD
Replenisher:
". [PO Replenisher was applied in single doses of
8.0 ml/kg to the shaved unabraded dorsal skin of 5 male
and 5 female New Zealand whi te rabbi ts. The si te of
application was wrapped throughout the 24-hour exposure
period. Following the 24-hour exposure period, the
wraps were removed and the animals were observed for a
l4-day period after which all surviving animals were
sacrificed and necropsied.] Signs observed during the
study included decreased activity, decreased muscle
tone, abnormal gait, abnormal stance and prostration.
A yellow-brown discoloration, [a] slight to moderate
erythema and necrosis of the skin at [the] application
site were observed during the course of the study.
Three of ten rabbits [(one male and two females)] died
during the study. Necropsy findings on these animals
revealed multiple black lesions throughout the stomach,
pale or discolored intestines and discolored cecums
with multiple lesions. No visible lesions were observed
in any of the remaining animals upon terminal necropsy.
"Based upon the observations made.
dermal L050 for PO Replenisher. .
be greater than 8.0 ml/kg."
., the estimated
. was determined to
319
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Page 4 of 5
Submission Evaluation
Immediately upon receipt of FYI-OTS-0288-0599 and 8EHQ-0588-0733,
the Chemical Screening Branch provided complete copies of these
submissions to the Chemical Control Division (CCDjOTS) which is
responsible for administering EPA's TSCA section 5 "New Chemicals
program" (NCP).
Based on an initial review of the study submitted by AT&T under
Section 8(e) of TSCA, PO Makeup appears to elicit delayed dermal
contact hypersensitivity in guinea ?igs when challenged with the
test compound after an induction period. AT&T should be asked to
descr i be the studies that the company has underway or plans to
conduct to determine whether accidental ingestion of PO Makeup or
PO Replenisher produced the behavioral signs and digestive tract
lesions observed in the acute studies of these palladium plating
compounds.
Current production and Use
In its TSCA Section 8(e) and FYI submissions, AT&T provided the
following information regarding the use of and the potential for
exposure to PO Makeup or PO Replenisher:
"This material, like all similar plating solutions, is
used in a plating process which is fully enclosed and
designed to avoid any loss of the plati ng compounds,
which frequently, as in this case, contain precious
metals. Moreover, the [Material Safety Data
Sheet (MSDS)] requires that individuals handling this
substance wear gloves, goggles and protective overalls.
Accordingly, dermal exposure, even under the worst con-
ditions, will be minimal."
It should be noted that PO Replenisher and PO t1akeup MSDSs were
submitted to EPA with PMH No. P-88-444 and PMr1 No. P-88-445,
respectively.
The sanitized (i.e., non-confidential) versions of PMN No. P-88-
444 and PMN No. P-88-445 obtained from EPA's public document
files state that PO Replenisher and PO 1'1akeup are plating bath
component solutions "for deposition of palladium on electronic
componen t con tact s . " Acco rd i ng to these PMNs, the pallad i urn
system is a replacement for gold cyanide plating systems.
Regarding the production volumes of PO Makeup and PD Replenisher,
the sanitized versions of PMN ~o. P-88-444 and PMN No. P-88-445
state that past yearly production of these materials has been
less than 1000 kg each and future production for each is not
expected to be illore than l10J to 1500 kg per year.
320
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8J::HQ-0588,-0733
Page 5 of 5
Comments/Recommendations
a)
In view of EPA's generat interest in corporate actions
taken on a voluntary basis in response to n9W chemica~
toxicity or exposure information, AT&T will be asked to
describe the nature and results, if available, of all
studies (other than those reported already to EPA or
those cited in the published scientific literature)
about which AT&T is aware or that AT&T has conducted,
is conducting or plans to conduct to determine the
toxicity of PO Makeup and PO Replenisher.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of these palladium plating compounds.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA, OPP/OPTS/EPA and
CCO/OTS/OPTS/EPA. In addition, copies of this status
report will be provided to the TSCA Assistance Office
(TAO/OTS/OPTS/EPA) for further distribution.
321
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JLl - 1 1988
Page 1 of 3
SUIJECT:
status Report*
8EHQ-!3688-!3734 S
APproved!t-r ~/7-M
Coordinator
FROM:
David R. Wi1liams~ection 8(e)
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The submitting company has claimed its company name and the exact
identi ty (ies) of the subj ect chemical (s) to be TSCA Confidential
Business Information (CBI); the Information Management Division
(IMD/OTS) will be requesting the submitter to substantiate these
TSCA CBI claims. It should be noted that in the "sanitized"
(i.e., non-confidential) version of the Section 8(e) submission,
the company stated that the test material was a "silane mixture."
In addition, the company stated non-confidentially that a portion
of the test material was the subject of a previous submission to
the Agency under Section 5, the "Pre-Manufacture Notification"
(PMN) provision of TSCA. The company-sanitized version of the
Section 8(e) submission identified that PMN number as P-88-ll68.
According to the company-sanitized version of P-88-ll68 obtained
from the Agency's public files, the PMN chemical was identified
generically by the submitting company as a "modified aliphatic
alicyclic polyester" intended for use as an "industrial coating
component" with a reported production range of 212,1300 to 248,000
kilograms/year. It should be noted also that the "DESCRIPTION OF
ON-GOING HEALTH EFFECT TESTING" (the last page of the sanitized
version of P-88-1168) provides the following information:
"The subject of this notification has been submitted
for toxici ty testing at . . . [the company's] in-house
tox ico10gy laboratory. Tests to be performed include
the following: .
28-Day Repeated Inhalation on Final Product
Containing the New Substance
"The results and tests protocols will be forwarded [to
the Agency] when the studies are complete."
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e}, the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or interi~ with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
322
.~A '0- ".. c".v. 10'81
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8EHQ-0688-0734 S
Page 2 of 3
Submission Description
In the sanitized version of the TSCA Section 8(e) submission, the
company provided the following information regarding the conduct
and preliminary findings from a 28-day inhalation study of the
silane mixture in rats:
"This silane mixture was the subject of a repeated, 28-
day study, in which male and female Fischer 344 rat s
were exposed to target concentrations of 0, 25, 100. or
300 mgjm3. The duration of the exposures was six hours
a day, five days a week for four weeks. At the conclu-
s ion 0 f the study, [the] animals were necrops ied and
subjected to an extensive histopathological evaluation.
The relevant findings thus far from this investigation
have revealed significant respiratory distress and the
majori ty of the animals were necropsied in a moribund
condition at the 300 mgjm3 concentration. Additionally,
during the final week of exposure, one male rat died in
the 100 mgjm3 exposure group. At necropsy, lungs were
filled with fluid in these exposure groups. However,
after a two-week recovery period, the [animals in the]
100 mgjm3 exposure group showed weight gain which was
normal and no gross pathology during necropsy. Animals
exposed to 25 mgjm3 resembled the control group wi th
respect to in-life evaluations with the exception that
females showed a decreased body weight gain during the
fourth week of exposure [as] compared to the controls.
Histopathology results are not available at this time.
Finally, in a separate study, the sensory irritation
response in S-W mice was evaluated. The RD50 ([ i.e.,
the] concentration which caused a 50% decrease in res-
piratory rate) was found to be 700 mgjm3."
Submission Evaluation
Immediately upon receipt of this Section 8 (e) submission, the
Chemical Screening Branch sent copies of the submission to the
Chemical Control Division (CCDjOTS) for review and appropriate
followup attention. The Chemical Control Division is responsible
for administration of the Agency's TSCA Section 5 "New Chemicals
Program" (NCP).
Current Production and Use
Considering the submitter's TSCA CBI claims, no information with
regard to the TSCA Chemical Substance Inventory status of the
subject chemical(s) will appear in this status report. In its
Section See) notice, the submitting company reported that the
test "material was confined to . . . [the company's] research and
development [(R&D)] and toxicology laboratories."
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8EHQ-0688-0734 S
Page 3 of 3
Comments/Recommendations
In its TSCA Section 8(e) submission, the company stated that upon
completion and quality assurance review of the 28-day inhalation
study, a copy of the final report of that study would be provided
to the Agency. In addition, the submitter reported that although
II no fu r ther work is scheduled for thi s [si lane] mixture, II any
further information that may be obtained would be submitted to
the Agency for review. Finally, the submitter reported that all
employees who worked with the test material have been notified in
writing.
a)
The Chemical Screening Branch wi 11 ask the submi tting
company to ensure that the Agency receives a full copy
of the final report (including the actual experimental
protocols, results of gross/histopathological examina-
tions, etc.) from the 28-day inhalation study ci ted in
the company's Section 8(e) submission. In addition,
the submi tter wi 11 be asked to submi t a complete copy
of the final report of the RD50 study in S-W mice that
was cited also in the company's Section 8(e) notice.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which the company is aware or that the company
has conducted that are designed to determine the
toxicity of the test material.
b)
As was the case with the initial Section 8 (e) notice,
the Chemical Screening Branch will immediately send all
reported information to CCD/OTS staff for review and
appropriate followup attention.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
CCD/OTS/OPTS/EPA. In addition, copies of this status
report will be provided to the TSCA Assistance Office
(TAO/OTS/OPTS/EPA) for further distribution.
324
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
0" TI!::
Jll - 8 1988
Page 1 or 5
SU8JECT:
Status Report* 8EHQ-0688-0735
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
Aoproved: ~ r c;:;.
(j J
Coordinator
7~;;/ccf
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
Pursuant to Section 8(e) of TSCA, the Pennzoil Company provided a
report concerning the detection of arsenic in samples from oi 1
and gas operations in West virginia. The following information
regarding this detection is presented in the "EXECUTIVE SUMMARY"
portion of the submitted report:
" [Following] a series of laboratory tests by a
university and by its own technical staff, Pennzoil
determined that natural gas samples from two of its
production areas in West virginia contained trace
amounts of arsenic [(i.e., approximately 1 ug/l gas)].
"There is reason to believe that the arsenic traces are
organic in nature [(e.g., trimethyl arsine)] and as
such constitute no health hazard during the production,
gathering and distribution operations.
" . [pennzoi 1 does] not know the level of a r sen i c
exposure, if any, which would result from whatever
arsenic may be converted to arsenic trioxide [( an
inorganic arsenic compound)] during the combustion of
the gas. Consequently, at this time. . . [the company
is] unable to determine the precise nature of the
health risk, if any, which prolonged exposure to the
combusted gas/arsenic mix presents. ....
"Also included in this report is information pertaining
to arsenic which Pennzoil has found in produced water
from certain crude oil production in West Virginia.
Because of its potential relevance to West virginia's
NPDES permit program for produced water discharges,
this information has been previously reported to the
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
l~fo~atlon s~bmltted to EPA pursuant to Section 8(e), the substantial
rlsk lnformatlon reporting provision of the Toxic Substances Control
Act (TSCA): Th~ statements.made i~ this report should not be regarded
as e~presslng flnal E~A POllCY or lntent with respect to the subject
chemlcal(s). Any reVlew of this status report should take into account
the fact that the report may be based on incomplete information.
325
.~A I'OMI u»t ,,,.v. 10'81
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SEHQ-068S.,..0735
Page 2 of 5
West virginia Department of Natural Resources. All
[of] the arsenic detected in the water samples is in
the org ani c methy la ted form, mostly the tr imethyla ted
species. Concentrations ranged from very low levels
(less than 0.3 milligrams per liter (mg/l» in water
samples taken from wellheads to high levels (up to 388
mg/l) in [water] samples taken from oi 1 storage tanks.
The levels of arsenic observed in the wellhead samples
are well within the concentrations for arsenic in pro-
duced water reported in the published literature. The
produced water containing high levels of arsenic from
[oil] storage tanks is being disposed of at a permitted
disposal facility.
"[Monitoring] data from the State of West virginia show
no exceedances of the drinking water standard or the
ambient water quality standard (each is 0.05 mg/l) for
inorganic arsenic anywhere in the sta te - Because 0 f
the relatively low toxicity of organic (particularly
trimethylated) arsenic and the minimal exposure poten-
tial involved, as confirmed by the West Virginia
drinking water supply and stream [monitoring] data, the
information regarding arsenic in produced water clearly
does not present a substantial risk to health or the
environment."
Pennzoil also provided the following information about a worst-
case analysis involving potential arsenic exposure in homes:
"Based on a worst-case scenario, (conditions described
below), . [Pennzoil] arrived at a calculated upper
bound exposure level of 1 ug/m3. This calculated ex-
posure level must not, however, be used to calculate
risk. To employ this already uncertain exposure level
in calculating health risk would only compound the un-
certainties. In order to obtain any reasonable degree
of confidence, actual exposure measurements inside
homes would be required. A more accurate estimate of
the dose to humans can only be determined based on the
exposure measurements, time spent inside the homes, and
the amount of arsenic retained in the body.
"The assumptions employed in . [Pennz,oil's]
calculation of [an] exposure level of 1 ug/m3 are:
Concentration of arsenic in gas
= 1 ug/l
Volume of home (850 sq. ft. equivalent) = 200 m3
Natural gas consumption rate
3 m3/day
= 15
=
Number of air changes in home/day
Exposure time
= 24 hours/day
326
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aE1JQ-0688-0735
l'age 3 of 5
"The [preceding] calculations further assumed that none
of the combustion products were vented to the outside,
but rather that they were exhausted to the interior of
the home."
Submission Evaluation
The assumptions used by Pennzoil in their worst-case exposure
assessment raise a number of concerns. While the values used for
home volume and air changes per day are reasonably conservative,
a natural gas qonsumption rate of 3 m3 per day is far below the
5.5 m3 per day calculated from the data in the u.s. Department of
Energy Residential Energy Consumption Survey (DOE/EIA-0321/1(82).
In addition, the use of 1 ug/l arsenic in natural gas does not
appear to be consistent wi th the actual sampling data contained
in the company's submission (e.g., arsenic concentrations ranged
from .17 to 63 ug/l with values predominantly in the 1 to 6 ug/l
range). Even if one assumes the 63 ug/l value to be unreliable,
employing some of the other values gives rise to theoretical
output concentrations in the home of over 4 ug/m3. It should be
noted that this theoretical concentration exceeds the National
Insti tute of Occupational Safety and Heal th (NIOSH) Recommended
Exposure Limit (REL) of 2 ug/m3 for arsenic in the workplace.
wi th regard to the provided water data, Pennzoil' s report shows
that arsenic concentrations in produced water that is released to
surface waters are in excess of the 0.05 mg/l inorganic arsenic
standard in the West virginia Water Quality Criteria. Pennzoi1
does not appear to perceive this to be a problem because 1) the
arsenic in the produced water is most likely in an organic form
(and therefore less toxic than inorganic forms), and 2) the water
quality tests for West Virginia's streams and water supplies do
not indicate exceedances of the standard. It should be noted,
however, that although Pennzoi 1 assumes that the arsenic in the
produced water is in a less toxic form (e.g., trimethyl arsine)
and assumes further that this form will persist, EPA believes
that it is possible that the trimethyl arsine could be partially
oxidized to the inorganic form in surface waters. Considering
the fact that Pennzoil does not know the exact species of arsenic
present in the produced water, it is possible that a species of
arsenic of greater concern is already present or could form upon
release to surface waters. It should be noted also that the Safe
Drinking Water Act (SDWA) standard of 0.05 mg/l at the tap is
applicable to all forms of arsenic and not just to inorganic
arsenic. Finally, the fact that West Virginia water quality data
do not show exceedances for arsenic is not relevant except for
samples collected from those streams or surface waters that
receive produced water.
An additional point of concern is the possibility that liquids in
the gas transmission/distribution pipelines may contain arsenic.
Typically, natural gas pipelines contain liquids consisting of
organic compounds (mainly alkanes) condensed from the natural gas
stream, water, and contaminants introduced into the pipeline from
327
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8EHQ-06~8-U735
Page 4 of 5
outside sources (e.g., addi tion of anti-corrosion agents; fluid~
enter i ng as the result of leak i ng compressor seals). Pipe 1 i ne
liquids move wi th the gas throughout a pipeline system and tend
to collect in low-lying areas of the pipeline and at points in
the pipeline where pressure changes occur. The line must be
cleaned out ("pigged") periodically to prevent pipeline corrosion
and/or d'amage to the compressors. The points of liquid removal
("pig receivers" and "pig launchers") are typically located at
compressor stations and at low-lying areas along the pipeline
right-of-way. Further, "pigging" operations for some pipeline
systems i nvol ve collect i on and di sposal of thousands of gallons
of liquids. In addition, some pipelines vent the natural gas
directly to the atmosphere during compressor start-up operations.
Such venting may occur as often as daily during peak-use seasons
and may involve coincidental release and dispersion of pipeline
liquids over a large area.
Finally, it should be noted that in November 1987, the Agency for
Toxic Substances and Disease Registry (ATSDR), in collaboration
with EPA, published a DRAFT "Toxicological Profile for Arsenic."
Accord'ing to the draft document, requests for copies of this
profile should be sent to:
Office of External Affairs
Agency for Toxic Substances
and Disease Registry
Chamblee 28 South
1600 Clifton Road
Atlanta,GA 30333
Comments/Recommendations
Immediately upon receipt, the Chemical Screening Branch provided
complete copies of Pennzoil's Section 8(e) submission to EPA's
Office of Water (O~), Office of Air and Radiation (OAR), Office
of Research and Development (ORD), Office of Solid Waste and
Emergency Response (OSWER), EPA"s Region III Office (located in
Philadelphia, PA), the Department of Energy (DOE), the Consumer
Product Safety Commission (CPSC), the National Institute for
Occupational Safety and Health (NIOSH), and the Occupational
Safety and Health Administration (OSHA); copies of Pennzoil's
Section 8 (e) notice were also sent immediately to the Exposure
Evaluation Division (EED/OTS) and Regional Risk Guidance Staff
(RRGS) in the Existing Chemical Assessment Division (ECAD/OTS).
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure data, Pennzoil will be asked to
describe the actions the company has taken or plans to
take to not i fy workers and others about the reported
information. In addition, Pennzoil will be asked to
descr i be the nature and resul ts, if ava i lable, of all
studies (other than those reported already to EPA)
328
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oEHQ-Ob88...0735
Page 5 of 5
about which Pennzoil is aware or that the company has
conducted, is conducting or plans to conduct that are
designed to determine human or environmental exposure
to arsenic in any form resulting from production and
distribution of natural gas.
b)
In conjunction with other OTS Divisions, the Chemical
Screening Branch will review the reported information
to determine the need for further OTS assessment. The
Chemical Screening Branch will send Pennzoil's response
to all EPA Offices and other Federal agencies that
received Pennzoil's initial TSCA Section 8(e) notice.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, DOE, OW/EPA,
OSWER/EPA, OAR/EPA, ORD/EPA, EPA's Region III Office,
EED/OTS and RRGS/ECAD/OTS. In addition, copies of this
status report will be provided to the TSCA Assistance
Office (TAO/OTS/OPTS/EPA) for further distribution.
329
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
0... TE:
J1. - 1 1988
Page 1 of 4
SU8JECT:
Approved: p.-.. 1: ~=- 7l; I if-
David R. Williams~ction 8(e) Coordinator
Chemical Screening Branch/ECAD
Status Report*
8EHQ-f3688-f3736
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Reilly Tar & Chemical Corporation submitted the following
information with regard to several workplace incidents involving
2-amino-5-chloropyridine (CAS No. 11372-98-6):
"The first incident occurred on April 313, 1988 during
the reprocess i ng of the above product. Reprocessing
involved washing the product with water then spinning
the water off in an electric centrifuge. The affected
employee was involved in the operation for his entire
shift (12 hours). While showering prior to leaving
work, the employee noticed that his skin was slightly
blue in color. At that time, he also reported that for
the last four hours of his shift he had felt light-
headed and nauseated, but thought he was coming down
with the flu. He was sent to a local hospital where he
stayed overnight for observation. He returned to work
on his next shift. At least one other employee was
working in the area on a different process at this time
and suffered no apparent ill effects.
"At the time of the incident, the affected employee was
wearing the protective equipment specified in the run-
sheet for this product, which included the following:
Tyvek (non-porous) coveralls with hood, nitrile latex
gloves, Tyvek foot coverings, chemical goggles, and
half-face chemical cartridge respirator. The indivi-
dual did not recall any specific contact with the
product with the exception of a small amount he noticed
on his wrists which he washed off. After this incident,
the protective equipment requirements were modified to
include protective sleeve cuffs, and [a] full-face
respirator with supplied air. In addition, the cuffs
at the wrist were to be taped.
=:===========:================================:==:==================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
lnformatlon submltted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
.~A I'OMI ,... ,...v. "'8'
330
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8EHQ-0688-0736
Page 2 of 4
"On May 19, 1988, the same individual and another
chemical operator were involved in sweeping the floor
and cleaning the area where the product had been dried
and drummed. Both operators were wearing the required
protective equipment. After 2-3 hours of doing this,
at approximately 1330 hours, the previously affected
individual reported to the first aid room. He was
having difficulty breathing, had a bluish caste to his
skin, and numbness of his extremities. He was given
oxygen, an ambulance was summoned, and he was admitted
to the hospital. He was released from the hospital on
May 20. His co-worker was also sent to the hospi ta 1
for a blood test as a precautionary measure, although
she was not experiencing any of the symptoms seen in
the first individual.
"This, in addition to the fact that the product had
been manufactured previously without incident, led.
[Reilly] to believe that the individual in question
had heightened sensitivity to the product. A decision
was made to continue the clean-up by hosing down the
area with water using the same protective equipment,
but employing the buddy-system to complete the job.
Two chemical operators alternated on the clean-up until
2020 hours when it was noticed that one of the opera-
tors was beginning to turn blue about the ears, hands,
and toes. He was sent to the hospital for observation
and subsequently released at 2400 hours [on] the same
evening. The other operator was unaffected.
"At 2100 hours, a third operator who had been working
with the material on the previous shift reported for
work. He stated that he had passed out while at home
and still had a headache. He was sent to the hospital
for observation."
Reilly reported also that the company has taken the following
actions as a result of the incidents described above:
"1.
The drummed product has been isolated and will
remain so until a written release is received from
the customer. The customer has been notified
about the problems experienced at this site with
this chemical.
"2.
The material safety data sheet [(MSDS)] has been
revised to reflect the new information on this
product. The labels will be revised prior to
shipment.
"3.
The drying room where these incidents occurred has
been decontaminated using a jet spray device
operated by an individual in a fully encapsulated
suit.
331
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"4.
"5.
"6.
"7.
8EHQ-0688-0736
Page 3 of 4
The supplied-air system has
inspected to ensure that it was
responsible for the incidents.
detected.
been thoroughly
not in some way
No problems were
The results of any medical tests have been
requested through Reilly's insurance carr ier,
American International Adjustment Company, Inc.
As of this time, Reilly has not yet received the
results.
A review of the protective equipment, specifically
the coveralls and gloves specified for use with
this product and related products, is in progress.
Reilly will not manufacture this product again
until such time that all [of] the safety concerns
and questions have been satisfactorily addressed
and answered. II
Submission Evaluation
The symptoms (cyanos is, I ight-headedness to pass i ng out, nausea
and headaches) observed in the affected workers are typical of
acute toxic methemoglobinemia. This condi tion is qui te serious
and can be life-threatening. In view of the fact that methemo-
globinemia is known to be induced by certain aromatic amines
(e.g., aniline), it is very possible that exposure to 2-amino-5-
chloropyridine, which is an aromatic amine, caused the symptoms
observed in and/or reported by the workers. It would be of
interest to know if the affected workers' blood was tested to
determine methemoglobin levels and NAOH-Oiaphorase enzyme
act i v i ty leve 1 s; the resul ts of these two tests would help in
determining if the workers were suffering from acute toxic
methemoglobinemia.
Current Production and Use
The subject chemical, 2-amino-5-chloropyridine (CAS No. 1072-98-
6), was not found in the non-confidential computerized or printed
versions of the initial TSCA Chemical Substance Inventory. The
submitter did not provide any information about the production
volume or use (s) of the subject chemical substance nor was such
information located in the secondary literature sources consulted
by the Agency.
Comments/Recommendations
It should be noted that the Office of Toxic Substances (OTS) has
received TSCA Section 8(e) notices on other pyridine derivatives.
In 1982, the Chemical Screening Branch/ECAO/OTS prepared Chemical
Hazard Informa ti on Prof i les (CHI ps) on 2-methyl-, 3-methyl- and
4-methylpyridine; these particular pyridine derivatives are the
subject of a Section 8(d) health and safety data reporting rule.
332
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8EHQ-0688-0736
Page 4 of 4
It should be noted further that pyridine itself was recommended
by the Interagency Testing Committee (ITC) for testing under
Section 4 of TSCA; pyridine is the subject of TSCA Section 8(a)
and Section 8(d) information reporting rules. Finally, it should
be noted that EPA has received a number of TSCA Section 8(e) and
"For Your Information" (FYI) submissions on aroma tic ami nes; a
number of aromatic amines are the subject of TSCA Section 4 test
rules as well as TSCA Section 8(a) and 8(d) information gathering
rules.
a)
The Chemical Screening Branch will request Reilly to
ensure that the Agency is kept abreast of the company's
ongoing investigation of the reported incidents. In
addition, Reilly will be requested to submit, if/when
available, the results of all clinical studies of the
affected workers, especially the results of tests that
would help to determine if the workers were suffer i ng
from acute toxic methemoglobinemia.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Reilly will be asked
to describe the nature and results, if available, of
all studies (other than those reported already to EPA
or those cited in the open scientific literature) about
which Reilly is aware or that Reilly has conducted, is
conducting or plans to conduct that are designed to
determine the toxicity of or the exposure to 2-amino-5-
chloropyridine.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
IMD/OTS/OPTS/EPA. In addition, copies of this status
report will be provided to the TSCA Assistance Office
(TAO/OTS/OPTS/EPA) for further distribution.
333
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JLL I 5 1988
Page 1 of 4
SU8JECT:
Status Report* 8EHQ-0688-0737
David R. Williams~ction 8(e)
Chemical Screening BranchjECAD
Approved: ~"4 r ~ 7/If/Pf
o
FRO",:
Coordinator
TO:
James F. Darr, Section Head
Chemical Risk Identification SectionjCSBjECAD
Submission Description
On behalf of the Antimony Oxide Industry Association (AOIA)
member companies (M&T Chemicals; AMSPEC Chemical; ASARCO
Incorporated; Laurel Industries, Inc.; and ANZON, Inc.), an
outside counsel submitted the final report of a genotoxicity
study of antimony trichloride (CAS No. 10025-91-9) administered
to groups of Swiss mice in single oral doses of 0.5, 1.0 or 1.5
gjkg body weight. According to the cover letter, the animals
were sacrificed at 24, 48 or 72 hours post-administration and the
spleen cells were then analyzed for DNA damage and repair. The
cover letter states that the results of this in vivo study show
that the high dose of antimony trichloride "produced DNA damage
in spleen cells and reduced their ability to repair other DNA
damage produced later by UV irradiation." The cover letter also
provides the following points to be considered in reviewing the
reported findings:
"1.
The methodology used, while suitable for investi-
gation of chemical damage to DNA, is not normally
employed for measuring mutagenic activity. Direct
damage to DNA does not necessarily imply that
mutations are produced. Damage which is either
cell-lethal or repaired by error-free repair
systems will have no mutational consequence.
"2.
DNA damage may simply be one manifestation of
gross toxicity if the high dosage employed in this
study was generally toxic. This seems quite pos-
sible because the oral LD50 of [antimony
trichlor ide] to the rat is 525 mgjkg. The [sub-
mitted final] report gives no information on the
systemic toxicity of the dosages employed, and the
mice may have been generally sick.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
i~fo~ation s~bmitted to EPA pursuant to Section 8(e), the substantial
rlsk lnformatlon reporting provision of the Toxic Substances Control
Act (TSCA): Th~ statements,made i~ this report should not be regarded
as expresslng flnal EPA POllCY or lntent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
334
II~A "0"" II" '''!IV. ..,.1
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Page 2 of 4
"3.
The dosing vehicle used [in the mouse genotoxicity
study] was a 50% DMSO solution. This material is
known to greatly increase the passage of many
chemicals through biological membranes, and may
have produced a degree of absorption quite unlike
what would be expected following any possible
human exposure."
The cover letter states further that the hypothesis that damaged
DNA may not result in mutation is supported by published data
showing that antimony trichloride, antimony pentachloride and
antimony trioxide "caused DNA damage to the bacterium B. subtilis
but induced no mutation in !:.. coli or ~ typhimurium .~ ."
Finally, the cover letter presents the following information with
regard to the AOIA's ongoing chronic study of antimony trioxide,
a chemical designated by the Interagency Testing Committee (ITC)
for testing consideration under Section 4 of TSCA:
"AOIA is currently sponsoring a two-year inhalation
study of antimony trioxide in Fischer 344 rats as part
of a [TSCA Section 4-associated] voluntary test program
with EPA. 48 Fed Reg. 39979 (September 2, 1983). The
rats were exposed to airborne concentrations of 0.05,
0.5 or 5.0 mg/m3 for a period of one year and are now
in a one-year recovery period. A final report of the
study will be available in 1989. ...."
Submission Evaluation
The submitted data show that antimony trichloride does induce DNA
damage in spleen cells of treated mice. This damage is manifested
as DNA fragmentation, reduced replicative DNA synthesis and a
reduced ability of cells to repair gamma-irradiation induced DNA
damage.
It should be noted that in general there is a higher level of
concern for those agents that have been shown to interact wi th
DNA to produce detectable damage than for those for which no such
evidence exists. While it is plausible that agents that interact
wi th DNA to produce detectable damage may be carcinogenic when
tested in vivo, a direct cause/effect relationship has not been
establishedrlror cancer induction and the types of DNA damage
observed in the submitted study.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for antimony trichloride (CAS No. 10025-91-9), which
is listed in the initial TSCA Chemical Substance Inventory, has
shown that 122 thousand to 1.22 million pounds of this chemical
were reported as manufactured and/or imported in 1977. This
production range information does not include any information
claimed to be TSCA Confidential Business Information (CBI) by the
335
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8EHQ-0688-0737
Page 3 of 4
person (s) reporti ng for the ini tial TSCA Inventory, nor does it
include any information that would compromise TSCA CBI. All data
reported for the initial TSCA Inventory, including the production
range data, are subject to the limitations that are contained in
the initial TSCA Inventory Reporting Regulations (40 CFR 710).
According to the Condensed Chemical Dictionar~ (10th Edition),
antimony trichloride has the following uses: [production of]
antimony salts; bronzing iron; mordant; manufacturing lakes [in
dyestuff technology]; chlorinating agent in organic synthesis;
pharmaceuticals; fireproofing textiles; analytical reagent."
Comments/Recommendations
When considered alone, positive genotoxicologic findings such as
those presented in this submission may not be sufficient to offer
reasonable support for a conclusion of substantial risk as that
term is defined in the Agency's March 16, 1978 TSCA Section 8(e)
policy statement ("Statement of Interpretation and Enforcement
Policy; Notification of Substantial Risk" 43 FR 11110). However,
it should be noted that EPA does believe that such results are of
value in assessing possible risks posed by exposure to chemical
substances or mi xtures. The Agency also bel ieves that posi ti ve
genotoxicity findings, when considered in combination with other
pertinent information (e.g., knowledge of potential exposure to
and/or high production of the subject chemical or mixture), would
suggest the need, in many cases, to conduct further studies that
are designed to better define the toxicologic properties of or
exposure to the subject chemical(s). The results of such further
testing should be considered also for submission to EPA pursuant
to Section 8(e) of TSCA.
It should be noted that EPA' s Office of Toxic Substances (OTS)
has published TSCA Section 8 (a) and Section 8 (d) information
reporting rules on antimony trioxide. Further, OTS has received
a number of TSCA Section 8 (e) and "For Your Information" (FYI)
submissions on antimony compounds, including antimony trioxide.
The Chemical Screening Branch prepared (in 1981) a "Chemical
Hazard Information Profile" (CHIP) on antimony trioxide.
a)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to AOIA and ask AOIA to send copies
of the report to their member companies.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxici ty or exposure data, AOIA will be requested to
descr ibe the nature and results, if avai lable, of all
studies (other than those reported al ready to EPA or
those published in the open scientific literature)
about which AOIA member companies are aware or that
AOIA member companies have conducted, are conducting or
plan to conduct to determine the toxici ty of antimony
trichloride.
336
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Page 4 of 4
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
337
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
D. TE:
JJN 2 9 1988
SUBJECT:
Status Report*
8EHQ-0688-0738
Page 1 of 5
Approved: ~ r tf;;;, - 7/1/"
FROM:
David R.
Chemical
Williams~ection 8(e)
Screening Branch/ECAD
Coordinator
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Mobay Corporation submitted the final reports from oral
teratology/toxicity studies of alpha-[2-(4-chlorophenyl)ethyl]-
alpha-(1,1-dimethylethyl)-lH-l,2,4-triazole-l-ethanol (HWG 1608;
CAS No. 107534-96-3) in mice and rabbits; these studies were
conducted by/for Mobay's parent company (Bayer AG) located in
West Germany. The reports of the mouse studies are in German
with English translations of the study summaries only.
The following information with regard to the conduct and results
of the first mouse study is presented in the English summary:
"25 sperm-positive NMRI mice per group received HWG
1608 daily on days 6 through 15 of gestation by oral
doses of 0, 10, 30 and 100 mg/kg body weight.
"The pregnant females were observed for body weight,
appearance, and behavior. The fetuses obtained on the
18th day of gestation by Cesarean-section were tested
for embryotoxicity by determining their body weight as
well as by exterior and interior morphological changes.
"No deaths occurred. Indications of a maternal toxicity
were not apparent.
"No indications of embryotoxici ty or teratogenici ty of
HWG 1608 were seen in the 10 mg/kg/bw dose per day
group.
"Starting at dose levels of 30 mg/kg/day, fetotoxic
effects (stunted growth) were seen. In addition, in-
creased numbers of terata [(e.g., cleft palate)] were
seen in the 100 mg/kg body weight group which are
regarded as [test] substance related.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e}. the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
338
.... 1'0- ..... '''lEV. 1-181
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8EHQ-068c-0738
Page 2 of 5
"This investigation showed that 1@ mg/kg body weight of
HWG 16@8 administered orally [to pregnant mice] did not
produce embryotoxici ty or fetotoxici ty. 3@ mg/kg body
weight and higher doses produced fetotoxici ty and 1@@
mg/kg body weight was teratogenic."
The following information wi th regard to conduct and results is
presented in the English summary of a followup toxicity study of
the subject chemical in mice:
"Because there was no indication of maternal toxicity
evident in . . . [the previously descr ibed study] with
doses up to 1@@ mg/kg body weight, a second study. . .
was conducted.
"Ten sperm-positive NMRI mice per group received HWG
16@8 daily on days 6 through 15 of gestation in oral
doses of @, 1@, 2@, 3@ and l@@ mg/kg body weight.
"The dams were observed for body weight, appearance and
behavior.
liOn the 16th day of gestation, the animals were sacri-
ficed and blood was drawn from half the animals for
hematological and clinical/chemical testing. Liver
weight determinations and histopathological studies
were done on the remaining half.
"No deaths occurred.
affected.
Body weights of dams were not
"Beginning at dose level 1@ mg/kg body weight, the
activities of the transaminases AST and ALT in the
plasma were higher than those of the controls. Signi-
ficant differences were noted at 1@ mg/kg body weight
(ALT) and at 3@ mg/kg body weight (AST and ALT). In the
3@ mg/kg body weight groups, the hematocrit values and
the mean erythrocyte volumes (MCV - Mean Corpuscular
Volumes) were decreased. Triglycerides in the livers
of the 1@@ mg/kg group were significantly increased.
"Organ weights were not significantly changed, however,
the liver weights of all dosed animals were clearly
higher than in the control group. HE-stained paraffin
slides showed cytoplasmic vacuoles in [the] liver cells
in all animals of the l@@ mg/kg group. These livers
contained increased lipids, which was seen clearly on
the ORO-stained frozen sl ides. In compar i son to the
control group, the fat content of the livers in the 2@
mg/kg body weight and 3@ mg/kg body weight groups was
slightly increased, but this effect was not seen in the
1@ mg/kg group.
339
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8EHQ-06M8...0738
Page 3 of 5
"In conclusion, doses starting at 19 mg/kg body weight
are regarded as slightly maternally toxic and at 39
mg/kg are regarded as clearly maternally toxic."
The following information with regard to the conduct and results
of the oral embryotoxicity/teratogenicity study in rabbits is
presented in the "SUMMARY" section of the submitted final report:
"The purpose of this. study was to assess the
effects of HWG 1698 TECHNICAL on embryonic and fetal
development when administered by oral gavage once daily
to mated female rabbits (Kfm: CHINCHILLA, hybrids, SPF
Qual i ty) from day 6 thr ough 18 pos t co i turn a t dose
levels of [9 (vehicle control), 10, 39 or 109
mg/kg body weight/day].
"Each group consisted of 16 mated female rabbits. The
doses. . . [selected were based on an oral dose range-
finding study in rabbits] (RCC project 974968)."
"Distilled water with 9.5% Cremophor EL . . . was used
as the vehicle for the test article in the dose groups
and was administered as the control article to the
females of the Control group. A standard dose volume
of 4 ml/kg body weight, with a daily adjustment to the
actual body weight, was used.
"On day 28 post coitum, the females were sacrificed and
the fetuses removed by Cesarean-section. The examina-
tion of the females/dams and fetuses was performed in
accordance with international recommendations. All [of
the] parameters recorded were evaluated and reported.
"From this study, the following results were obtained:
- There were no mortalities, behavioral changes or
necropsy findings (including liver weights) in the
mated females considered to be related to treatment
wi th HWG 1698 TECHNICAL. One female at 199 mg/kg died
during the treatment period - this death was attributed
to intubation error.
- Evaluation of the food consumption data resulted in
a slight reduction during the treatment period in the
dams of the high dose group (199 mg/kg). Mean body
weight gain relative to day 0 post coitum showed
statistically significant differences from the Control
value on most days between days 7 and 25 post coitum.
- The mean post-implantation loss in the high dose
group (100 mg/kg) was increased and significantly
different from that of the vehicle control group. No
further differences in the mean reproduction data were
noted which could be attributed to treatment. . .
340
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8EHQ-0688-0738
Page 4 of 5
- External examination of fetuses resulted in eight
(8.9%) fetuses with malformations at the high dose
level (11313 mg/kg). Peromelia of the left or right
foreleg was noted in five fetuses and malrotation of
the right hindlimb together with an enlarged fonta-
nelle, agenesis of a few claws or palatoschisis were
found respectively, in a further three fetuses.
- The abnormal findings noted during [the] internal
examination of the fetuses (skeletal examination and
examination of fetal heads by [the] Wilson technique)
did not change the malformation rate because findings
were noted only in the fetuses which were found to be
malformed already at external examination.
- Evaluation of the mean body weights of fetuses
showed a 6% reduction (not statistically significant)
at the high dose level (11313 mg/kg) .
- The examination of the stage of skeletal development
resulted in a slightly increased percentage of non-
ossified phalangeal nuclei in the high dose group (11313
mg/kg) fetuses. This finding was considered to be the
consequence of a slightly delayed maturation associated
with the slightly reduced mean body weight of the
fetuses."
Submission Evaluation
Copies of the submi tted German reports have been transmi tted to
the Health and Environmental Review Division (HERD/OTS) and
forwarded for translation. An Agency evaluation of the overall
significance of the reported findings, including the rabbit study
findings, should be possible upon receipt of those translations.
Current Production and Use
The subject chemical was not located in the non-confidential
computerized or printed versions of the initial TSCA Chemical
Substance Inventory.
According to Mobay's TSCA Section 8(e) submission, HWG 16138 "is
an experimental pesticide being evaluated by Mobay for possible
use as a fungicide." Mobay reported also that this chemical "has
been used and distributed solely for the purpose of research and
development [(R&D)]." with regard to exposure, Mobay stated that
"the. potential for exposure to this [R&D] substance provides a
very limited risk because the levels to which humans are exposed
are low. n Mobay reported further that" the safety factor for
workers under expected exposure conditions is approximately 61313,
based on studies with similar products."
341
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8EHQ..U688..--u738
Page 5 of 5
Comments/Recommendations
In its Section 8 (e) notice, Mobay stated that its employees and
those persons to whom Mobay distributed the subject chemical are
being advised of the reported findings.
a)
The Chemical Screening Branch will ask Mobay to submit
a complete copy of the final report from the oral dose
range-finding study ("RCC project 074068") cited in the
"SUMMARY" section of the provided final report from the
oral embryotoxicity/teratogenicity study of HWG 1608 in
rabbits.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Mobay will be asked
to describe the nature and results, if available, of
all studies (other than those reported already to EPA
or those cited in the open scientific literature) about
which Mobay is aware or that Mobay has conducted, is
conducting or plans to conduct that are designed to
define the toxicity of the subject chemical.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
342
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DA T!:
JJ. -11988
Page 1 of 3
SUBJECT:
Status Report*
BEHQ-~6BB-~739
Approved: ~d'.l2Iv'd4z- ;Ie
ahUL/~..r~~1tl~llV~ James F. Darr Pl'/rRP
~-~~R.-Williams,;-Section B(e) Coordinator
Chemical Screening Branch/ECAD
"ROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Eastman Kodak Company provided a report pertaining to the
acute toxicity of propyl cyanoacetate (CAS No. 14447-15-5) in
laboratory animals. Eastman Kodak's cover letter 1) states that
the report was "submitted because of adverse neurological effects
observed during an acute oral toxicity test" in rats, and 2) pro-
vides the following information wi th regard to the conduct and
results of this particular study as well as other acute studies
of propyl cyanoacetate:
"Groups of 5 male and 5 female rats were gi ven 125~,
25~~, or 5~~~ mg/kg body weight of the test compound in
a single oral gavage dose. . ." At 5~~~ mg/kg, nine of
ten animals died or were euthanati zed wi thin two days
of dosing. Treatment-related abnormalities seen at
necropsy in animals dying prior to study termination
included evidence of severe gastrointestinal irritation
and evidence of leakage of the test chemical through
the stomach wall. Two of [the] three animals that sur-
vived to day 2 exhibited functional abnormalities and
degenerative lesions in the brain related to cerebral
neurovascular damage. Neurological abnormalities
included evidence of both sensory and motor deficits
such as lack of response to sound or tail pinch,
vigorous spontaneous head search movements, retro-
pulsion, and hypotonic gait in the hind limbs.
"At 25~~ mg/kg, one female developed weakness, ataxia,
and tremors and died on the day of dosing. As at the
high-dose level, lethality was associated with severe
gastrointestinal irritation. All other animals sur-
vived the scheduled observation period. The only
abnormal clinical sign was slight weakness on the day
of dosing. No treatment-related changes were observed
at necropsy. but three rats (one male and two females
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
lnformatlon submltted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA): Th~ statements.made i~ this report should not be regarded
as expresslng flnal EPA POllCY or lntent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
343
.~A ~OMl ".. ."IEV. 1-'1'
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8EHQ-0688-0739
Page 2 of 3
including the one which died on the day of dosing) had
microscopic lesions in the brain which were similar to
those seen at the 5000 mg/kg dose level. At 2500 mg/kg,
brain lesions were generally less extensive than those
seen at 5000 mg/kg.
"The 1250 mg/kg dose level was the no-observed-adverse-
effect level (NOAEL). At this dose level, rats showed
no mortality or abnormal clinical signs, they gained
weight normally, and did not have either necropsy or
neurohistological lesions.
"other data which are included in this [Section 8 (e)]
submission include a dermal toxicity study [in rats], a
dermal irritation study [in guinea pigs], an eye irri-
tat ion stud y [i n r a b bit s], and ask ins ens i t i z a t ion
study [in guinea pigs]. When applied to the skin, the
test article had an estimated acute lethal dose of
greater than 20 ml/kg for rats and did not produce
abnormal clinical signs. The test article was a slight
skin irritant [in guinea pigs], producing only transi-
ent erythema at the site of its application, and it was
not a skin sensitizer [in guinea pigs]. When placed in
the [rabbit] eye, the test article produced variable
responses indicative of slight to strong irritation.
Immediate irrigation of the eye following exposure to
the test article was beneficial and significantly
reduced the irritation caused by the test article.
"In summary, the test article produced funct ional and
morphological evidence of central nervous system damage
at high oral doses which were also associated with
gastrointesti nal damage. The NOAEL for oral tox ic i ty
was 1250 mg/kg. High dermal doses of the test article
did not result in similar effects. The test article
was not a skin sensitizer and was only a slight skin
irritant, but it may cause strong eye irritation if not
promptly washed out of the eye."
In addition to the findings discussed above, Eastman Kodak also
submitted a propyl cyanoacetate Material Safety Data Sheet (MSDS)
that had been updated to include a warning concerning potential
neurotoxicity.
Submission Evaluation
The provided data indicate that the acute oral administration of
propyl cyanoacetate to rats caused dose-related neurotoxicity as
evidenced by behavioral changes and histopathological changes in
the nervous system. Although a NOAEL of 1250 mg/kg was reported
for this acute study, a lower NOAEL could have been found if 1) a
more complete neurobehavioral assessment had been performed, or
2) a repeated (e.g., 28-day) exposure study had been conducted.
344
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8EHQ-0688-0739
Page 3 of 3
Current Production and Use
Propyl cyanoacetate (CAS No. 14447-15-5) was not located in the
non-confidential computerized or printed versions of the initial
TSCA Chemical Substance Inventory. In its Section 8 (e) notice,
Eastman Kodak provided the following information wi th regard to
the manufacture and use of, as well as the potential for exposure
to, the subject chemical substance:
"This chemical has been manufactured only as a non-
isolated intermediate that is completely consumed in
the manufacture of a photographic dye. Approximately
4~~0 kg of the intermediate is produced per year. None
of the intermediate is expected to be present in the
final dye. No employee exposure is anticipated since
the reaction is carried out in a totally enclosed
vessel. [Eastman Kodak is] not aware of any
adverse health problems associated wi th production or
use of this material."
Comments/Recommendations
In addition to updating the propyl cyanoacetate MSDS to include a
neurotoxicity warning, Eastman Kodak stated that additional toxi-
cological studies of this chemical are being considered.
a)
The Chemical Screening Branch will ask Eastman Kodak to
submit a complete copy of the final report (including
the actual experimental protocol, results of gross and
histopathological examinations, etc.) from the acute
oral study cited in the company's initial submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Eastman Kodak will be
asked to describe the nature and results, if available,
of all studies (other than those submitted already to
EPA or those cited in the open scientific literature)
about which Eastman Kodak is aware or that the company
has conducted, is conducting or plans to conduct that
are designed to determine the toxicity of propyl cyano-
acetate. Eastman Kodak will be informed that EPA would
be interested especially in the results of a repeated
exposure (e.g., a 28-day) study of this chemical.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPAi
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
345
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATI!:
JUL 2 5 1988
Page 1 of 4
SUBJI!CT:
Status Report*
8EHQ-0688-0740 S
ADproved:~R.U/d'Ua--' ~
James F, Darr ~
'f"~&!J
CbhVuLu-L-';:;;~ ~ ,
Da7idTR~Williams,!Section 8(e)
Chemical Screening Branch/ECAD
Coordinator
F ROW:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The Eastman Kodak Company has claimed the exact identi ty of the
subject chemical to be TSCA Confidential Business Information
(CBI); the Information Management Division (IMD/OTS) will ask
Eastman Kodak to substantiate this CBI claim. In the "sanitized"
(i.e., non-confidential) version of this Section 8(e) notice, the
chemical is identified as a "substituted thiazinohydrazine."
Submission Description
Eastman Kodak provided the following information about the
conduct and results of an acute oral toxicity study in rats:
"Groups of 5 male and 5 female rats were given [0,
625,] 1250, 2500 or 5000 mg/kg body weight of the test
compound in a single gavage dose as part of an acute
oral toxicity study. All [of the] animals receiving
2500 mg/kg or more of the test compound developed con-
vulsions within 30 minutes of dosing and died before
scheduled study termination. At 1250 mg/kg, 7/10
animals developed convulsions; 4/5 females died within
2.5 hours of administration of the test compound. All
remaining animals in the 1250 mg/kg dose group survived
and gained weight normally. At 625 mg/kg, all animals
survived and no abnormal clinical signs were observed.
"No significant lesions were observed at necropsy of
animals dying following convulsions or in those which
survived the l4-day observation period."
Eastman Kodak reported also that a 28-day gavage study of the
subject chemical is in progress and involves doses of 100, 300 or
1000 mg/kg body weight. According to Eastman Kodak, preliminary
results of this study "indicate that convulsions and mortality
occurred at 1000 mg/kg but were not seen at [the] lower doses."
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
l~fo~atlon submltted to EPA pursuant to Section 8(e), the substantial
rlsk lnformation reporting provision of the Toxic Substances Control
Act (TSCA): Th~ statements,made in this report should not be regarded
as expresslng flnal EPA POllCY or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
346
II~A "OMI U.. '''!IV. ...7..
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8EHQ-0788-0740 S
Page 2 of 4
In addition, Eastman Kodak submitted the following information
about the conduct and results of an acute skin toxicity study in
rats, an acute skin irritation study in guinea pigs, a skin
sensitization study in guinea pigs and an acute eye irritation
study in rabbits:
"wh e nap p lie d tot he ski n, the t est art i c Ie had an
estimated acute lethal dose of greater than 2000 mg/kg
for rats and did not produce abnormal clinical signs.
The test article was not a skin irritant, producing no
signs of irritation at the site of its application, and
it was not a skin sensitizer. When placed in the eye,
the test article produced only slight irritation."
Submission Evaluation
The submitted data provide strong evidence that the test compound
may produce neurotoxicity. Convulsions were observed in both a
dose- and time-dependent manner. The rapidi ty of onset of the
convulsions provides evidence that the effect may be mediated via
the nervous system. Further, these effects are consistent with
those reported for other hydrazine-like compounds (the reader's
attention is directed to the "Status Report" that was prepared by
EPA in response to a TSCA Section 8(e) submission on 3-methyl-2-
benzothiazolinone hydrazone hydrochloride (8EHQ-0287-0654». It
should be noted that the submi tted information also indicates a
sex-related difference, i.e., the females died at lower doses and
generally earlier than males. It must be pointed out, however,
that the information contained in the present submission is not
adequate to characterize fully the potential for neurotoxici ty.
For example, effects at the lower doses might have been observed
if more sensitive procedures had been employed (e.g., kindling or
electrophysiology) . Furthermore, acute level effects may differ
quantitatively and qualitatively from repeated exposure effects.
The results of the ongoing 28-day study should help characterize
the neurotoxic potential of the subject chemical substance.
It should be noted that although Eastman Kodak stated that "no
[other] significant lesions were observed at necropsy of animals
dying following convulsions or in those which survived the 14-day
observation period," the acute oral toxicity report presents the
following information about one male in the 625 mg/kg dose group:
"Only small testes from Rat 383 (625 mg/kg) were pro-
cessed for microscopic evaluation. Findings included
atrophic spermatogenic epithelium with [an] absence of
spermatozoa and spermatids, and [a] reduced number of
spermatocytes, but a normal number of spermatogonia."
Al though these adverse reproducti ve effects were not viewed by
Eastman Kodak to be treatment-related (because" s imi lar lesi ons
occasionally occur in untreated control animals and testicular
atrophy was not observed at the next higher dose level (1250
mg/kg)"), EPA is concerned for the following reasons:
347
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8EHQ-0788-0740 S
Page 3 of 4
1) Because histopathological examinations do not appear to
have been performed on any other animals in the study,
it cannot be ruled out that similar microscopic changes
did not occur in the other male rats in the 625 mg/kg
dose group. Further, the early deaths in the higher
dose groups would minimi ze the probab i 1 i ty tha t such
effects would have time to occur. It should be noted
also that testicular atrophy was not reported for any
animals in the concurrent control group.
2) Not all toxicological effects are necessarily dose-
related. For example, biphasic dose-response curves
are often found for certain classes of chemicals (e.g.,
depressants) .
3) Adverse reproductive effects have been seen in studies
of other hydrazine-like compounds (e.g., procarbazine).
The submi tter' s ongoing 28-day study should help in determining
the potential of the subject chemical substance to cause adverse
male reproductive system effects.
Current Production and Use
In view of the Eastman Kodak Company's CBI claim, no information
regarding the TSCA Inventory status of this substituted thiazino-
hydrazine will appear in this report.
In its TSCA Section 8 (e) submission, Eastman Kodak provided the
following information with regard to the company's production/use
of and the potential for workplace exposure to this substituted
thiazinohydrazine:
"Th is compou nd is a . [research and development
(R&D)] chemical being pursued as an early intermediate
in a multistep synthesis. None of the R&D chemical is
expected to be in the later intermediates. [The
company is] not aware of any adverse health problems
associated wi th its use. Employees are requi red to
wear company supplied clothing when working with chemi-
cals. Because [the toxicologic] testing is incomplete,
employees are also being required to wear Tyvek suits
and air-line respirators when working with the damp or
dry material."
Comments/Recommendations
In addition to conducting a 28-day gavage study to further define
the toxicity of this substituted thiazinohydrazine, Eastman Kodak
reported that the company is considering the need for additional
toxicity studies on this chemical. Also, Eastman Kodak provided
the current substituted thiazinohydrazine Material Safety Data
Sheet (MSDS) that contains a warning about the potential for
"adverse neurological effects."
348
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8EHQ-0788-0740 S
Page 4 of 4
a)
The Chemical Screening Branch will ask Eastman Kodak to
submit a complete copy of the final report (including
the actual experimental protocol, results of gross and
histopathologic examinations, etc.) from the acute oral
toxicity study cited in the company's TSCA Section 8(e)
submission. Eastman Kodak will be asked also to ensure
that EPA receives a complete copy of the final report
of the company's ongoing 28-day gavage study of this
substituted thiazinohydrazine in rats.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Eastman Kodak will be
asked to describe the nature and results, as available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which Eastman Kodak is aware or that the company
has conducted, is conducting or plans to conduct that
are designed to determine the toxicity of the subject
chemical substance.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this substituted thiazinohydrazine.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
349
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
OAT!:
JLt I 5 1988
Status Report*~EHQ-0788-0741
APproved&- r IJ:,~ 76,),p
Coordinator
SUBJECT:
"ROM:
David R. Williams, Section 8(e)
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
On behalf of its member companies, the International Isocyanate
Institute, Inc. (III) provided the following information with
regard to the conduct and preliminary findings from a two-year
inhalation study of polymeric diphenyl methylene diisocyanate
(MDI) in rats being performed for III by the CIVO Institutes,
Zeist, The Netherlands:
"Male and female rats (Cpb:WU, Wistar Random), 60/sex/
level, were exposed for 6 hours/day, 5 days/week for
two years to an atmosphere of respirable polymeric MDI
(CAS No. 9016-87-9) aerosol. Aerosol concentrations
for this study were 0, 0.2, 1. 0, and 6 mg/m3 and were
selected based on subchronic studies. An interim sac-
rifice of a satellite group of 10 additional rats/sex/
level was performed at week 52. Animals under study
were evaluated using clinical chemistry, hematological,
urine analysis, gross and histopathologic procedures.
"Due to . . . [the physical characteristics of the test
material], it was not possible to generate a vapor
atmosphere of MDI high enough to carry out a meaningful
study. Therefore, an aerosol atmosphere was used. The
aerosol atmosphere consisted of particles of which 95%
were less than 5 urn in diameter. polymer i c MD I wa s
chosen as the test substance as it is the most widely
used MDI-based product.
"In preliminary studies in rats, the toxicity of MDI
was confined to the respiratory tract where it caused
irritation at levels of 4 mg/m3 and above.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantia1
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
350
..-A I'OM "... '''EV. ~7.1
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8EHQ-0788-0741
Page 2 of 3
"In the animals [that were] killed after one year of
exposute, those exposed to 6 mg/m3 showed signs of
irritation in the nose and lungs and some accumulation
of a yellow material in the lungs. At 1 mg/m3, there
were some indications of minor irritation. No effects
were observed at 0.2 mg/m3.
"Examination of the rats killed after two years of
exposure showed that the irritation of the nose and
lungs and the accumulation of the yellow material in
the lungs continued in the rats exposed to 6 mg/m3.
In the rats exposed to 1 mg/m3, similar, but lesser,
changes were observed. Again, no effects were seen at
0.2 mg/m3.
"The overall tumor incidence, the incidence of malig-
nant tumors, the incidence of benign tumors and the
number of tumor-bearing animals did not show [any]
differences between the high exposure group and control
group. However, when considering individual organs,
there was a statistically significant increase in
benign tumors of the lung (adenoma) in 6 of the 60 male
rats exposed to 6 mg/m3. Four of 59 female rats exposed
to 6 mg/m3 and 1 of 60 female rats exposed to 1 mg/m3
also had a similar benign tumor in their lungs, but
nei ther was statistically significant. In addi tion, 1
of 60 male rats exposed to 6 mg/m3 showed a malignant
tumor in its lungs (adenocarcinoma). The presence of a
variety of non-neoplastic changes in the lungs, in-
cluding accumulation of yellow material, indicates the
tumors occurred concurrently with irritation of the
lungs."
In its Section 8(e) notice, III stated that the association 1) is
a non-profit organization comprised of producers of MOI and/or
toluene diisocyanate (TOI) "in the Americas, Europe and the Far
East," and 2) "was formed in 1972 to promote and fur ther the
interests of the public, the users and the manufacturers of TOI
and MOI in the safe use of these diisocyanates."
Submission Evaluation
Immediately upon receipt of this TSCA Section 8 (e) submission,
the Chemical Screening Branch sent a copy of the notice to the
Risk Analysis Branch (RAB/ECAO/OTS) for inclusion in the ongoing
review of MOI (including polymeric MOI) and other diisocyanates
(e.g., TOI). The Chemical Screeni ng Branch wi 11 request II I to
keep EPA apprised of any further significant findings from the
two-year inhalation study of polymeric MOI that was cited in the
submission.
351
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8EHQ-0788-0741
Page 3 of 3
It should be noted that in 1984, the Chemical Screening Branch
prepared "Chemical Hazard Information Profiles" (CHIPS) on MOl
(includ i ng polymer ic MOl) and TO!. These CHIPs contai n readi ly
available toxicity and exposure information (as of 1984) on these
chemical substances (persons wishing to obtain copies of these
CHI ps should contact the TSCA As s i stance Of f i ce (TAO/OTS) at
(2~2) 554-14~4 or wri te to the TSCA Assistance Office (TS-799),
Office of Toxic Substances, U.S. Environmental Protection Agency,
4~1 "M" Street, S.W., Washington, D.C. 2046~). Further, TOI and
MOl (including polymeric MOl) are subject of TSCA Section 8 (d)
and 8(c) information gathering rules. Finally. it should be
noted that the Interagency Testing Committee (ITC) has designated
hexamethylene diisocyanate (HOI) for testing under Section 4 of
TSCAi HOI is also the subject of TSCA Section 8 (a) and 8 (d)
information gathering rules.
Comments/Recommendations
In its Section 8(e) notice, III stated that its member companies
were being informed about the reported toxicological findings.
a)
The Chern i c a 1 S c r e e n i n g Bra n c h will r e que s t I I I to
ensure that the Agency is apprised about all further
significant findings from the two-year inhalation study
of polymeric MOl that was cited in Ill's Section 8(e)
submission. The Chemical Screening Branch will forward
all reported information to RAB/ECAO for inclusion in
the ongoing evaluation of MOl and other diisocyanates.
b)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORO/EPA, OPP/EPA, RAB/ECAO/OTS and
TROB/ECAO/OTSi copies of this status report will be
sent also to the TSCA Assistance Office (TAO/OTS) for
further distribution.
352
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DJ. TI!:
n. 2 I 1988
Page lof-3
SUIJI!CT:
Status Report*
8EHQ-~788-~742
Approved r ?: t::- 7h 7/.r-.p
Coordinator
"ROM:
David R~lliams, Section 8(e}
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Atlantic Richfield Company (ARCO) submitted a final report
from a U.S. Department of Transportation (D.O.T.) rabbit skin
corrosivity study of an undiluted emulsifiable metal-working oil
product (F-82) and asked that the information be "processed in
accordance with EPA's substantial risk [information handling]
procedures." In the cover letter to its submission, ARCO stated
that l} the tested product has a pH of 8.4, and 2} "emulsifiable
metal-working fluids (or soluble cutting oils), similar to this
test product, are petroleum lube/water/additive mixtures designed
to be used in a much diluted state [(i.e., water:product dilution
ratio of at least l~: 1 prior to use}]." ARCO did not submi t any
information with regard to the exact identity and amount of each
constituent of the tested product. ARCO's cover letter presents
the following information about the conduct and resul ts of the
skin corrosivity study:
". . . [Six New Zealand White] rabbits (2.~ to 4.~ kg)
had ~.5 ml of this product applied [undiluted] to their
shaved backs at four intact skin sites for each rabbit.
A gauze patch was placed over each site and securely
taped in place. The entire trunk of the animal was
then wrapped with impervious non-reactive rubberized
mater ial and securely taped in place. After 4 hours,
the sheeting and patches were removed and each site was
observed and scored for the appearance of irri tation
and/or corrosion. The si tes were scored according to
the techniques of Draize, and the skin evaluated for
ulceration and necrosis, or any evidence of tissue
destruction. The test si tes were then washed to pre-
vent further exposure. Addi tiona 1 sk i n observa t ions
were made at 24 and 48 hours after application of the
product. Based on the scores obtained and the eschar
noted, this product was designated as corrosive to
[the] skin. ...."
====================================================================================
* ~bTE: T~is stat~s report is the result of a preliminary evaluation of
l~fo~atl0n S~bmltted to EPA pursuant to Section 8(e). the substantial
rlsk lnformatlon reporting provision of the Toxic Substances Control
Act (TSCA): Th~ statements.made i~ this report should not be regarded
as expresslng flnal EPA POllCY or lntent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
353
.~A 1'0- "... C".V.1:78I
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8EHo-0788-0742
Page 2 of 3
In its Section 8 (e) submission, ARCO reported that because the
tested product is diluted at least 113:1 with water before use,
the "skin irritation/corrosivity potential is proportionately
reduced in the actual workplace." ARCO reported a Iso tha t the
current Material Safety Data Sheet (MSDS) and label "warn that
this product 'may cause skin irritation and sensitization' and to
'avoid prolonged and/or repeated skin contact and wash thoroughly
after handling' [the product]." According to ARCO, such warnings
and precautions "might explain why there have never been any
employee or customer complaints associated with. [the pro-
duct's] manufacture or use."
Submission Evaluation
In order for EPA to conduct a proper evaluation of the submitted
findings, ARCO should be asked to report the exact identity and
amount of each constituent of the tested product. Further, it
would be of interest to know the results of other toxicological
studies on the product or its constituents.
Current Production and Use
In general, metal-working fluids (known also as cutting/grinding
fluids) are applied to cutting tools to aid in machine operation
by serving as lubricants and/or coolants and by washing away
metal chips. It should be noted that the Agency 1) has received a
number of TSCA Section 8(e) notices on metal-working fluids, and
2) has issued "Chemical Advisories" outlining the potential risks
that are posed by exposure to metal-working fluids containing
amines or nitrites. Interested persons can obtain copies of these
"Chemical Advisories" by contacting the TSCA Assistance Office at
(2132) 554-14134 or by writing to: TSCA Assistance Office (TS-799),
Office of Toxic Substances, U.S. Environmental Protection Agency,
4131 "M" Street, S.W., Washington, D.C. 2134613.
Comments/Recommendations
In its Section 8(e) submission, ARCO stated that the company has
taken the following risk reduction-related actions involving the
tested product:
"In addi tion to updating the [product's] current MSDS
and precautionary label to reflect.. [the reported
findings], ARCO is informing both workers and customers
of the potential hazards of this product. A D.O.T.
'Corrosive' material placard will be attached to all
containers and bills of lading appropriately marked
with the 'Corrosive Liquid, N.O.S.' shipping name and
UN identification number. These communications will
reinforce the necessity of proper skin protection when
handling this product."
354
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8EHQ-0788...0742
Page 3 of 3
Based on a preliminary review of the provided information, it
does not appear that the reported findings warranted submission
to EPA under Section 8(e), the "substantial risk" information
reporting provision of TSCA. ARCO's rationale for reporting this
information under Section 8(e) of TSCA may become more apparent
upon EPA's receipt/review of further information from ARCO about
1) the constituents of the tested product, and 2) the results of
other toxicological studies conducted on th i s product and its
constituents.
a)
The Chemical Screening Branch will ask ARCO to report
the exact chemical identity (including the CAS Registry
Number, if known) and amount of each constituent of the
tested product.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, ARCO will be asked
to describe the nature and results', if available, of
all studies (other than those reported already to EPA
or those cited in the open scientific literature) about
which ARCO is aware or that the company has conducted,
is conducting or plans to conduct that are designed to
determi ne the toxici ty of the subject product or its
constituents.
b)
The Chemical Screening Branch will review the reported
data in order to determine the need for further OTS
assessment of the tested product or its constituents.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
355
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
/1LG I 6 1988
Page 1 of 4
SUIJECT:
status Report* 8EHQ-0788-0743
David RJP~lliams, Section 8{e)
Chemical Screening Branch/ECAD
APproved:r V r::.:.- t/n/rr
Coordinator
I"ROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB
Submission Description
The Procter & Gamble Company submitted the final report from an
in vi tro L5178Y TK+/- Mouse Lymphoma Mutagenesis Assay on Color
Index (C.I.) Acid Red #1 (CAS No. 3734-67-6). The "Summary"
section of the provided report presents the following information
regarding the conduct and results of this genotoxicity study:
". . . [C. I. Acid Red #1 was tested in this assay] in
the presence and absence of Aroclor induced rat liver
S9. The non-activated cultures selected for cloning
were treated with [C.I. Acid Red #1] doses of 4902 to
368 ug/ml and exhibited Total Growths from 86% to 134%.
The S9 activated cultures selected for cloning were
treated with [C.I. Acid Red #1] doses of 3000 to 225
ug/ml which produced from 18% to 98% Total Growths.
"None of the non-act i va ted cultures tha t were cloned
exhibi ted a mutant frequency which was at least twice
the mean mutant frequency of the sol vent controls. A
dose dependent response was not noted in the treated
cultures. Three of the S9 activated cultures (3000,
2250, and 1688 ug/ml) that were cloned exhibited mutant
frequencies which were significantly greater than the
mean mutant frequency of the solvent controls. The
Total Growths of the positive cultures ranged from 18%
to 72%. A dose dependent response was noted in the
treated cultures. No apparent increase in small mutant
colonies was observed.
liThe results indicate that, under the conditions of
these mutagenicity tests, . . . [C.I. Acid Red #1] was
positive in the presence but negative in the absence of
exogenous metabolic activation."
====================================================================================
* ~OTE: T~;s stat~s report is the result of a preliminary evaluation of
1~fo~atl0n s~bmltted t~ EPA pursuant to Section 8(e), the substantial
rlsk lnformatlon reportlng provision of the Toxic Substances Control
Act (TSCA): Th~ statements,made i~ this report should not be regarded
as e~presslng flnal E~A POllCY or lntent with respect to the subject
chemlcal(s). Any reVlew of this status report should take into account
the fact that the report may be based on incomplete information.
356
C~A 1'0" II" '''IV. ~1I1
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8EHQ-0788-0743
Page 2 of 4
Accord i ng to Procter & Gamble, two publi shed sc ienti f ic papers
reported that C. I. Acid Red #1 is weakly mutagenic in bacter i a
(E. coli and S. typhimurium) with exogenous metabolic activation,
negative in yeast gene conversion and Drosophila (fruit fly)
mutagenicity tests and negative in an unpublished carcinogenicity
study (species not specified). Copies of these scientific papers
were provided by Procter & Gamble in its submission.
Submission Evaluation
C. I. Acid Red #1 was tested in the L5l78Y TK+/- Mouse Lymphoma
Mutagenesis Assay both with and without exogenous metabolic acti-
vation using Aroclor l254-induced rat liver S9. The chemical was
not cytotoxic under non-activation condi tions. Therefore, the
non-activated cultures were dosed at 368 to 4902 ug/ml, which is
considered adequately high for a non-toxic chemical substance.
Total growths for the non-activated cul tures ranged from 86% to
134%. The activated cultures were dosed at 225 to 3000 ug/ml.
Due to severe cytotoxici ty, however, the first acti vated assay
was repeated and only the results from the second activated assay
were presented in the submitted report.
Under non-activated conditions, there were no increases in the
mutant frequency ver sus concur ren t so 1 ven t (wa ter) controls.
With activation, however, thre-e C.!. Acid Red #1 dose levels
demonstrated dose responsive significant increases in mutant
frequencies. The total growths for activated cultures showing
positive responses were 18% to 72%. The concurrent positive con-
trols demonstrated appropr iate responses. No apparent increase
in small colonies was observed which indicates that the positive
responses were probably not due to clastogenic (i.e., chromosome-
damaging) activity.
In conclusion, the submitted data show that C.I. Acid Red #1
induces gene mutations in cultured mammalian cells with, but not
without, exogenous metabolic activation.
Current production and Use
A review of the production range (includes importation volumes)
statistics for C.!. Acid Red #1 (CAS No. 3734-67-6), which is
listed in the initial TSCA Chemical Substance Inventory, has
shown that 20 thousand to 202 thousand pounds of this chemical
substance were reported as being manufactured and/or imported in
1977 - Thi s production range i nforma t i on does not i nc 1 ude any
information claimed as TSCA Confidential Business Information
(CBI) by the person(s) reporting for the initial TSCA Inventory,
nor does it include any information that would compromise TSCA
CBI. All information reported for the initial TSCA Inventory,
including the production range information, is subject to the
limitations contained in the initial TSCA Inventory Reporting
Regulations (40 CFR 710).
357
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8EHQ-0788-0743
Page 3 of 4
According to the COLOUR INDEX (3rd Edition), C.I. Acid Red #1 is
a monoazo dye known also as C.I. Food Red #l@; uses of this dye
are reported to include the coloring of fibers (wool, silk and
nylon), foods, drugs, cosmetics, inks, paper, plastics, pigments,
soaps and wood stains. According to information presented in the
publications submitted by Procter & Gamble, the subject dye was
and may still be approved in the U.K. for use as a food colorant;
U.s. Food and Drug Administration (FDA) staff reported by phone
that this dye has not been approved for use in foods, drugs, cos-
metics or medical devices in the U.S. Finally, Procter & Gamble
reported in its submission that the company is using C.I. Acid
Red #1 for research and development (R&D) purposes and that the
company "has no commercial activities associated with this
material."
Comments/Recommendations
Procter & Gamble reported that "the resul ts and implications of
the [submitted] mouse lymphoma study were reviewed promptly with
all appropriate R&D personnel, and they were reminded about the
safe handling of all research chemicals." Also, Procter & Gamble
stated that the company is "currently conducting an additional
assay (in vitro cytogenetics using Chinese hamster ovarian cells)
. . ." Procter & Gamble reported that the results of this cyto-
genetics assay will be sent to EPA as soon as they are available.
Although a positive in vitro genotoxicologic assay result, when
considered alone, maY-not be sufficient to reasonably support a
conclusion of substantial risk (as that term is defined in EPA's
TSCA Section 8(e) policy document ("statement of Interpretation
and Enforcement policy; Notification of Substantial Risk" 43 FR
llll@; March 16, 1978», EPA believes that such results are of
value in assessing possible risks posed by exposure to chemical
substances or mixtures. The Agency also believes that positive
genotoxicity findings, when considered in combination with other
pertinent information (e.g., knowledge of potential exposure to
and/or high production of the subject chemical or mixture), would
suggest the need, in many cases, to conduct further studies that
are designed to better define the toxicologic properties of or
exposure to the subject chemical(s). The results of such further
testing should be considered also for submission to EPA pursuant
to Section 8(e) of TSCA.
a)
The Chemical Screening Branch will ask Procter & Gamble
to ensure that the Agency receives a full copy of the
f i na 1 report (incl udi ng actual exper imental protocol,
data, results of any statistical analyses, etc.) from
the company's ongoing in vitro cytogenetics assay of
C.I. Acid Red #1.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Procter & Gamble will
358
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8EHQ-0788-0743
Page 4 of 4
be requested to descr i be the nature and resul ts, if
available, of all studies (other than those reported
already to EPA or those cited in the open scientific
literature) about which Procter & Gamble is aware or
that the company has conducted, is conducting or plans
to conduct that are designed to determine the toxicity
of C.I. Acid Red #1.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
359
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
OA TE:
SEP I 3 1988
Page 1 of 5
SU8JECT:
Status Report> BEHQ-07BB-0744 S APproved:-r "f ~ rJ4",
David R. Wi11iams?1~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Mobil Research and Development Corporation provided summary
information about the conduct and results of studies designed to
investigate "the toxicity of a generic jet engine oil and one of
its components, tr icresy1 phosphate (TCP [CAS No. 1339-78-5])."
It should be noted that TCP is a mi xture of the ortho-, meta-,
and para- isomers of TCP. According to the submitting company,
the tested jet engine oil "contained certain additive components
at concentrations representative of a cross section of those in
commercial production." The submitter provided the following
information regarding these studies:
" [The Mobil Research and Development Corporation]
research showed that repeated [skin] applications of
the generic jet engine oil containing 3% TCP (one der-
mal application/day, 5 days/week, for 99 days) to male
and female sprague-Dawley rats decreased the activities
of both serum and erythrocyte cholinesterase. A
follow-up study, designed to identify the component
causing cholinesterase inhibition, showed that the TCP
additive was entirely responsible. . ." An additional
acute study, performed in male Long-Evans rats, showed
that single. . . [oral or dermal doses of TCP or tri-
ortho-cresy1 phosphate (TOCPi CAS No. 78-39-8)] inhi-
bited both serum cholinesterase and brain neuropathy
target esterase (neurotox ic esterase i NTE). I n-
hibition of NTE is highly correlated with induction of
organophosphorus induced delayed neurotoxicity (OPIDN).
Surprisingly, there was very little difference between
the activities of TCP and TOCPi the TCP manufacturer's
product safety information sheet indicated that [the]
TOCP content is less than 9.1%."
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
l~fo~atlon s~bmltted t~ EPA pursuant to Section 8(e), the substantial
rlsk lnformatlon reportlng provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
360
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Page 2 of 5
". . . [The Mobil Research and Development Corporation
has been] under the impression that a commonly held
opinion is that TCP with TOCP levels below 1% is not
neurotoxic. ... [The company's] results indicate that
the TOCP level in TCP is not a reliablE! predictor of
potential neurotoxicity."
"Four batches of the TCP additive used in the tests. .
. and three other TCP samples also were evaluated for
acute cholinesterase and NTE inhibition. All
showed significant inhibitory effects that, on repeated
administration, would be expected to result in neuro-
toxi'City. All materials were derived" from cresylic
acids produced as a byproduct of petroleum refining.
Other commercially available TCPs are prepared from
synthetically derived materials, which can provide
better control of the content of potentially neurotoxic
components.
"A thorough li terature review. [appended to the
company's submission] revealed that the neurotoxic
properties of commercial TCP are known, but that there
is confusion over the appropriateness of using the TOCP
level as an indicator of neurotoxic potential. . . . ."
Immediately upon receipt of this TSCA Section 8 (e) submission,
the Chemical Screening Branch sent copies of the submission to
staff of the Test Rules Development Branch (TRDB/ECAD/OTS) for
inclusion in their ongoing review of available toxicologic and
exposure data on TCP, TOCP and other aryl phosphates. The aryl
phosphates category was designated by the Interagency Testing
Committee (ITC) for testing consideration under Section 4 of
TSCA. In addition, EPA has published TSCA Section 8 (a) and 8 (d)
information gathering rules on TCP, TOCP as well as other aryl
phosphates.
Submission Evaluation
The submitted data indicate that subchronic dermal application of
a generic jet engine oil containing 3% TCP to rats produced a
significant inhibition of erythrocyte and serum cholinesterase
activity levels relative to controls. The submitted data also
i nd i ca te tha t 1) a single oral dose of TCP to rats produced a
significant (83%) NTE inhibition and a significant (82%) serum
cholinesterase inhibition, and 2) a single TCP dose applied
dermally to rats resulted in a significant (55%) NTE inhibition
and a significant (65%) serum cholinesterase inhibition. The
doses of TCP required to produce the acute effects in rats were
approximately 2.9 g/kg for both the dermal and oral routes of
administration. It should be noted that 2.9 g/kg of TOCP pro-
duced generally a comparable amount of inhibition of the NTE and
cholinesterase levels.
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Page 3 of 5
Overall, the submitted summarized data indicate that TCP can
produce neurochemical effects (inhibition of cholinesterase and
NTE leve 1 s) comparable to those produced by TOCP. Cons ider i ng
that NTE inhibition is predictive of OPIDN, the submitted results
indicate further that TCP may also produce OPIDN. In the past,
the primary concern for mixtures of TCP isomers has focussed on
the concentration of TOCP in the TCP isomer mixture based on the
assumption that TCP isomer mixtures wi th TOCP levels below 1%
were not neurotoxic.
The submitted data also open the question of which species is the
most appropriate to study OPIDN. Until recently, it has been
argued that the .hen is the best animal model for evaluating OPIDN
because other species (e.g., the rat) were thought to be more
res i stan t to the neurotox ic effects of organophosphates (OPs).
However, recent published studies have shown that the rat is
sensitive to OPs and should be considered as a viable species for
testing OPIDN-like effects. The data contained in the present
submission support the use of the rat for such testing.
The Mobil Research and Development Corporation should be asked to
ensure that EPA receives a complete copy of the final report from
each study cited in the cover letter to the company's submission.
In addition, the company should be asked to submit a copy of the
Material Safety Data Sheet (MSDS) for the commercial TCP product
that reportedly produced "NTE inhibition after large single oral
doses in hens." This particular MSDS was cited in ATTACHMENT I
(TCP literature review section) of the company's submission.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for TCP (CAS No. 1339-7B-5), which is listed in the
initial TSCA Chemical Substance Inventory, has shown that 199
thousand to 1 million pounds were reported as manufactured and/or
imported in 1977. This production range information does not
include any information that was claimed as TSCA Confidential
Business Information (CBI) by the person(s) reporting for the
initial TSCA Inventory, nor does it include any information that
would compromise CBI. All of the information reported for the
initial TSCA Inventory, including the production range data, is
subject to the limitations that are contained in the initial TSCA
Inventory Reporting Regulations (49 CFR 719).
In its submission, the Mobil Research and Development Corporation
reported that "TCP is used as an anti-wear agent in jet engine
oils, and is required to meet both military and commercial jet
engine builders' specifications. II The company stated also that
TCP "is used as a minor component « or = 2%) in certain mineral
oil based lubricants." Finally, the company stated that "certain
fire resi stant hydraul ic fluids are based on 199% TCP, some of
which are synthetically derived."
362
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Page 4 of 5
According to the Condensed Chemical Dictionary (10th Edition),
tricresyl phosphate (mixture of 0-, m- and p- isomers) has the
following uses: "Plasticizer for polyvinyl chloride, polystyrene,
nitrocellulose; fire retardant for plastics; air filter medium;
solvent mixtures; waterproofing; additive to extreme pressure
lubricants; hydraulic fluid; heat exchange medium."
Comments/Recommendations
In its submission, the Mobil Research and Development Corporation
stated that although the company is "unaware of any neurotoxic
effects on humans having been caused by exposure to jet engine
oils in their intended application," the company is revising
product labels/MSDSs in order to inform workers and customers
about the submitted toxicological findings. In addition, the
company reported that copies of the submission were sent to the
U.S. Occupational Safety and Health Administration (OSHA), to
other TCP users and suppliers, and to a number of industry trade
associations (including the American Petroleum Institute (API».
a)
The Chemical Screening Branch will request the Mobil
Research and Development Corporation to submi t a full
copy of the final report (including the actual experi-
mental protocol, results of any gross/histopathological
examinations, results of statistical analyses, etc.)
from each study that was cited in the cover letter to
the submission. The company will be requested also to
provide to EPA a complete copy of the MSDS for the
commercial TCP product that reportedly produced "NTE
inhibition after large oral doses to hens." This MSDS
was cited in the last paragraph of ATTACHMENT I (TCP
literature review) in the company's submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the Mobil Research
and Development Corporation wi 11 be asked to descr i be
the nature and results, if available, of all studies
(other than those reported already to EPA or those
cited in the open scientific literature) about which
the company is aware or that the company has conducted,
is conducting or plans to conduct that are designed to
determine the neurotoxicologic properties of TCP or any
products (e.g., jet engine oil) containing TCP.
b)
As in the case of the initial Section 8(e) submission,
the Chemical Screening Branch will immediately send all
additional reported information to TRDB/ECAD/OTS. The
Chemical Screening Branch will also review the reported
information in order to determine the need for further
OTS assessment of any chemical substance(s)/product(s)
not already being evaluated within OTS.
363
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8EHQ-0788-0744 S
Page 5 of 5
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
TRDB/ECAD/OTS/OPTS/EPA. In add i t i on, copi es of th is
status report will be provided to the TSCA Assistance
Office (TAO/OTS/OPTS/EPA) for further distribution.
364
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
04 TE:
AID I 6 1988
Page 1 of 2
APprOVedr ?: C. - ;/;;;kJ:-
Coordinator
SUIJECT:
Status Report* 8EHQ-~788-~745 S
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
'ROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSS/ECAD
Note
The CIBA.-GEIGY Corporation has claimed the exact identi ty of the
subject chemical as TSCA Confidential Business Information (CBI);
the Information Management Division (IMD/OTS) will be requesting
CIBA-GEIGY to substantiate this CBI claim. In the "sanitized"
(i.e., non-confidential) version of CIBA-GEIGY's submission, the
subject chemical is identified generically as a "carbomonocyclic
aminobutyrolactone."
Submission Description
CIBA-GEIGY submitted the following information regarding the
conduct and interim results of a two-year dietary oncogenicity
and chronic toxicity study of the subject chemical in rats:
"The dose levels for the two-year dietary oncogenicity
and chronic toxicity study are ~, 2~, l~~, 25~~ and
5131313 ppm. Microscopic findings in interim sacrifice
animals after one year on study indicate an increased
incidence of hepatocellular adenomas and carcinomas in
males at the 5~13~ ppm dose level. Liver hypertrophy
was noted in both males and females at the 251313 and
59913 ppm dose levels."
According to CIBA-GEIGY, this two-year study is being "conducted
in toxicology laboratories of Research and Consulting Company AG,
Basel, Switzerland."
Submission Evaluation
Based on the submitted interim sacrifice data, this chemical does
appear to possess some degree of oncogenic activity in rats. An
evaluation of the overall significance of the reported findings
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
365
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8EHQ-0788-0745 S
Page 2 of 2
should be possible upon EPA's receipt of information from future
interim sacrifices and a full copy of the final report (including
the actual experimental protocol, results of gross/histopatho-
logic examinations, results of statistical analyses, etc.) from
this ongoing two-year study.
Current Production and Use
In view of CIBA-GEIGY's TSCA CBI claim, no information regarding
the TSCA Inventory status of the subject chemical substance will
appea r in th i s repor t. Accordi ng to CIBA-GEIGY, the subject
chemical is "a research and development compound being evaluated
solely for pesticidal purposes." CIBA-GEIGY also stated that
"these evaluations for pesticidal purposes are being conducted
under the supervi sion of technically qualified personnel, [who
are] knowledgeable in handling potentially hazardous chemicals."
Comments/Recommendations
In its Section 8(e) notice, CIBA-GEIGY reported that in response
to the submitted preliminary findings, the company is updating
the subject chemical's Material Safety Data Sheet (MSDS) to state
that the "compound may cause cancer in laboratory animals."
a)
The Chemical Screening Branch will ask CIBA-GEIGY to
ensure that 1) EPA is kept abreast of the res u 1 ts 0 f
future interim sacrifices from the ongoing two-year
study, and 2) EPA receives a complete copy of the final
report (including the actual experimental protocol, the
results of gross and histopathologic examinations, the
results of any statistical analyses performed, etc.)
from that two-year study.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, CIBA-GEIGY will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which CIBA-GEIGY is aware or that CIBA-GEIGY has
conducted, is conducting or plans to conduct that are
designed to determine the toxicological properties of
the subject chemical substance.
b)
The Chemical Screening Branch will review the reported
information to determine the need for further OTS
assessment of this carbomonocyclic aminobutyrolactone.
c)
The Chemical Screening Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
366
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
SEP I 3 1988
Page 1 of 5
SUBJECT:
Status Report* 8EHQ-0888-0746
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
Approved: &- r ~
Coordinator
c,hs!rp-
IIROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The Monsanto Company provided the following information regarding
the conduct and preliminary results of a single oral dose level
teratology study of 4-aminodiphenylamine (4-ADPA; CAS No. 101-54-
2) in Sprague-Dawley rats:
" . [Monsanto] recently received unaudi ted tabular
data. . for a single [dose level] rat teratology
study consisting of one [25-member] group dosed with
4-ADPA and a [25-member] control group. The 4-ADPA was
administered by gavage at 150 mg/kg[/day] in corn oil.
[(The submitted information does not indicate on which
days of gestation the 4-ADPA was administered.)] The
data show significant maternal toxicity, embryotoxicity
(i.e., increased resorptions) and developmental effects
in the fetal population, including gross external and
internal malformations. Several of the malformations
were well in excess of what could be considered spon-
taneous occurrences, and they are considered [to be]
related to treatment. Additional visceral and skeletal
evaluations of the fetuses are in progress. ....
"It is important to note that these preliminary
observations differ substantially from [the] published
resul ts of teratogenici ty testing of 4-ADPA used as a
component of hair dyes (picciano, et al., Drug & Chern.
Toxicol. 7:167, 1984). According to the published
report, 4=-ADPA in propylene glycol failed to produce
developmental effects or terata when given by gavage to
Sprague-Dawley rats (the same strain used in the study
being reported [herein by Monsanto] to the Agency) at
dosages up to 200 mg/kg.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
367
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8EHQ-0888-0746
Page 2 of 5
"The reason for the dramatic differences in biological
response between the two studies is not known. The
material used in . . . [Monsanto I s] study was analyzed
before and after the teratology study and [was] shown
to be stable. The stability of the 4-ADPA used in the
published study was not stated."
The fo 11 owing" ABSTRACT" is from the picciano art icle ci ted by
Monsanto in its TSCA Section 8(e) submission:
" The 0 x i d a t i ve dye. [ 4 - AD P A ( a 1 s 0 k n 0 wn as N -
phenyl-p-phenylenediamine)] was evaluated for terato-
genic potential. The dye was administered by gavage to
[groups of 12] pregnant Sprague-Dawley rats at dose
levels of 50, 100, and 200 mg/kg on gestation days six
through fifteen. No signs of toxicity were observed
during the treatment period. A significant reduction
in mean maternal body weight gain was noted during
treatment at the high dose level of 200 mg/kg. The
test material did not produce embryotoxic nor fetal
toxic effects at the dose levels utilized. Evaluation
of fetal external, visceral, and skeletal anomalies re-
vealed no statistically significant differences between
dye treated and [the propylene glycol vehicle] control
groups. Oral exposure of dams to the positive control,
vitamin A, resulted in a significant increase in the
number of litters with fetuses having external, vis-
ceral and skeletal anomalies."
It shou Id be noted also that the" INTRODUCTION" secti on of the
picciano paper stated that a National Cancer Institute (NCI) two-
year carcinogenesis bioassay of 4-ADPA "administered in the feed
to [Fischer 344] rats and [B6C3Fl] mice revealed that the dye was
not carcinogenic to ei ther species [(DHEW Publication No. (NIH)
78-1332)]." According to staff at the National Toxicology
Program (NTP), 4-ADPA was tested by NTP in a number of in vitro
genotoxicity studies; the results of these studies were reported
to be mixed.
Submission Evaluation
The submitted data indicate that 4-ADPA when administered orally
to pregnant Sprague-Dawley rats at a dose of 150 mg/kg/day for an
unknown number of days during gestation produced maternal and
d~velopmental toxicities.
with regard to adverse maternal effects, the mean maternal body
weight was strikingly lower for the 4-ADPA-treated animals than
con trol animals on day 11, and at all later measurements. The
maternal weight gain was depressed beginning in the interval of
gestation day 6 to day 11 (presumably treatment commenced on day
6) continuing through the end of the study (including the inter-
val between days 15 and 20. In a standard developmental toxicity
368
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8EHQ-0888-0746
Page 3 of 5
study this latter interval covers the time period after treatment
ceases) . There were also corresponding decreases observed for
maternal food consumption.
Most striking among the li tter parameters was a decrease .in mean
fetal weight from 3.42 g to 1.94 g in the treated animals. Among
the external abnormalities that occurred at elevated frequencies
among the fetuses from the 4-ADPA-treated animals were: edema,
"flexure," shortened digits (forepaws), and reduced number of
digits (fore- and hind-paws). The overall frequency of external
malformations was found to be 0% for the control fetuses and 21%
of the fetuses in 39% of the litters in the 4-ADPA-treated group.
Categori~ed as "external variations" were "areas of subcutaneous
discoloration on [the] snout" (hematoma?) and a glassy or shiny
appearance. These particular variations were reportedly observed
at a frequency of 21% of the fetuses in 52% of the 4-ADPA-treated
litters compared to 0% for the controls.
The internal malformations and variations that occurred at high
frequencies in treated relative to control fetuses included:
"aortic arch vessels appear to be reversed," abnormal position of
the heart vessels, presence of addi tional aortic arch vessels,
descending aorta to the right side of the heart, absence of the
pulmonary arteries, absence of the innominate artery, absence of
the ductus arteriosus, absence of the postcaval lobe of the lung,
small kidneys, ectopic ovaries, undescended testes, and distended
ureters. Overall, the heart and great vessels appeared to be the
most seriously affected by treatment with 4-ADPA.
The reason(s) for the dramatic difference between the results of
the Monsanto and picciano studies may become apparent upon EPA's
~eceipt and review of a full copy of the final report (including
the actual experimental protocol, results of gross/histopatho-
logical examinations, results of statistical analyses, etc.) from
Monsanto's study. In submitting this final report to the Agency,
Monsanto should be asked to ensure that all terminology used in
the report is def ined clearly. For example, it is not enti rely
clear what is meant by "flexure" and "areas of subcutaneous dis-
coloration on [the] snout" as those terms are used in the initial
submission. In addition, Monsanto should be asked if the company
is planning to conduct a developmental toxicity study in Sprague-
Dawley rats exposed orally to 4-ADPA at doses of 150 mg/kg/day
and below.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for 4-ADPA (CAS No. 101-54-2), which is listed in the
initial TSCA Chemical Substance Inventory, showed that between 10
thousand to 100 thousand pounds of this chemical were reported as
manufactured and/or imported in 1977. This production range data
does not include any data claimed as TSCA Confidential Business
Information (TSCA CBI) by the person(s) reporting for the initial
369
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Page 4 of 5
TSCA Inventory, nor does it include any information that would
compromise TSCA CB1. All data reported for the initial TSCA
Inventory, including the production range data, are subject to
the limitations contained in the initial TSCA Inventory Reporting
Regulations (40 CFR 710).
In its submission, Monsanto provided the following information
regarding the manufacture/use of 4-ADPA:
"Monsanto manufactures. . . 4-ADPA . . . primarily as
a non-isolated intermediate which is further converted
to subs ti tuted p-phenylenediamines, which are used as
antiox idants. Smaller amounts [of 4-ADPA] are sold in
bulk to other producers of p-phenylenediamines."
According to the "INTRODUCTION" section of the picciano paper, 4-
ADPA "is listed as an ingredient of oxidative hair dyes" and "is
used in the manufacture of several dyes and dye reagents."
According to the Colour Index (Third Edition), 4-ADPA is known by
a number of names, including C.!. Oxidation Base 2, C.!. Azoic
Diazo Component 22, C.I. Developer 15, C.I. 76085, C.I. 37240 and
Diphenyl Black.
In its TSCA Section 8 (e) submission, Monsanto also provided the
following information concerning the potential for workplace
exposure to 4-ADPA at Monsanto:
"Monsanto manufactures 4-ADPA in a closed system and
much of it is converted wi thout being isolated. Thus,
potential exposures to the few employees involved are
low and contact with 4-ADPA is minimal in normal opera-
tions. Potential for exposures can be greater during
sampling or maintenance work or in preparing bulk ship-
ments. Protective equipment is required in .
[Monsanto's] operations if it is considered that air-
borne concentrations [of 4-ADPA] could exceed 0.1 mg/m3
(TWA) or if there is potential for skin contact. The
airborne limits and limitation of skin contact are
derived, by analogy, from the standards (PEL,TLV)
establ ished for p-phenylenediamine and are based upon
the sensi ti zation properties of that chemical. Thus
[Monsanto] previously adopted 0.1 mg/m3 as a
workplace exposure guideline."
Comments/Recommendations
Monsanto reported that its "employees and customers are being
notified directly regarding these preliminary findings." Also,
Monsanto stated that it is initiating a review of "work prac-
tices, labeling, safety data sheets and other company literature
on . . . [4-ADPA] with a view to revising them if necessary."
370
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Page 5 of 5
It should be noted that immediately upon receipt of this TSCA
Section 8(e) submission, the Chemical Screening Branch sent a
copy of the submission to the U.S. Food and Drug Administration
(FDA) for review and appropriate fo11owup attention.
a)
The Chemical Screening Branch will request Monsanto to
ensure that the Agency receives a complete copy of the
final report (including the actual experimental proto-
col, results of gross and histological examinations,
resu 1 ts of any sta tis tical analyses performed, etc.)
from Monsanto's single oral dose level teratology study
of 4-ADPA in pregnant Sprague-Dawley rats. Monsanto
will be asked also to ensure that all terminology used
in the submitted report is defined clearly.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure data, Monsanto will be asked to
describe the nature and results, if available, of all
studies (other than those reported already to EPA or
those cited in the published scientific literature)
about which Monsanto is aware or that the company has
conducted, is conducting or plans to conduct that are
designed to determine the toxicity of 4-ADPA. Monsanto
will be informed that the Agency would be interested
especially in the results of a developmental toxicity
study in Sprague-Dawley rats exposed orally to 4-ADPA
at doses of 150 mg/kg/day and below.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of 4-ADPA.
c)
The Chemical Screening Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP.
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPAi
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
371
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DA T!:
SEP 2 3 1988
Page 1 of 4
SUBJECT:
status Report* 8EHQ-0888-0747
David R. Williams,~ection 8(e)
Chemical Screening Branch/ECAD
Approved: g-,r. ~ 1~,1u
Coordinator
!"ROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The CIBA-GEIGY Corporation provided the following information
regarding the conduct and results of 49-day and 90-day feeding
studies of 2-(2H-benzotriazol-2-yl)-4,6-bis(1,1-dimethylethyl)-
phenol (Tinuvin 320; CAS No. 3846-71-7) in rats:
IIIn the short-term [49-day] test [in which 2 groups of
30 (lS male/1S female) rats were exposed to Tinuvin 320
in the feed at dose levels of ei ther 0 and 2000 ppm],
decreased growth rate, food consumption, and food
efficiency occurred at the 2000 ppm feeding level,
whereas water intake was not affected. Relative weights
of livers and kidneys were increased. Moreover, the
1 i vers were di scolored and showed severe pathol og i ca 1
changes [(i.e., 'hypertrophy and necrosis of hepatic
parenchyma and proliferation of bile ducts')]. Gross
and microscopic examination of the kidneys were
essentially negative.1I
II The pr imary effects produced dur i ng .. [the 90-day
subchronic feeding study] of Tinuvin 320 were lesi ons
of the kidney and liver. After feeding [0,] 100, 200,
400, 800 and 1600 ppm to [6 groups of 20 (10 male/10
female) rats] for 90 days, all males. . . had enlarge-
ment and discoloration of the liver and kidneys. Upon
gross examination, multiple tiny foci of necrosis were
occasionally visible on the livers of the males in the
800 and 1600 ppm groups. Single cell necrosis and
hypertrophy of the parenchymal cells were observed in
the livers of all males and females in the 400, 800 and
1600 ppm groups. The hepatic damage increased with dose
with the top dose causing numerous necrotic hepatocytes
(occasionally foci of necrosis were present) and slight
proliferation of bile ducts wi th necrosis of the epi-
thelian lining of the larger bile ducts. Toxic tubular
nephrosis was found for males (200, 400, 800 and 1600
ppm groups) and females (800 and 1600 ppm groups) .11
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
372
.~" 1'0'"' U... '''I[V. 10711
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Page 2 of 4
Submission Evaluation
In the 49-day feeding study, the Tinuvin 320-dosed animals showed
decreased growth rate, decreased food intake, decreased food
efficiency (i.e., digestive efficiency), increased liver weights,
increased kidney weights and morphological abnormalities of the
liver. Specifically, these hepatic changes were hypertrophy and
necrosis of the hepatic parenchyma and proliferation of the bile
duct. Wi th regard to kidney tox ic i ty, the performed hi stolog ic
examination did not reveal any morphological differences between
the Tinuvin 320-dosed rats and the control rats.
In the 90-day study, distinct growth depression occurred for the
male rats at the two highest Tinuvin 320 dose levels (800 ppm and
1600 ppm); growth depression occurred also in the females but was
less pronounced. At the lower feeding levels, the body weights
of the males were lower, but not significantly lower, than the
controls. Food consumption and food efficiency were similar
except at 800 ppm and 1600 ppm. At these feeding levels, food
consumption and food efficiency were decreased in both sexes,
although only during the first two weeks of this 90-day feeding
study.
An altered blood profile was observed in the 90-day feeding
study. Specifically, hemoglobin content, packed cell volume and
number of erythrocytes were decreased in all Tinuvin 320-dosed
male rats. These effects were also evident in the female rats in
the two highest dose level groups (800 ppm and 1600 ppm). The
packed cell volume was found to be decreased in females receiving
200 ppm and 400 ppm Tinuvin 320. At 100 ppm, the blood profile
for the female rats was comparable to the controls.
In both sexes in the 90-day study, the average liver and kidney
weights were increased at all Tinuvin 320 dose levels, except in
females in the 100 ppm and 200 ppm dose groups. Additionally,
spleen, thymus, pituitary and adrenal weights were decreased in
female rats in the 1600 ppm dose group. Microscopic examination
of the livers revealed distinct hepatic damage in all male rats
at all Tinuvin 320 dose levels and in female rats at the three
highest dose levels (i.e., 400 ppm, 800 ppm and 1600 ppm). The
hepatic damage consisted of necrosis of individual liver cells,
homogenous cytoplasm of hepatocytes occasionally containing
yellowish-green bi-refringent slightly PAS-positive pigment
granules. The appearance of such yellowish-green pigmented
granules indicates an abnormal accumulation of bilirubin in the
hepatocytes. The observed liver damage increased in severity
wi th i ncreas i ng Tinuvin 320 dose levels. Microscopically, the
kidney toxici ty was evidenced by tubular nephrosis found at 200
ppm and above in the male rats and at 800 ppm and 1600 ppm in the
female rats.
Overall, the observed target organ effects caused by Tinuvin 320
are consistent with those reported in other benzotriazole-based
chemical toxicity studies that have been evaluated to date by the
373
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8EHQ-0888-0747
Page 3 of 4
Office of Toxic Substances (OTS). (The reader's attention is
directed to the second paragraph in the Comments/Recommendations
section of this status report.)
Current Production and Use
A review of the production range (includes importation volumes)
statistics for CAS No. 3846-71-7, which is listed in the initial
TSCA Chern i ca 1 Substance Inventory, showed that 1,000 to 10,000
pounds were reported as imported in 1977. This production range
information does not include any data that were claimed as TSCA
Confidential Business Information (TSCA CBI) by the person(s)
reporting for the initial TSCA Inventory, nor does it include any
information that would compromise TSCA CBI. All data reported
for the initial TSCA Inventory, including the production range
data, are subject to the limitations contained in the initial
TSCA Inventory Reporting Regulations (40 CFR 710).
In its submission, CIBA-GEIGY provided the following information
concerning the importation, use and sale of Tinuvin 320:
"Tinuvin 320 is a benzotriazole-type ultraviolet [(UV)]
light absorber used for stabilizing polymers. It is not
currently sold in the Uni ted States, nor has it been
for the past several years. Tinuvin 320 is not manu-
factured in the united States. This product, which is
not being actively promoted, was last imported in 1984.
As a result of a comprehensive [CIBA-GEIGY] inventory
cleanup in 1985, in which inactive products were either
disposed of or shipped back to [CIBA-GEIGY' s parent
company in Basel,] Switzerland, . no remaining
stock of Tinuvin 320 [is] in inventory [in the U.S.]."
CIBA-GEIGY reported, however, that although Tinuvin 320 is not
being sold or distributed in the United States at the present
time, the company has "some expectations of having a potential
customer [for Tinuvin 320] in 1989."
Comments/Recommendations
CIBA-GEIGY reported that because there may be a new customer for
Tinuvin 320 in 1989, the product's Material Safety Data Sheet
(MSDS) and label are being updated to reflect the reported
toxicological findings. In addition, CIBA-GEIGY reported that
the company is informing its "laboratory employees and warehouse
personnel of these new findings through wr i tten commun i ca t ions
and, possibly, personal meetings."
It should be noted that EPA has received a number of Section 8(e)
and "For Your Information" (FYI) notices on benzotriazole-based
UV light stabilizers. Also, the Chemical Screening Branch is in
the process of preparing a "Chemical Hazard Information Profile"
(CHIP) on benzotriazole-based UV light stabilizers; a CHIP on
piperidinyl-based UV light stabilizers is in preparation as well.
374
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8EHQ-0888-0747
Page 4 of 4
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, CIBA-GEIGY will be
asked to describe the nature and results, if available,
of all stud i es (other than those reported already to
EPA or those cited in the open scientific literature)
about which CIBA-GEIGY is aware or that the company has
conducted, is conducting or plans to conduct that are
designed to determine the toxicity of or the exposure
to Tinuvin 320.
b)
Staff of the Chemical Screening Branch will ensure that
any relevant reported information on Tinuvin 320 is in-
cluded in the benzotriazole-based UV light stabilizers
CHIP now in preparation.
c)
The Chemical Screening Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
375
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
ocr 2 0 1988
Page 1 of 5
SU8JECT:
Status Report*
8EHQ-0988-0748
Aoorovedr r~ lo~dFr
Coordinator
FROM:
David R. Williams~ection 8(e)
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The CIBA-GEIGY Corporation provided the final resul ts of 49-day
and 90-day feeding studies of 2-(2H-benzotriazol-2-yl)-4,6-bis-
(1,1-dimethylpropyl)phenol (Tinuvin 328; CAS No. 25973-55-1) in
rats and a 90-day feeding study of Tinuvin 328 in dogs. The sub-
mitter's cover letter presents the following information with
regard to the conduct and results of these studies:
"During the 49- and 90-day oral study with rats. . . ,
animals were fed diets containing 0, 100, 200, 400, 800
and 1600 ppm (90-days) or 2000 ppm (49-days) of [the]
Tinuvin 328. The primary findings centered on renal
and hepatic toxicity. In brief, toxic tubular nephrosis
and foci of hepatic necrosis were observed in the 800
and 1600 ppm groups. A more limited degree of hepatic
damage was observed down to the 100 ppm group. ....
"Our i ng the 90-day dog study. . . , dogs recei ved 0,
15, 30, 60, 120 and 240 mg/kg doses of Tinuvin 328.
One animal died in the 2413 mg/kg group. The primary
effect was liver toxicity with fatty changes/fatty
degeneration and monocellular necrosis, fibrosis and
inflammation occurring at doses >60 mg/kg. Certain
liver effects, however, were seen in the 15 mg/kg group
which included increased liver enzyme levels (SGPT,
SGOT & SAP), serum bilirubin levels and fatty changes
in the Kupffer cells. Other major effects seen in this
study include fatty changes in the renal glomeruli (>30
mg/kg), abnormal spermiogenesis/atrophy of tubules ()60
mg/kg), atrophy of the prostate (>30 mg/kg) and atrophy
of the uterus (~60 mg/kg). ... -."
CIBA-GEIGY also submi tted the final resul ts from two addi tional
9@-day studies in rats; the cover letter presents the following
information about the conduct and results of these studies:
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
376
IEPA FORM 1321>-6 (REV. 3-761
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8EHQ-0988-0748
Page 2 of 5
"Tinuvin 328 was added to the diet at concentrations of
~, l~~, 250, 500, 750 and 1000 ppm during a 90-day rat
study.. The primary finding concerned increased
liver and kidney weights, and increased serum alkaline
phosphatase; however, there were no histopathological
correlates to these organ weight changes. ....
"Tinuvin 328 was administered to rats in feed at a
concentration of 1~00 ppm during a l3-week study.
While there were no histopathological changes, the
primary finding indicated liver damage: increased liver
weight with increased liver enzyme levels (SGPT, SGOT &
SAP). .... "
In its' submission, CIBA-GEIGY reported that the final reports
from these studies had been obtained recently from CIBA-GEIGY's
parent company, CIBA-GEIGY Ltd. located in Basel, Switzerland.
Submission Evaluation
In the 49-day feeding study in rats, Tinuvin 328 at a dose of
2000 ppm caused 1 i ver discolorat ion and" severe" hepatic damage
in both sexes. Accord i ng to the prov ided pathology report, the
livers of the treated animals were distinctly enlarged (i.e., an
increase in liver weight) and were of a greenish-drab color. The
microscopic examination of the livers revealed overtly enlarged
parenchymal cells with homogeneous, eosinophilic cytoplasm and
nuclei varying greatly in size and shape as well as in quantity
of chromatin. In addition, large eosinophilic droplets and a few
yellowish-green pigment granules (most likely bilirubin) were
reportedly found occasionally in the cytoplasm of the parenchymal
cells. Necrosis of individual hepatocytes and, in some livers, a
slight proliferation of bile duct epithelium was seen. Although
no kidney lesions were reportedly found, there was an increase in
relative kidney weight (P(0.0l) in both sexes in the Tinuvin 328-
treated groups. Further, the relative testicular weights were
found to be slightly higher than controls but the difference was
not statistically significant.
In the 90-day rat feeding study involving Tinuvin 328 dose levels
of 100, 2~0, 400, 800 and 1600 ppm, decreased body weights and
food efficiency were reportedly observed only at the 1600 ppm
feeding level. The submitted final report provides the following
additional information with regard to other findings from this
stud y :
"Hemoglobin content and packed cell volume showed a
dose related decrease at [feeding] levels of 200 ppm
and above. Glucose-6-phosphatase activity in the
livers was increased at all levels, the lowest level
(1~0 ppm) included. Rela ti ve weights of [the] li vers,
kidneys and thyroids were increased, the effect on the
livers being significant already at the lowest level.
377
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8EHQ-0988-0748
Page 3 of 5
"Gross exa:nination at week 14 [of this 90-day study]
revealed enlargement and discoloration of livers at all
Jose levels in males. Livers of females and kidneys of
males and females showed distinct enlargement and dis-
coloration only at the 800 and 1600 ppm feeding level.
Microscopically, hepatic damage was observed at all
levels i n11 ale s and f e In ale s . Signs of toxic tubular
nephrosis were present in kidneys of males at the 800
and 1600 ppm feeding level [s] ."
In the 90-day study in Beagle dogs (3/sex/group), Tinuvin 328 was
administered in the feed at dose levels of 15, 30, 60, 120 or 240
mg/kg. One (1) dog in the high dose group (240 mg/kg) died in
the 8th week of the study. Depression of food consumption and
loss of body weight were observed in the higher dose groups; the
major finding in the two highest dose groups was an "icterus" or
jaundice. It should be noted that this particular effect may
have been accompanied by anemia because there was a decrease in
number of erythrocytes, decreased packed cell volume, decreased
mean corpuscular hemoglobin concentration, "shrivelled" erythro-
cytes and anisocytosis (i.e., an excessive size variation of
erythrocytes). The anisocytosis was evident in the 30 mg/kg dose
group as well as in the two highest dose groups.
Fur ther wi th regard to the 90-day dog study, the testes of the
animals in the higher Tinuvin 328 dose groups showed altered
spermi ogenes is and atrophy of the tubules. Test icular changes
were evident also in one dog in the 30 mg/kg dose group. Atrophy
was evident in the prostate gland of several dogs in the higher
dose groups as well as in one dog in the 30 mg/kg dose group. In
the female dogs, atrophy of the uterine wall was observed in the
60 mg/kg dose groups and higher. In the liver at most Tinuvin 328
dose levels, there were fatty changes in the hepatocytes and
Kupffer cells, protein globules in the cytoplasm, brownish-yellow
pigmentation in the hepatocytes and Kupffer cells, Kupffer cell
hyperplasia, monocellular necrosis of hepatocytes, fibrosis and
signs of inflammation. Some of these adverse effects were seen
at the lowest dose level (15 mg/kg). Compound-related atrophy of
the cortex of lymph nodes was observed as were changes in the
spleen at the 30 mg/kg dose level and above.
Regarding the 90-day study in which rats (IS/sex/group) received
Tinuvin 328 dose levels of 100, 250, 500, 750 and 1000 ppm in the
diet, 7 animals died but not in a dose-related manner (1 female
at 1000 ppm, 1 male at 750 ppm, 2 males at 500 ppm, 1 male at 100
ppm and 2 control males). According to the submitted report, an
acute respiratory infection was believed to have been responsible
for these deaths. In general, the li ver and kidney weights in
the Tinuvin 328-exposed males and females were higher than in the
control animals. As for hematological findings, urine analysis,
gross pathologic findings in spleen and microscopic pathology,
the submitted study report states that there were no differences
in these parameters between the Tinuvin 328-treated and control
rats.
378
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8EHQ-0988-0748
Page 4 of 5
with regard to the 9f3-day (13-week) feeding study in which rats
received Tinuvin 328 at a dose of 1131313 ppm, another target organ
(Le., the heart) was identified. According to the submitted
summary report (none of the actual data from the study were pro-
vided), Tinuvin 328 caused distinctly enlarged (P
-------
8EHQ-0988~0748
Page 5 of 5
"Any dermal and inhalation exposure to this product
which may occur during transfer and blending operations
can be controlled by local exhaust or other engineering
controls, or by the use of personal protective equip-
ment, including impervious gloves and dust respirators.
"Low use concentrations are employed (-0.5%) and, once
incorporated into the polymer or coating, the product
remains physically encapsulated therein, virtually
precluding exposure to the end user."
Comments/Recommendations
In the cover letter to its TSCA section 8(e) notice, CIBA-GEIGY
reported that the Tinuvin 328 Material Safety Data Sheet (MSDS)
and label are being updated to reflect the reported toxicological
f i ndi ngs. In addi tion, CIBA-GEIGY reported that the company is
informing its customers by letter about the submi tted findings.
Finally, CIBA-GEIGY reported that the company is notifying its
"plant and laboratory personnel of the new findings through
written communication and/or personal meetings."
It should be noted that EPA has received a number of section 8(e)
and "For Your Information" (FYI) notices on benzotriazole-based
UV light stabilizers. Also, the Chemical Screening Branch is in
the process of preparing a "Chemical Hazard Information Profile"
(CHIP) on benzotriazole-based UV light stabilizers; a CHIP on
piperidinyl-based UV light stabilizers is in preparation as well.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, CIBA-GEIGY will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which CIBA-GEIGY is aware or that the company has
conducted, is conducting or plans to conduct that are
designed to determine the toxicity of or the exposure
to Tinuvin 328.
b)
Staff of the Chemical Screening Branch will ensure that
any relevant reported information on Tinuvin 328 is in-
cluded in the benzotriazole-based UV light stabilizers
CHIP now in preparation.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
380
-------
UNiTED STATES ENVIRONMENTAL PROTECTION AGENCY
DATI!:
SEP 2 8 1988
Page 1 of 3
SUIJECT:
Status Report* 8EHQ-0988-0749 S A r . Ą
David R. Williams~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
I'ROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The submitting company claimed its name and the exact identity of
the subject chemical substance to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will be requesting the submitter to substantiate these TSCA CBI
claims. In the "sanitized" (Le., non-confidential) version of
its Section 8 (e) notice, the submitter stated that the subject
chemical is an "alkyl pyridine" that is "currently manufactured
exclusively for [research and development (R&D)] purposes."
Submission Description
In its Section 8 (e) submission, the submi tting company provided
the following summary information with regard to the conduct and
preliminary results of a pilot teratology study of the subject
alkyl pyridine in rats:
"In this study, [the alkyl pyridine] was administered
by gavage to 6 groups of 8 mated female rats at dose
levels of 0, 25, 50, 100, 200 and 400 mg/kg/day during
gestation days 6 - 15. Surviving dams were sacrificed
on ges ta t i on day 20. Fetuses were removed, weighed,
sexed and examined for possible external malformations.
"Three of eight females at 400 mg/kg/day died during
the study. All of the remaining high dose animals and
most of the animals at 200 mg/kg/day exhibited at least
a moderate degree of weight loss and/or decreased
weight gain during at least part of the gestation
period. There were no viable fetuses in the surviving
dams at 400 mg/kg/day. Fetal weights were decreased at
====================================================================================
* ~OTE: T~is stat~s report is the result of a preliminary evaluation of
l~fo~atlon s~bmltted to EPA pursuant to Section 8(e}, the substantial
rlsk lnformatlon reporting provision of the Toxic Substances Control
Act (TSCA): Th~ statements. made i~ this report should not be regarded
as e~presslng flnal E~A polley or lntent with respect to the subject
chemlcal(s}. Any reVlew of this status report should take into account
the fact that the report may be based on incomplete information.
381
.~A 1'0" ..»4 ",.v. 10181
-------
8EHQ-0988-0749 S
Page 2 of 3
200 mg/kg/day. In addition, 17 fetuses from 4 litters
at 200 mg/kg/day exhibited a number of external malfor-
mations. These malformations included a variety of tail
defects, distended abdomens (apparently from enlarged
and malpositioned livers), cleft palate and umbilical
hernia. No indication of maternal or developmental
toxicity was noted at 100 mg/kg/day."
The submitting company stated that upon completion of the final
report from this pilot teratology study, a copy of that report
would be provided to EPA.
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon the Agency's receipt of a full
copy of the final report (including the actual experimental pro-
tocol, results of gross/histopathological examinations, resul ts
of statistical analyses, etc.) from the teratologic study ci ted
in the company's TSCA Section 8(e) submission.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information with
regard to the initial TSCA Chemical Substance Inventory status of
the subject chemical will appear in this status report.
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submitting
company to ensure that EPA receives a complete copy of
the final report (including the actual experimental
protocol, results of gross/histopathological examina-
tions, results of any statistical analyses, etc.) from
the teratology study that was cited in the company's
TSCA Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure data, the submitter will be asked
to describe the actions the company has taken or plans
to take 1) to notify workers and others about the
reported information, and 2) to reduce or eliminate ex-
posure to the subject chemical. The company wi 11 be
requested also to descr ibe the nature and resul ts, if
available, of all studies (other than those reported
a 1 ready to EPA or those publ i shed in the scienti f ic
litera ture) about which the company is awa re or tha t
the company has conducted, is conducting or plans to
conduct that are designed to determine either the
toxicity of or the exposure to the subject chemical.
382
-------
b)
8EHQ-0988-0749 S
Page 3 of 3
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
383
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
SEP 2 8 1988
SUBJECT:
Status Report* 8EHQ-0988-0750 S
.p
David R. Williams"section 8(e}
Chemical Screening Branch/ECAD
Aooroved:r r r;;;;/ cJaf<.d"
Coordinator
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The submitting company claimed its name and the exact identity of
the subject chemical substance to be TSCA Confidential Business
Information (CBI}i the Information Management Division (IMO/OTS)
will ask the company to substantiate these TSCA CBI claims. In
the "sanitized" (i.e., non-confidential) version of the TSCA
Sect ion 8 (e) notice, the submi tti ng company r epo r ted tha t the
subject chemical substance is a "heterocyclic aryl amide" that is
being produced solely by the company for the purpose of research
and development (R&D).
Submission Description
The submitting company provided the following information about
the conduct and preliminary results of a pilot teratology study
of this heterocyclic aryl amide in rats:
"In this study, [the subject chemical substance] was
administered by gavage to 6 groups of 8 mated female
rats at dose levels of 0, 75, 150, 250, 500 and 1000
mg/kg/day during gestation days 6-15. Surviving darns
were sacrificed on gestation day 20. Fetuses were
removed, weighed, sexed and examined for possible
external malformations.
"No maternal mortality occurred during the study.
However, darns at 1000 and 500 mg/kg/day exhibited mean
weight losses of 8 grams and 1 gram, respectively,
during gestation days 6-9 (as compared to a mean weight
gain of 5 grams in the controls). Mean weight gain
from gestation days 9-12 was normal at 500 mg/kg/day
but lower than controls at 1000 mg/kg/day. Mean fetal
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
lnformatlon submltted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
K~A 1'0'" "... C"KV. ~181
384
-------
8EHQ-0988-0750 S
Page 2 of 3
weights appeared to be slightly decreased relative to
control at 1131313 mg/kg/day but [were] comparable to
control at the other dose levels. One fetus each from
four litters at 1131313 mg/kg/day exhibited a thread-like
tail. One fetus each at 75 and 51313 mg/kg/day exhibited
microphthalmia. All of these defects are observed
occasionally in control animals and it cannot be deter-
mined whether or not the defects observed in this study
were related to treatment."
The submitting company stated that a copy of the final report
from this pi lot teratology study would be transmi tted to EPA as
soon as the report is completed.
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a full copy of
the final report (including the actual experimental protocol,
results of gross and histopathological examinations, results of
statistical analyses, etc.) from the oral teratology study ci ted
in the company's Section 8(e) notice.
Current Production and Use
In light of the submitting company's CBI claims, no information
about the initial TSCA Chemical Substance Inventory status of the
subject chemical will appear in this status report.
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submitter to
ensure that the Agency receives a complete copy of the
final report (including the actual experimental proto-
col, results of gross/histopathological examinations,
results of statistical analyses, etc.) from the pilot
teratology study that was ci ted in the company's TSCA
Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the actions the company has taken or
plans to take 1) to notify workers and others about the
reported information, and 2) to reduce or eliminate
exposure to the subject chemical. In addition, the
company will be requested to describe the nature and
results, if available, of all studies (other than those
reported already to the Agency or those that have been
published in the scientific literature) about which the
company is aware or that the company has conducted, is
conducting or plans to conduct that are designed to
determine either the toxicity of or the exposure to the
subject chemical substance.
385
-------
b)
c)
8EHQ-0988-0750 S
Page 3 of 3
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
The Chemical Screening Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
386
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
04 T!:
SEP 2 8 1988
Page 1 of 2
SU8JECT:
status Report* 8EHQ-0988-075l S Approved: L r: ~ t}btJp-f'
David R. Williams~ection B(e) Coordinator (7
Chemical Screening Branch/ECAD
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will be asking the submitting company to substantiate these TSCA
CBI claims. In the "sanitized" (Le., non-confidential) version
of its Section 8 (e) submission, the company reported that the
subject chemical substance was a "diaryl ether." In addi tion,
the company reported non-confidentially that this chemical is
currently being manufactured by the company solely for research
and development (R&D).
Submission Description
The submi tting company provided the following summary regarding
the conduct and preliminary results of a pilot teratology study
of this diaryl ether in rats:
". . . [The subject chemical] was administered by gavage
to 6 groups of 8 mated female rats at dose levels of 0,
50, 100, 200, 400 and 600 mg/kg/day during gestation
days 6-15. Surviving dams were sacrificed on gestation
day 20. Fetuses were removed, weighed, sexed and
examined for possible external malformations.
"Maternal death occurred in 3/8 and 8/8 animals at 400
and 600 mg/kg/day, respectively. Decreased ma terna 1
body weight gain and clinical signs of toxicity were
noted at 200 mg/kg/day. No live fetuses were found in
the survivors at 400 mg/kg/day. An increase in early
resorptions and a decrease in fetal weights were noted
at 200 mg/kg/day. No external malformations were ob-
served in any group. No maternal or developmental
toxicity was noted at or below 100 mg/kg/day."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
387
.~A 1'0- "... ,,,.v. 10181
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8EHQ-0988-0751 S
Page 2 of 2
In its TSCA Section 8(e) submission, the company stated that EPA
would receive a copy of the final report of this teratology study
as soon as that report is available.
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon the Agency's receipt of a full
copy of the final report (including the actual experimental pro-
tocol, results of gross/histopathological examinations, results
of all statistical analyses, etc.) from the oral teratology study
cited in this TSCA Section 8(e) notice.
Current Production and Use
Considering the submitting company's TSCA CBI claims, this status
report will not contain any information concerning the initial
TSCA Chemical Substance Inventory status of the subject chemical.
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submi tting
company to ensure that EPA receives a complete copy of
the final report (including the actual experimental
protocol, results of gross/histopathological examina-
tions, resul ts of sta ti stical analyses, etc.) from the
teratologic study ci ted in the company's Section 8 (e)
submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity/exposure data, the submitter will be asked to
describe the actions the company has taken or plans to
take 1) to notify workers and others about the reported
information, and 2) to reduce or eliminate exposure to
the subject chemical. In addition, the company will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those that have been published in the scientific
literature) about which the company is aware or that
the company has conducted, is conducting or plans to
conduct that are designed to determine either the
toxicity of or the exposure to this diaryl ether.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
388
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UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DATE:
SEP 2 9 1988
Status Report> 8EHQ-0988-0752 S Aoproved: #""'" r C 1/~,Jt
David R. Williams~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
Page 1 of 3
SUBJECT:
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The 3M Company claimed the exact identity of the subject chemical
substance to be TSCA Confidential Business Information (CBI); the
Information Management Division (IMD/OTS) will be requesting 3M
to substantiate this TSCA CBI claim. In the "sanitized" (i.e.,
non-confidential) version of its TSCA Section 8(e) submission, 3M
stated that the subject chemical was an "inorganic fiber with [a]
diameter [of] less than one micron and length ranging from less
than 5 microns to greater than 100 microns."
Submission Description
3M reported that "aqueous suspensions of [inorganic fiber] sample
were deposited in the lungs of albino rats by intratracheal
insufflation" and "after six months the lungs were fixed in 10%
formalin, stained (hematoxylin and eosin) and examined by light
microscope." According to 3M, verbal reports received by the
company indicate that "all samples caused pulmonary fibrosis to
one degree or another." Finally, 3M stated that a copy of the
final report from this study would be submi tted to the Agency
when that report becomes available.
Immediately upon reqeipt of this TSCA Section 8(e) submission,
the Chemical Screening Branch provided copies of the submission
to staff of the Chemical Control Division (CCD/OTS) for inclusion
in the ongoing OTS review of available toxicological and exposure
data on a number of man-made and naturally-occurring fibers.
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a full copy of
the final report (including the actual experimental protocol, the
results of gross/histopathological examinations, the results of
statistical analyses, etc.) from the intratracheal insufflation
study cited in the company's TSCA Section 8(e) submission.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
389
.~A '0"" II'" IIUV..1-711
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8EHQ-0988-0752 S
Page 2 of 3
Current Production and Use
In view of 3M's TSCA CBI claim, no information about the initial
TSCA Chemical Substance Inventory status of this inorganic fiber
will appear in this status report.
In its TSCA Section 8 (e) submission, 3M provided the following
non-confidential information concerning the manufacture of and
the potential for exposure to this inorganic fiber:
"This [inorganic fiber] is a research and development
[(R&D)] material. About 1,000 kg have been manufactured
in a closed process. During manufacture, exposure may
occur wi th transfer or shu tdown and c 1 ea n-up d u ring
which personnel use high efficiency filter respirators.
No airborne fibers have been detected (.001 fibers/
cc) . Approximately 200 potential customers have been
sampled with quantities of less than 10 grams each and
two customers have recei ved ki logram quanti ties. The
latter and all future recipients will be advised of
these [toxicological] findings and that 3M has an ex-
posure guideline of 0.2 fibers per cubic centimeter
[(cc)], time weighted average [(TWA)]. They will also
be advised to use high efficiency filter respirators
and local exhaust ventilation."
Comments/Recommendations
It should be noted that the Office to Toxic Substances (OTS) has
received a number of TSCA Section 8(e) and "For Your Information"
(FYI) submissions on a variety of naturally-occurring and man-
made fibers.
a)
The Chemical Screening Branch will ask the 3M Company
to ensure that the Agency recei ves a complete copy of
the final report (including the actual experimental
protocol, results of gross/histopathological examina-
tions, results of any statistical analyses, etc.) from
the cited intratracheal insufflation study.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity/exposure data, 3M will be asked to describe
the nature and results, if available, of all studies
(other than those reported already to EPA or those
cited in the scientific literature) about which 3M is
aware or that 3M has conducted, is conducting or plans
to conduct that are designed to determi ne either the
toxicity of or the exposure to these inorganic fibers.
b)
The Chemical Screening Branch will immediately provide
copies of all reported information to the CCD/OTS for
review and appropriate followup attention.
390
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8EHQ-0988-0752 S
Page 3 of 3
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FOA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORO/EPA, CCO/OTS and RAB/ECAO/OTS;
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
391
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
SEP 2 9 /988
Page 1 of 2
SU8JECT:
Status Report* 8EHQ-0988-0753 S
David R. Williams~ection 8(e)
Chemical Screening BranchjECAD
APproved:r "tC'lftdh-
Coordinator
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification SectionjCSBjECAD
Note
The Hoechst Celanese Corporation has claimed the exact identi ty
of the subject chemical substance as TSCA Confidential Business
Information (CBI); the Information Management Division (IMDjOTS)
will be requesting the company to substantiate this CBI claim.
In the "sanitized" (Le., non-confidential) version of its TSCA
Section 8 (e) notice, Hoechst Celanese stated that the subject
chemical was a "substituted indoleninium salt." In addition,
Hoechst Celanese reported non-conf identia lly tha t the chern i ca 1
substance had been the subject of a "Premanufacture Notification"
(PMN No. P-88-1019) submitted to EPA under Section 5 of TSCA.
Submission Description
The Hoechst Celanese Corporation submitted the final report of an
acute eye irritation study of the subject chemical in rabbits.
The submitter's cover letter provides the following information
regarding the conduct and results of this toxicologic study:
"Three rabbits each received 100 mg of the test
material in one eye. Within one hour, two of the
rabbits had died and no irritation evaluation was
performed. Th~ third rabbi twas evalua ted after one
hour and substantial irritative effects on the cornea,
iris and conjunctiva were noted. This rabbit died
within four hours."
Submission Evaluation
Immediately upon receipt of this TSCA Section 8 (e) submission,
the Chemical Screening Branch sent copies of the notice to the
Chemical Control Division (CCDjOTS) for review and appropriate
followup attention; CCD is respons,ible for administering EPA's
TSCA Section 5 "New Chemicals program" (NCP).
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
392
EPA FO- 13.. {REV. J-nl
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8EHQ-0988-0753 S
Page 2 of 2
Current Production and Use
In its TSCA Section 8 (e) submission, Hoechst Celanese reported
that this subst i tuted i ndoleni nium sa It" is not in the publ i c
TSCA Chemical Substance Inventory" and "has not been imported to
the U.S. for commercial purposes." Finally, Hoechst Celanese
reported that a "Notice of Commencement" (NOC) for this chemical
has not as yet been sent by the company to EPA.
The sanitized version of PMN No. P-88-1019 provides the following
information about the use of this substituted indoleninium salt:
"This PMN substance is a cationic dyestuff used for the
coloration of acrylic fibers. A solution of the dye-
stuff in dimethyl formamide [(DMF)] is prepared and
int~oduced into the fiber as a DMF solution."
The sanitized version of PMN No. P-88-1019 also reports that the
projected importation range for the subject chemical substance is
5,000 to 10,000 kilograms per year.
Comments/Recommendations
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Hoechst Celanese will
be asked to describe the actions the company has taken
or plans to take 1) to notify workers and others about
the reported information, and 2) to reduce or eliminate
exposure to this substituted indoleninium salt. Also,
Hoechst Celanese will be asked to describe the nature
and results, if avai lable, of all stud ies (other than
those reported already to EPA or those that have been
published in the scientific literature) about which the
company is aware or that the company has conducted, is
conducting or plans to conduct that are designed to
determine either the toxicity of or the exposure to the
subject chemical substance.
b)
As in the case of the initial Section B(e) notice, the
Chemical Screening Branch will immediately send copies
of the reported information to CCO/OTS for review and
appropriate followup attention.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FOA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORO/EPA, OPP/OPTS/EPA and CCO/OTS;
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
393
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UtotlTED STATES ENV'lRONMEtotTAL PROTECTION AGENCY
DA TE:
SEP 3 0 1988
Page 1 of 4
APproved:~ r. ~/ 9;'0/n
Coordinator
SU8JECT:
Status Report* 8EHQ-0988-0754
David R. Williams,~ection 8(e)
Chemical Screening Branch/ECAD
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
In this fully non-confidential TSCA Section 8(e) submission, the
American Cyanamid Company reported that the subject chemical sub-
stance (2-amino-2,3-dimethylbutanenitrile (hereinafter termed
"aminonitrile"); CAS No. 13893-53-3) had been the subject of a
"premanufacturing Notification" (PMN No. P-83-603) submitted
previously to EPA under Section 5 of TSCA. In addition, the
company reported that a TSCA Section 5(e) Consent Order is in
effect for the subject chemical.
Submission Description
In its Section 8 (e) submission, American Cyanamid provided the
following information with regard to the conduct and preliminary
results of an acute inhalation study of the subject aminonitrile
as a 60% solution in toluene:
"Groups of 5 male and 5 female Sprague-Dawley rats were
exposed to [aminonitrile/toluene] vapors for one hour.
Concentrations of aminonitrile were measured analyti-
cally by gas chromatography. In the first exposure,
rats were expo~ed to 169 ppm aminoni tr i le in the' pre-
sence of 21 ppm '[hydrogen cyanide (HCN)], a degradation
product of aminonitrile, for one hour. All ten animals
were dead at the conclusion of the one-hour exposure.
In a second exposure, rats were exposed to 100 ppm
aminonitrile in the presence of 11 ppm HCN. Six of the
10 animals were dead at the conclusion of the one-hour
exposure. Symptoms of intoxication included dyspnea,
hypoactivity and prostration prior to death. Although
the 14-day post-exposure observation period is still
continuing for the 100 ppm exposure group, there have
been only two further deaths observed. Nei ther death
appeared to result from delayed systemic toxicity-"
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
394
E~A "ORM 11.. (REV. 3-711
-------
8EHQ-0988...0754
Page 2 of 4
In its TSCA Section 8(e) notice, American Cyanamid also provided
the following summary of toxicologic findings submitted thus far
to EPA by the company:
IIData previously reported to the Agency indicate that
2-amino-2,3-dimethylbutanenitrile of greater than 95%
purity is moderately toxic by ingestion and
highly toxic by single skin application or ocular
instillation. The acute oral LD50 in male and female
albino rats is 83 mg/kg. The acute dermal LD50 in
rabbits is 23 mg/kg. The instillation of aminonitrile
(89 mg) into the eyes of rabbits resulted in the deaths
of five of the six animals tested.
IIA 28-day rat dermal toxicity study was conducted on
aminonitrile to evaluate if this chemical, like other
nitriles, was neurotoxic. Aminonitrile when admini-
stered dermally at 0, 3, 10 or 30 mg/kg produced no
overt signs of neurotoxicity. Skin irritation was
observed at the application site in the 10 and 30 mg/kg
dose groups. The No Observed Effect Level [(NOEL)] was
3 mg/kg.
IIAminonitrile was not mutagenic in S. typhimurium (TA
98, TA 100, TA 1535, TA 1537) or E:--coli WP-2uvrA in
the presence or absence of Aroclor1254-induced rat
liver S-9.11
American Cyanamid reported in its Section 8 (e) notice that the
company was submi tting the acute inhalation data IIbecause test
i nforma t i on on the inhalation hazard of aminoni tri le was here-
tofore unavai 1able. II In addi ti on, Amer i can Cyanamid reported
that the submitted inhalation data IIconfirm that aminonitri1e,
like other aliphatic nitriles, is an acute inhalation hazard
([see] Table 1 [below]):
Table 1
Nitrile
Inhalation Result
Lactonitrile [1]
LCLO 4 hour/rat = 125 ppm
Malononitrile [2]
LC50 2 hour/rat =
57 ppm
G1yco10nitrile [3]
LC50 8 hour/rat =
27 ppmll
[1] 2-hydroxypropanenitrile (CAS No. 78-97-7)
[2] propanedinitrile (CAS No. 109-77-3)
[3] hydroxyacetonitrile (CAS No. 107-16-4)
395
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8EHQ-0988-0754
Page 3 of 4
American Cyanamid stated that a copy of the final report from the
company's acute inhalation study would be submi tted to EPA when
that report is completed.
Submission Evaluation
Immediately upon receipt of this TSCA Section 8 (e) submission,
the Chemical Screening Branch sent copies of the submission to
staff of the Chemical Control Oi vi s ion (CCO/OTS) for review and
followup attention; CCO is responsible for the administration of
EPA's TSCA Section 5 "New Chemicals Program" (NCP).
Current Production and Use
In its TSCA Section 8 (e) submission, American Cyanamid provided
the following information regarding the production/use of and the
potential for exposure to the subject chemical:
"Aminonitrile is made and processed in a closed system.
Wherever there is a possibility of exposure, American
Cyanamid Company is currently handling aminonitrile as
an inhalation hazard. . [The company's] procedure
for handling the material specifies that the following
protective equipment must be worn when the possibility
of exposure exists:
"positive pressure, full facepiece, air-
supplied respirator, total encapsulating
SARANEX-coated Tyvek suit with ultrasonic
sealed seams, or butyl rubber suit. Gloves
must be of butyl rubber or viton. Boots must
be butyl rubber or made from a heavy
nitrile/PVC combination.
"Engineering, industrial hygiene and environmental
controls minimize risk during manufacture.
"Since the aminonitrile is solely an intermediate for
the production of a class of herbicides of very low
toxici ty and is not sold as an article of commerce or
transferred to any contract manufacturer, there is a
low potential for exposure of humans or the environ-
ment."
Comments/Recommendations
a)
American Cyanamid will be asked to ensure that EPA
receives a complete copy of the final report (including
the actual experimental protocol, the results of gross
and histopathological examinations, the results of any
statistical analyses, etc.) from the acute inhalation
study cited in the company's Section 8(e) notice. In
add it i on, the company will be asked to descr i be the
nature and results, if available, of all studies (other
396
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8EHQ-0988-0754
Page 4 of 4
than those reported already to the Agency) about which
the company is aware or that the company has conducted,
is conducting or plans to conduct that are designed to
determine the toxicity of the subject chemical.
b)
Immediately upon receipt, the Chemical Screening Branch
will send copies of the reported information to CCO/OTS
for review and appropriate followup attention.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FOA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORO/EPA, OPP/OPTS/EPA and CCO/OTS;
copies of this report will be sent also to the TSCA
Assisiance Office (TAO/OTS) for further distribution.
397
-------
UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
DJ. TE:
OCT 2 4 1988
Page 1 of 4
SUBJECT:
Status Report*
8EHQ-1088-0755
Approved: [y~h c:r.{::/ /ob
-------
8EHQ-I088-07SS
Page 2 of 4
"During the process, the materials were processed in an
airmill and a hammermill to reduce 45 percent of the
particles to below 5 microns and 0.5 percent to below 1
micron."
In reporting this information to EPA under Section 8(e) of TSCA,
Eli Lilly submi tted copies of two scientific articles reporting
that monolinuron was implicated as the cause of methemoglobinemia
in humans. El i Li lly stated that based on these articles, the
effects observed in the Van Diest workers "may have been due to
the monolinuron." Eli Lilly stated also that Eli Lilly "has not
seen this effect [(i.e., methemoglobinemia)] with ethalfluralin."
Further, Eli Lilly provided a copy of a February 20, 1987 Hoechst
A.G. Safety Data Sheet for monolinuron (trade name: Aresin) which
provides the following information on the mammalian toxicity of
monolinuron:
"Acute oral toxicity (LD50): 1800 mg/kg (rat)
Literature: WHO
Acute dermal toxicity (LD50): >1500 mg/kg (female rat)
Primary dermal irritation: non-irritant (rabbit)
primary eye irritation: non-irritant (rabbit eye)"
Eli Lilly and Company stated that the Elanco Products Company (a
division of Eli Lilly and Company) had provided the subject
information to EPA's Office of Pesticide Programs (OPP) pursuant
to Section 6 (a) (2) of the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA); Eli Lilly's TSCA Section 8(e) submission
contained a copy of Elanco's FIFRA Section 6(a) (2) notification
letter which referenced the following:
"SONALAN (ETHALFLURALIN) TECHNICAL
EPA REG. NO. 1471-144"
It should be noted that immediately upon receipt of this TSCA
Section 8 (e) submission, the Chemical Screening Branch trans-
mitted a full copy of the submission to EPA's Office of Pesticide
Programs for review and appropriate followup attention under
FIFRA.
Submission Evaluation
The company's suspicion that monolinuron is the agent responsible
for the observed adverse effects in the Van Diest Supply Company
workers has some merit in that 1) methemoglobinemia has not been
seen by the company with ethalfluralin, and 2) the published
medical literature cites a number of animal studies and .human
incidents in which monolinuron caused or was suspected as having
caused methemoglobinemia and/or sulfhemoglobinemia.
The significance of the blood effects observed in the workers
lies in the associated pathophysiology. Methemoglobin is hemo-
globin in which the iron has been oxidized. Methemoglobin is
399
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8EHQ-I088-0755
Page 3 of 4
being formed continuously in normal red blood cells (in the
absence of exogenous oxidizing drugs or toxins) and is reduced
continuously to hemoglobin. In normal red cells (in man) under
steady state conditions, the methemoglobin level does not exceed
2% of the total hemoglobin content. A methemoglobin level in
excess of 1.5 g/100 ml (10% of total hemoglobin) leads to visible
cyanosis. If methemoglobin exceeds 35% of the total hemoglobin
content, headache and dyspnea may occur, while methemoglobin
levels over 70% are lethal. Methemoglobinemia can develop when
red blood cells are exposed to excess oxidant drugs or toxins or
when the red cells are congenitally deficient in NADH diaphorase
(the enzyme that catalyzes the reduction of methemoglobin back to
hemoglobin) .
Sulfhemoglobinemia is associated with a condition in which the
blood contains a poorly characterized hemoglobin derivative with
a characteristic absorption spectrum that distinguishes it from
methemoglobin. This condition can be produced in vivo by various
oxidant drugs including sulfonamides, phenacetin and acetanilid.
Unlike methemoglobin, sulfhemoglobin cannot be converted back to
hemoglobin. When sulfhemoglobin is formed, it persists until the
red cells containing the chemical are destroyed.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for monolinuron (CAS No. 1746-81-2) showed that 2
million to 20 million pounds of this chemical were reported as
manufactured and/or imported in 1977. This production range
information does not include any information claimed as TSCA
Confidential Business Information (TSCA CBI) by the person(s)
reporting for the initial TSCA Inventory, nor does it include any
information that would compromise TSCA CBI.
A review of the production range (includes importation volumes)
statistics for ethalfluralin (CAS No. 55283-68-6), which is also
listed in the initial TSCA Chemical Substance Inventory, showed
that no 1977 manufacture/importation of the chemical was reported
or that all of the manufacturing and/or importation data reported
were claimed as TSC~ Confidential Business Information (TSCA CBI)
by the person(s) reporting for the initial Inventory and cannot
be disclosed (Section 14(a) of TSCAi U.S.C. 2613(a».
hll of the information submi tted for the ini t ial TSCA Chemical
Substance Inventory, including the reported production range
information, is subject to the limitations that are contained in
the initial TSCA Inventory Reporting Regulations (40 CFR 710).
In its TSCA Section 8 (e) submission, Eli Lilly stated that the
subject pesticide product was being formulated for export.
400
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8EHQ-I088-07SS
Page 4 of 4
Comments/Recommendations
It is important to note that Part VII of EPA's March 16, 1978
TSCA Section 8(e) policy statement ("Statement of Interpretation
and Enforcement Policy; Notification of Substantial Risk". 43 FR
11110) explains that information would not need to be reported to
EPA under Section 8(e) of TSCA if the subject information "has
been submitted in writing to EPA pursuant to mandatory reporting
requirements under TSCA or any other authority administered by
EPA (including the Federal Insecticide, Fungicide and Rodenticide
Act. .." In other words, if Elanco was not required to report
the subject information to EPA under Section 6(a)(2) of FIFRA,
then Eli Lilly was correct in submitting the information to the
Agency under Section 8(e) of TSCA.
a)
The Chemical Screening Branch will ask Eli Lilly to
ensure that EPA is kept abreast of any further health-
or exposure-related developments that arise from the
reported incident.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance(s).
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA;
copies of this status report will be sent also to the
TSCA Assistance Office (TAO/OTS/OPTS/EPA) for further
distribution.
401
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
OCT 2 6 1988
Page 1 of 3
SU8JECT:
status Report*
8EHQ-1088-0756
Approved ~ r: c;;:: )ot,-,f.,.p
Coordinator
David R. Williams~ection 8(e)
FROM: Chemical Screening Branch/ECAD
TO: James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The CIBA-GEIGY Corporation submi tted the final reports from two
90-day feeding studies of 2-(5-chloro-2H-benzotriazol-2-yl)-4,6-
bis- (1, l-dimethylethyl) phenol (Tinuvin 327; CAS No. 3864-99-1) in
rats. The following information with regard to the conduct and
results of these subchronic studies was presented in CIBA-GEIGY's
cover letter:
"During a 90-day feeding study in rats, Tinuvin 327, at
a dietary concentration of 2,000 - 50,000 ppm, produced
distinct hepatic damage: scattered necrotic liver cells
and, in some cases, foci of necrosis. There were also
signs of anemia in these animals. ....
"During. . . [another 90-day] feeding study, increased
liver weight and isolated cell necrosis in the liver
were observed in the 100 and 200 ppm groups. ...."
In its submission, CIBA-GEIGY reported that the final reports
from these studies had been obtained recently from CIBA-GEIGY's
parent company, CIBA~GEIGY Ltd. located in Basel, Switzerland.
Submission Evaluation
In the 90-day feeding study involving Tinuvin 327 dose levels of
2,000 to 50,000 ppm in the daily diet of rats, "distinct" liver
damage evidenced by necrotic hepatic cells (and foci of necrosis
in some cases) and signs of anemia were observed in the male
rats. In addition, this 90-day feeding study also showed that
the pancreas of the male rats had lesions. It is important to
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
402
E~A !fORM 11.. (REI/. J-711
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8EHQ-I088-0756
Page 2 of 3
recogn i ze that the formation of many digesti ve enzymes and the
regulation of carbohydrate metabolism are among the functions of
the pancreas. Further, conditions that impair normal functions
of the pancreas usually evoke signs or symptoms when far advanced
because there is a large reserve for both endocrine and exocrine
functions. In the other 913-day feeding study of Tinuvin 327,
decreased hemog lobin content and packed cell volume, increased
liver, kidney and thyroid weights, and isolated liver cell
necrosis were observed in the male rats only.
It should be noted that a number of benzotriazo1e-based chemical
toxicity studies have been evaluated to date by EPA's Office of
Toxic Substances (OTS). (The reader's attention is directed to
the second paragraph in the Comments/Recommendations section of
this status report.) There is a cons is tency in the types 0 f
effects that have been observed in these studies, which have been
mainly repeated oral short-term (28- or 49-day) studies in rats.
These effects include death, decreased size and/or weight of the
seminal vesicles, decreased splenic weight, decreased thymic
weight, focal liver hemorrhages, liver necrosis, dose-related
increased liver weight, hepatic discoloration, increased kidney
weight and renal tubular degeneration. In a previously received
TSCA Section 8(e) notice (8EHQ-13888-13747) on a 913-day feeding
study of another benzotriazo1e-based chemical (Tinuvin 32(3),
similar toxicologic effects as well as an altered blood profile
(decreased hemoglobin content, decreased packed cell volume and
decreased number of erythrocytes) were observed. The presen t
TSCA section 8 (e) submission on Tinuvin 327 as well as another
recent TSCA Section 8(e) submission (8EHQ-13988-13748 concerning
Tinuvin 328) demonstrate further consistency with this overall
toxicological profile and also identify the heart (in the case of
Tinuvin 328) and the pancreas (in the case of Tinuvin 327) as
other target organs.
Current production and Use
A review of the production range (includes importation volumes)
statistics for CAS No. 3864-99-1, which is listed in the initial
TSCA Chemical Substance Inventory, has shown that 113 thousand to
11313 thousand pounds were reported as manufactured in 1977. This
production range information does not include any data that were
claimed as TSCA Confidential Business Information (TSCA CBI) by
the person(s) reporting for the initial TSCA Inventory, nor does
it include any data that would compromise TSCA CBI. All of the
data reported for the initial TSCA Inventory, including the pro-
duction range data, are subject to the limitations contained in
the initial TSCA Inventory Reporting Regulations (413 CFR 71(3).
In its TSCA Section 8 (e) submission, CIBA-GEIGY reported that
Tinuvin 327 "is a benzotriazole-type ultraviolet [(UV)] light
absorber used primarily for stabilizing plastics and polymer
coa tings." CIBA-GEIGY also submi tted the following information
on the potential for worker and end user exposure to Tinuvin 327:
403
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8EHQ-1088-0756
Page 3 of 3
"Any dermal and inhalation exposure to this product
which may occur during transfer and blending operations
can be controlled by local exhaust or other engineering
controls, or by the use of personal protective equip-
ment, including impervious gloves and dust respirators.
"Low use concentrations are employed (approximately
~. 5%) and, once incorporated into the polymer or
coating, the product remains physically encapsulated
therein, virtually precluding exposure to the end
user."
Comments/Recommendations
In its TSCA Section 8 (e) submission, CIBA-GEIGY stated that the
Tinuvin 328 Material Safety Data Sheet (MSDS) and product label
were being updated to reflect the reported toxicologic findings.
In addition, CIBA-GEIGY reported that the company is 1) informing
its Tinuvin 327 customers "in accordance with the notification
requirements of the OSHA Hazard Communication Standard (29 CFR
191~.12~~)," and 2) notifying CIBA-GEIGY workers via the revised
MSDS and "the company's OSHA Hazard Communication Program."
It should be noted that EPA has received a number of section 8(e)
and "For Your Information" (FYI) notices on benzotriazole-based
UV light stabilizers. Also, the Chemical Screening Branch is in
the process of preparing a "Chemical Hazard Information Profile"
(CHIP) on benzotriazole-based UV light stabilizers; a CHIP on
piperidinyl-based UV light stabilizers is in preparation as well.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, CIBA-GEIGY will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which CIBA-GEIGY is aware or that the company has
conducted, is conducting or plans to conduct that are
designed to determine the toxicity of Tinuvin 327.
b)
Staff of the Chemical Screening Branch will ensure that
all relevant reported information on Tinuvin 327 is in-
cluded in the benzotriazole-based UV light stabilizers
CHIP now in preparation.
c)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
404
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
tOI - 3 1988
Page 1 of 4
SUBJECT:
Status Report* 8EHQ-1088-0757
.., .
David R. WIllIams, SectIon 8(e)
Chemical Screening Branch/ECAD
Approved: r r ~ "Mff
Coordinator
'RDM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
The CIBA-GEIGY Corporation provided the final report of a 28-day
oral (gavage) toxicity study of 1-[bis(2-hydroxyethyl) amino]-3-
(4-isononylphenoxy) -2-propanol (CAS No. unknown) in rats. The
submitter's cover letter presents the following information with
regard to the conduct and results of this study:
"During a 28-day toxicity study, rats received oral
doses of 0, 10, 50, and 300 mg/kg/day. Li ver and
spleen damage were observed at 300 mg/kg in male and
female rats. The effects included slight necrosis of
the centr i lobular reg i on of the 1 i ver and there wa s
moderate to marked atrophy of the splenic whi te pulp.
Mortality, ataxia, and partial motor paralysis were
observed for males in the 300 mg/kg group. These
effects were not seen at 50 mg/kg. ...."
CIBA-GEIGY reported also that the subject chemical is
to eyes and is also a skin sensitizer."
"corrosive
Submission Evaluation
In this 28-day toxicity study, the subject chemical substance was
administered to 5 albino rats/sex/group at doses of 0, 10, 50 and
300 mg/kg/day by gavage and the animals were then evaluated for
mortality, clinical signs, body weight gain, hematology, clinical
chemistry, gross pathology and histopathology.
Three of 5 male rats at 300 mg/kg/day died between days 13 - 16.
A fourth male in the same dose group was found moribund on day
17. There were no other mortali ties in any of the other groups
in the study. Adverse cl i nical signs such a ocular di scharge,
salivation, labored breathing, hypoactivity, ataxia, and/or
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
405
.~A '0- II" '''EV. to?"
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8EHQ-I088-0757
Page 2 of 4
paresis (i.e., partial paralysis) were observed in some but not
all of the male rats in the highest dose group (300 mg/kg/day);
some of these signs were seen but only infrequently in the high
dose female rats. Although these clinical signs were not observed
in the animals in any other groups in the study, some of these
antemortem signs {as well as certain other clinical signs (e.g.,
tremors, sedation, ataxia) reportedly observed during an acute
oral dose range-finding study in rats) do suggest that the test
chemical may produce neurotoxicologic effects.
Body weight gains were statistically significantly reduced for
both sexes a t the 300 mg/kg/day dose level, wi th the male and
female body weights being 35% and 12%, respectively, below those
of the control animals. The weight gain for animals at the lower
dose levels was comparable to those of the controls.
The hematology results were confusing in that the males showed a
dose-related decrease in total whi te blood cells (WBCs) bu tan
increased level of specific WBC types (neutrophils, monocytes,
eosinophils). Furthermore, the female rats showed a similar
increase in specific WBC types and the more logical increase in
total WBCs. (There is some question as to whether the male total
WBC counts could have been reversed.) In general, however, this
occurrence may not be that critical because the total WBC counts
are well within normal physiological range for rats and hence,
may not be of any biological significance.
The biochemical analyses that were performed showed increased
levels of serum cholesterol, aspartate aminotransferase (GOT) and
alanine aminotransferase (GPT) and decreased levels of alkaline
phosphatase (Alp) for males in the 300 mg/kg/day group. These
results may not be valid, however, because the values were
derived from only the one remaining male rat in the 300 mg/kg/day
dose group. The females, on the other hand, showed definite
dose-related increases in serum cholesterol and globulin; dose-
related decreases were noted also in the albumin/globulin ratio.
The females also exhibited significantly increased GOT and GPT
levels and significantly decreased Alp levels at 300 mg/kg/day.
These alterations in biochemical parameters are strong indicators
of hepatocellular injury.
The major finding at necropsy was a significant dose-related
increase in absolute and relative liver weights in rats in the 50
and 300 mg/kg/day dose groups. The relative liver weights at 300
mg/kg/day were 1.5 to 2 times those of the controls. The males
also had increased relative kidney and testes weights at 300
mg/kg/day. The females showed definite dose-related increases in
the relative weights of the kidney, brain, heart and adrenals
which were statistically significant at 300 mg/kg/day.
The histopathological examination provided microscopic evidence
to support the meaning of the observed alterations in biochemical
parameters and organ weights. At 300 mg/kg/day, 4/5 males and
5/5 females exhibited centrilobular necrosis and cytoplasmic
406
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8EHQ-I088-0757
Page 3 of 4
vacuolization of the liver. Hepatocellular hypertrophy was
present in 3/5 females at 300 mg/kg/day. All (5/5) females at
300 mg/kg/day exhibited cytoplasmic vacuolization of the renal
tubules and 1/5 males at 300 mg/kg/day showed dilatation and
casts in the renal tubules. Phagocytic cells were found to be
present in the spleens of both sexes and atrophy of the splenic
white pulp occurred in 4/5 males at 300 mg/kg/day. No treatment-
related histopathologic effects were evident at the lower doses.
Although the final report "Summary" states that 10 mg/kg/day was
determined to be the no-observed-adverse-effect-level (NOAEL) for
the subject chemical in this 28-day oral toxicity study in rats,
EPA suggests that 10 mg/kg/day be considered the lowest-observed-
adverse-effect-level (LOAEL) based on the following rationale.
The primary toxic effects of the tested chemical substance appear
to occur in the liver. Although the serum biochemistry values
and organ weights in the animals in the 10 mg/kg/day dose groups
did not differ statistically from those of the controls, there
was a definite linear dose-related increase in these parameters
beginning at 10 mg/kg/day; such increases are indicative of
hepatocellular injury.
Current Production and Use
CIBA-GEIGY provided the following information with regard to the
importation/use of the subject chemical:
"It is an imported research and development [(R&D)]
material used as a corrosion inhibitor for lubricants.
To date, approximately 1.8 kg of this material has been
imported into the U.S. for laboratory testing and
limited distribution to one customer for R&D testing (a
total of 0.28 kg). Approximately 0.9 kg still remains
in . . . [CIBA-GEIGY's] laboratory.
CIBA-GEIGY also provided the following information concerning the
potential for exposure to the subject chemical:
"a) Exposure is minimal since very little material has been
imported.
"b) This is a research and development material. It has
been used only by or under the direct supervision of a
technically qualified individual(s).
"c) Distribution has been limited to one customer
small quantities.
in very
"d) The material is corrosive to eyes and is also a skin
sensitizer. It is labeled accordingly. Therefore,
dermal exposure is already avoided or minimized by
anyone handling the material by the use of impervious
gloves and chemical goggles as recommended in .
[the company's] Material Safety Data Sheet [(MSDS)].
407
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8EHQ-I088-0757
Page 4 of 4
lie) The product is a viscous liquid of low vapor pressure
(2.2 x 10-8 torr at 2SoC). Inhalation exposure is thus
of limited concern.
"f) The product has been discontinued from further develop-
ment in the o.s. for technical reasons."
Comments/Recommendations
In addition to discontinuing its activities with the subject
chemical, CIBA-GEIGY reported that the company is 1) revising the
product MSDS to reflect the submi tted toxicologic findings, and
2) i nformi ng CIBA-GEIGY laboratory workers and the cus tomer in
writing about those findings.
a)
The Chemical Screening Branch will ask CIBA-GEIGY to
submit full copies of the final reports (including the
actual experimental protocols, results of gross and
histopathological examinations, results of statistical
analyses, etc.) from 1) the acute rat oral dose range-
finding study that was cited in the final report of the
submi tted 28-day oral study, and 2) the dermal sens i-
tization and eye irritation studies that were cited in
the cover letter to the company's Section 8(e) notice.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, CIBA-GEIGY will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those ci ted in the open scientific li terature)
about which CIBA-GEIGY is aware or that the company has
conducted, is conducting or plans to conduct that are
designed to determine the toxicity of the subject
chemical.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP /OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA As s i stance Off ice (TAO/OTS/OPTS/EPA) for
further distribution.
408
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
OCT 2 1 1988
Page 1 of 3
SU8JECT: Status Report* 8EHQ-1088-0758 S
"OM, David R. Williams:r'fection 8 (e)
Chemlcal Screening Branch/ECAD
APproved~ TS:::- IOh.7/fr
Coordinator
TO: James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
Valent U. S .A. Corporation has claimed the exact identi ties of
the four (4) subject chemical substances as TSCA Confidential
Business Information (CBI); the Information Management Division
(IMD/OTS)will be requesting Valent U.S.A. to substantiate these
CBI claims. In the "sanitized" (i.e., non-confidential) version
of its Section 8(e) notice, Valent U.S.A. provided the following
generic names for these chemicals: Substituted Phthalimide I,
Substituted Phthalimide II, Substituted Phthalimide III, and
Substituted Cyclohexenone.
Submission Description
Valent U.S.A. (a joint venture of Chevron Chemical Co. and
Sumitomo Chemical Co. created in order to develop and market
agricultural pesticides in the U.S.) provided the following
summarized information regarding the conduct and preliminary
results of several toxicologic studies of the subject chemicals:
\
"In a series ot teratogenicity screening studies,
compounds Substi tuted Phthalimides II and II I and the
Substituted Cyclohexenone showed varying degrees of
teratogenic potential in the rat. [According to the
provided information, Substituted Phthalimides II and
III caused ventricle septal defects and wavy ribs,
while the Substituted Cyclohexenone caused omphalocele
and anoma 1 ies of the vertebral bodies.] None of the
subject chemicals showed teratogenic potential in the
rabbit.
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
409
IE~A "0"" ..... (REV. 3-,.1
-------
8EHQ-1088-0758 S
Page 2 of 3
"Compounds Substituted Phthalimides I, II and III
produced a pos i ti ve mutagenic response in an in vi tro
chromosomal aberration test (CHO-Kl) in the presence of
S-9 activation. These chemicals did not show mutagenic
potential in an in vivo mouse micronucleus test or in
--
the Ames Test.
"Compound Substi tuted Phthal imide I was shown to be a
very strong skin sensitizer in the guinea pig."
Submission Evaluation
An EPA evaluation of the
toxicologic findings should
of full copies of the final
company's TSCA Section 8(e)
overall significance of the reported
be possible upon the Agency's receipt
reports from all studies cited in the
notice.
Current Production and Use
Valent U. S .A. reported non-confidentially that these chemicals
are "experimental" and are being "imported from Sumitomo in Japan
exclusively for pesticidal efficacy [testing] . . ." According to
Valent U.S.A., the company plans to apply for an Experimental
Use Permit (EUP) under the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA) if the results of these efficacy tests
"show promi se ."
In its submission, Valent U.S.A. also stated non-confidentially
that there is no "undue hazard to persons handling the chemicals"
because "the amounts involved are small, testing is conducted
under the direct supervision of professionals trained in the use
of hazardous chemicals and di~tribution is very limited."
Comments/Recommendations
Valent U.S.A. stated non-confidentially that the company is 1)
revising the Material Safety Data Sheets (MSDSs) for the subject
chemicals to reflect the reported toxicological findings, 2)
advising persons who handle the chemicals about the submitted
findings, and 3) reminding persons who work with the chemicals to
"utilize proper handling procedures."
a)
The Chemical Screening Branch will ask Valent U.S.A. to
ensure that EPA receives a complete copy of the final
report (including the actual experimental protocol,
results of gross and histopathological examinations,
results of any statistical analyses, etc.) from each
study that was cited in the company's Section 8(e)
submission.
410
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8EHQ-I088-0758 S
Page 3 of 3
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Valent U.S.A. will be
asked to describe the nature and results, if available,
of all studies (other than those reported already to
EPA or those cited in the open scientific literature)
about which Valent U.S.A. is aware or that the company
has conducted, is conducti ng or plans to conduct that
are designed to determine the toxici ty of the subject
chemical substances.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemicals.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
411
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
OCT 2 7 1988
Page 1 of 4
SU8JECT:
Status Report*
8EHQ-1088-0759
Approved: ~ r: k- lo6.'/f?
()
David R. Williams~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
E. I. DuPont de Nemours & Company, Inc. submitted a status report
summarizing initial findings of an ongoing groundwater monitoring
study being performed by DuPont at its Spruance facility located
in Richmond, VA. According to DuPont, a number of chemicals,
including trichlorofluoromethane (TCFMi CAS No. 75-69-4), chloro-
form (CAS No. 67-66-3), hexamethylphosphoramide (HMPAi CAS No.
680-31-9) and carbon disulfide (CAS No. 75-15-0), were detected
in the groundwater samples taken.
In its submission, DuPont stated that this groundwater monitoring
study was being conducted "under consent order entered with the
State of Virginia" and was "initiated as the result of the dis-
covery that trichlorofluoromethane (TCFM) had been released from
a manufacturing unit into the ground and had apparently reached
the groundwater in an undetermined amount." According to DuPont,
this TCFM release was reported to the National Response Center
(NRC) by telephone on November 14, 1986 and was reviewed by the
Virginia State Water Control Board and Chesterfield County
authorities on November 25, 1986. DuPont reported that under the
consent order, it was agreed that Dupont would "investigate the
possibility of contaminants in the groundwa~er present in concen-
trations above 10 ppb in addition to the TCFM that was released."
DuPont reported further that the company has 1) kept the State of
Virginia abreast of the company's efforts throughout preliminary
data collection, and 2) presented a comprehensive review of the
preliminary analytical data to the Virginia State Water Control
Board on October 5, 1988.
DuPont provided EPA with the following summarized information
regarding the conduct and results of the company's monitoring
studies:
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
412
E~A '0'"" U.. (REV. 10711
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8EHQ-I088-0759
Page 2 of 4
"The nature and extent of the contamination at the site
was investigated in four quarterly sampling events over
the course of a year. Samples were obtained from on-
site monitoring wells and from [the] nearby surface
waters (Grindall Creek; the James River). All samples
were analyzed for u.S. EPA Priority Pollutant Volatile
Organic compounds. No organic or inorganic contaminants
attributable to operations at the facility were found
in any of the surface water samples. Most of the pri-
ority pollutant volatile organic constituents were not
detected in any of the groundwater samples. [I Priority
pollutant metals were not generally found in the
groundwater samples. However, concentrations of zinc
(ppm range) were associated with low pH (5 or below)
wherever there was a measurement of both pH and zinc
concentration. The monitoring record for the bedrock
well locations (7 wells) is not as extensive as in
shallower wells. Two bedrock wells near the James
River were analyzed for volatile organics and HMPA; the
remainder for priority pollutants only. No contamina-
tion was detected west of Grindall Creek and in wells
nearest the James River. Acetone was found in two wells
in the main plant area (2,600 and 1,500 ppb); chloro-
form at one well (11 ppb). Low levels of zinc (3.4 ppm)
and low ppb levels of arsenic, beryllium, chromium,
[methylethylketone (MEK)], phenol, phthalate and carbon
disulfide were found in one well in the main plant area
(total concentration of organics (excluding acetone) of
174 ppb) .'] However, trichlorofluoromethane, chloro-
form, carbon disulfide and hexamethylphosphoramide
(HMPA) were detected in [the] groundwater samples
taken. HMPA has not been used at the site since 1982."
DuPont provided the following information specifically regarding
the detection of TCFM, chloroform and HMPA:
"0 TCFM: The preliminary findings show that the concentra-
tion of TCFM in groundwater in the western half of the
site range from <10 ppb to >1000 ppm. The contamination
is distributed in two plumes: (1) one plume extends
east beyond the property boundary (the full easterly
extent currently not quantified); and (2) the second
plume extends to the southern boundary of the facility
in a south south-eastern direction.
"0 Chloroform: Concentrations of chloroform in groundwater
range from <10 ppb to >10 ppm. The contamination is
distributed in two plumes: (1) one plume extends north-
easterly across the si te boundary; and (2) the second
plume extends to the southern boundary of the facility
in a south south-eastern direction. [DuPont believes
the] patterns of TCFM and chloroform contamination to
be generally consistent with prior plant use.
413
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8EHQ-I088-0759
Page 3 of 4
"0
HMPA: Concentrations of HMPA in groundwater range from
<10 ppb to >100 ppm. The contamination is distributed
in two plumes extending southeast and northeast,
respectively, and in an area in the northwest corner of
the plant. Highest HMPA concentrations (>100 ppm) were
detected adjacent to the site of primary past usage.
Monitoring wells immediately to the west of the James
River show HMPA concentrations of approximately 100
ppb. HMPA has not been detected in the James River (5
ppb limit of detection). The pattern of HMPA contamina-
tion in the plume extending northeast is consistent
with origin in an on-site landfill. The source of HMPA
at the northwest corner of the plant is currently
unknown but may have originated from a past spill. The
source of the HMPA in the plume extending southeast is
believed [to be] consistent with the prior use of the
solvent in the manufacturing area."
DuPont also provided the following information about the possible
impact(s) of this groundwater contamination on the James River:
" [Dupont believes] that, while no contaminants
attributable to the Spruance facility were detected in
the James River during this investigation, the James
River is the probable discharge zone for HMPA, chloro-
form and TCFM. [lIt is likely that HMPA originating in
the site landfill area is discharging to the river;
TCFM and chloroform plumes may also have reached the
river nor theas t of the Spruance fac i 1 i ty. . ] The con-
centrations of these three compounds in groundwater
discharging to the river are likely to increase for a
number of years. Very gross approximations of transport
rates using current levels of contaminants suggest that
maximum concentrations [of these contaminants] will be
attained at the river in 20 to 30 years. [I These same
gross approximations suggest that, averaged across the
entire zone of river discharge, maximum concentrations
of TCFM, HMPA and chloroform in groundwater will be on
the order of 100,000 ppb. 20,000 ppb and 5,000 ppb,
respecti vely. I] Assuming complete and instantaneous
mixing of the contaminated groundwater with the river,
calculated maximum concentrations of TCFM, HMPA and
chloroform in the river are (within an order of mag-
ni tude) 50, 5 and 1 ppb, respectively. The calculated
maximum concentrations at average annual flow are
(within an order of magnitude) 5. 0.5 and 0.1 ppb,
respectively. II
Comments/Recommendations
DuPont stated that although it IIhas not, at this time, determined
potential human exposure to the groundwaterll nor has the company
IIrnade a hazard assessment of the chemicals found. ., II DuPont
414
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8EHQ-I088-0759
Page 4 of 4
"will continue to closely coordinate wi th the state of Virginia
to assure that further efforts to quantify and assess the prob-
lem, and to develop and implement an appropriate remediation
strategy, can be effected expeditiously in an environmentally
sound manner."
It should be noted that most, if not all, of the detected
chemical substances have been or are currently the subject of
data gathering, assessment and/or rules promulgated under the
many environmental protection authorities administered by EPA.
Therefore, immediately upon receipt of this TSCA Section 8 (e)
submission, the Chemical Screening Branch transmitted full copies
of the notice to EPA's Region III Office (Philadelphia, PA), the
Office of Water (OW/EPA), the Office of Groundwater Protection
(OGWP/OW/EPA), the Office of Solid Waste and Emergency Response
(OSWER/EPA), the Office of Air and Radiation (OAR/EPA) and the
Exposure Evaluation Division (EED/OTS/OPTS/EPA); complete copies
of the submission were sent also to the Chemical Control Division
(CCD/OTS/OPTS/EPA) for inclusion in the ongoing review of chloro-
fluorocarbons (CFCs) and chlorinated solvents, and to the Test
Rules Development Branch (TROB/ECAD/OTS/OPTS/EPA) and the Risk
Analysis Branch (RAB/ECAO/OTS/OPTS/EPA) for inclusion in their
ongoing reviews of several of the detected chemicals (e.g., MEK,
phthalates) .
a)
The Chemical Screening Branch will ask DuPont to ensure
that EPA is apprised of any new health impact-related
or exposure-related findings from the company's ongoing
groundwater monitoring efforts at this virginia plant
site and surrounding area.
b)
The Chemical Screening Branch will distribute copies of
all reported information to appropriate EPA offices.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, EPA's Region III
Office, OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, EED and
CCD/OTS/OPTS/EPA, and RAB and TRDB/ECAO/OTS/OPTS/EPA;
copies of this status report will be sent also to the
TSCA Ass istance Off ice (TAO/OTS/OPTS/EPA) for fu r ther
distribution.
415
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
tDI - 8 1988
Page 1 of 3
SU8JECT:
Status Report*
8EHQ-1088-0760 S
Approved: L r tC- Ilh/;-;
(j
'ROM:
David R. Williams~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will be asking the company to substantiate these TSCA CBI claims.
The submitting company reported non-confidentially by phone on
October 18, 1988 that the subject chemical substance is an "alkyl
heterocyclic nitrogen compound."
Submission Description
The submitting company provided the following summary information
regarding the conduct and preliminary results of a two-year skin
application study of this alkyl heterocyclic nitrogen compound in
rats:
"In this study, the test article was applied daily to
the shaved skin of the dorsum of four groups of Wistar
rats at an application rate of 2 ml/kg in concentra-
tions of 0 (control), 1%, 2.5% or 5% in isopropanol for
104 weeks. Control rats were treated with [the] vehicle
(isopropanol) only. A total of eighteen squamous cell
carcinomas were diagnosed in the treated rats (males
and females combined) compared to none in the control
group. Other neoplas tic and non- neoplastic les ions
recorded in the study were within the range of morpho-
logical alterations commonly diagnosed in rats of this
~ge and strain."
The submitting company also provided the following information
wi th regard to the results of other tox icological st ud i es tha t
have been conducted with the subject chemical substance:
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation.of
information submitted to EPA pursuant to Section 8(e), the substantlal
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be re~arded
as expressing final EPA policy or intent with respect to th~ subJect
chemical(s). Any review of this status r~port shoul? take l~to account
the fact that the report may be based on lncomplete lnformatlon.
416
I[~A "0"" U" (REV. ,"711
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8EHQ-I088-0760 S
Page 2 of 3
"A dermal two-year bioassay of the subject chemical has
also been conducted in mice. No carcinogenic effect
was observed in the long-term mouse study. ...
Furthermore, five mutagenicity studies. . . were also
negative. Acute and subchronic dermal [application]
studies, including a twelve month study in monkeys, a
six month study in rats, and teratogenicity studies in
mice and rabbi ts were also conducted on the subject
chemical. No signi f icant systemic effects were found
in any of these studies."
Submission Evaluation
According to a submi tted draft pathology report, in addi tion to
the squamous cell carcinomas of the skin of rats in the 2-year
dermal application study, there were squamous cell carcinomas
reportedly found in the posterior portion of the nasal cavity of
the male rats (1 in the low dose group, 3 in the mid dose group
and 2 in the high dose group) but not in the females or in the
isopropanol controls. (NOTE: Immediately upon receipt of this
TSCA Section 8(e) submission, the Chemical Screening Branch sent
a copy of the submission to the Test Rules Development Branch
(TRDB/ECAD/OTS) for inclusion in their ongoing evaluation of
available toxicologic and exposure information on isopropanol.
Isopropanol was designated by the Interagency Testing Committee
(ITC) for testing under Section 4 of TSCA and is the subject of
TSCA Section 8(a) and 8(d) information gathering rules.)
An EPA evaluation of the overall significance of the reported
findings should be possible upon the Agency's receipt of a full
copy of the final report from the company's 2-year bioassay in
rats. Further, the submitter should be asked to provide to EPA
full copies of the final reports from all other company studies
that were cited in this Section 8(e) submission.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information with
regard to the TSCA Chemical Substance Inventory status or use of
the subject chemical will appear in this status report. The sub-
mitter did report non-confidentially, however, that the chemical
"is not being produced in commercial quantities."
Comments/Recommendations
In its TSCA Section 8(e) notice, the company reported that it has
informed its customers about the submitted toxicologic findings.
a)
The Chemical Screening Branch will ask the submi tting
company to ensure that EPA receives a full copy of the
final report (including the actual experimental proto-
col, results of gross/histopathological examinations,
results of any statistical analyses, etc.) from each
company study cited in the submission.
417
-------
8EHQ-1088-0760 S
Page 3 of 3
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the actions the company has taken or
plans to take 1) to notify its own workers about the
reported information, and 2) to reduce or eliminate
exposure to the subject chemical. In addition, the
submitting company will be asked to describe the nature
and resul ts, if avai lable, of all stud ies (other than
those reported already to EPA or those cited in the
open scientific literature) about which the company is
aware or that the company has conducted, is conducting
or plans to conduct that are designed to determine the
toxicity of this alkyl heterocyclic nitrogen compound.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this alkyl heterocyclic nitrogen
compound. As in the case of the initial submission,
all reported information pertaining to isopropanol will
be sent immediately by the Chemical Screening Branch to
the Test Rule Development Branch for inclusion in their
ongoing review of isopropanol.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA and
TRDB/ECAD/OTS/OPT S/EPA. I n add i t i on, cop i es of th is
status report will be provided to the TSCA Assistance
Office (TAO/OTS/OPTS/EPA) for further distribution.
418
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DA TE:
NOV I 0 1988
Page 1 of 3
SUBJECT:
Status Report* 8EHQ-1088-0761 INIT A r f ~NV
8EHQ-1088-0761 SUPPs pproved:
/q/O/88
David R. Williams~ection 8(e) Coordinator
Chemical Screening Branch/ECAD
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification Section/CSB/ECAD
Submission Description
Gelman Sciences reported that it has obtained data showing the
presence of 1,4-dioxane (CAS No. 123-91-1) in automotive/truck
engine coolants. In addition, the company reported that on the
basis of these data, as well as other data showing the presence
of 1,4-dioxane in air, soil and groundwater, the company believes
this chemical substance to be widespread in the environment.
According to tabularized data provided by Gelman from a study
conducted on a number of new and used foreign and domestic car
and truck coolants of various ages, the concentrations of 1,4-
dioxane ranged between 10 and 22,000 pa r ts per bill ion (ppb).
The provided table also showed that 1,4-dioxane was found in
concentrations of 100 to 3400 ppb in "off-the-shelf" automotive
engine coolants. Further, Gelman reported that concentrations of
1,4-dioxane detected in "radiator boil-over pools" at a number of
rest areas in Michigan ranged from <10 ppb to over 2,000 ppb.
In its submissions, Gelman also provided a 122-page draft "Health
and Environmental Effects Assessment for 1,4-Dioxane" prepared
for the company by an environmental toxicology consultant, as
well as two German articles on cosmetic preparations (particulary
shampoos and bath preparations) found to contain 1,4-dioxane.
Gelman also provided an October 13, 1988 newspaper article that
reports that the Michigan Department of Natural Resources (DNR)
"has charged Gelman Sciences wi th polluting soil, surface water
and groundwater [with 1,4-dioxane] near the company's plant. . .
[outside Ann Arbor, Michigan]." The article states that the
Michigan DNR is "suing Gelman to restore the groundwater to its
original purity." According to the submitted article, Gelman
claimed that based on already available information on sources of
1,4-dioxane exposure as well as the company's analytical studies
showing the presence of 1,4-dioxane in engine coolants and boil-
over pools at rest stops, "'the government and other individuals'
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
lnformatlon submltted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
419
II~A I'OMI U'" U"IV. ..,..
-------
8EHQ-I088-0761
Page 2 of 3
may be polluting drinking water with the same chemical solvent
the company is charged with releasing into the environment." The
provided article states further that at a recent Michigan state
hearing "to consider changes to Michigan rules governing public
water supply [('the state standard for safe levels of 1,4-dioxane
in drinking water is 2 parts per billion')], a Gelman Sciences
attorney claimed that the state has ignored the potential for
groundwater contamination from puddles of antifreeze in the
parking lots of rest areas along Michigan highways." The article
reports also that Gelman's attorney in this matter stated that
the company's automotive/truck coolant and highway rest-stop
monitoring data show that "'. . . every service station, garage,
parking lot and rest-stop as well as homes in the state [are]
possible sources of 1,4-dioxane contamination.'" The article
reports further, however, that "the state's leading attorney in
its case against Gelman Sciences said the claims by the company
have no bea ring on the [1, 4-d ioxane] contami nat ion around the
[company's] plant site. "The article also reports that an
official with Michigan DNR stated that the DNR was "'aware of the
potential for contamination from 1,4-dioxane in antifreeze prior
to the Gelman study.'"
Finally, Gelman submitted an October 20, 1988 news release in
which Gelman announced that the company had prevailed in a
lawsuit filed against the Michigan DNR that pertained to the
DNR's review and evaluation of the Gelman plant site prior to
publishing an assigned priority ranking for response action(s).
According to the news release, Gelman had charged in its lawsuit
tha t "( 1) the DNR fa i led to promulgate rules necessary to carry
out Act 307 (the Michigan Environmental Response Act-MERA)," and
" (2) the DNR did not provide Gelman Sciences wi th a reasonable
and meaningful public hearing and opportunity to comment on . . .
[the DNR's most recent ranking of the Gelman plant site] as
required by MERA."
Comments/Recommendations
EPA has received a number of TSCA Section 8 (e) and "For Your
Information" (FYI) submissions on 1,4-dioxane and the Chemical
Screening Branch prepared a "Chemical Hazard Information Profile"
(CHIP) on this chemical in 1979. In addition, it should be noted
that like many polyethylene glycols, 1,4-dioxane (an anhydride of
diethylene glycol) can produce toxic effects in the human kidney
and liver. A characteristic nephrosis of the kidney tubules
(hydropic degeneration) with an associated liver cell necrosis
can occur regardless of the route of 1,4-dioxane exposure (oral,
inhalation and/or dermal). Further, the Fourth Annual Report on
Carcinogens (National Toxicology program (NTP) 85-002; 1985)
provides the following information regarding the carcinogenicity
of 1,4-dioxane in laboratory animals:
"There is sufficient evidence for the carcinogenicity
of 1,4-dioxane in experimental animals.2l8 1,4-Dioxane
administered in drinking water is carcinogenic in rats
420
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8EHQ-I088-0761
Page 3 of 3
and guinea pigs. It produced cancers of the nasal
cavity and liver in rats and tumors of the liver and
gall bladder in guinea pigs. It was also active as a.
promoter in a two-stage skin carcinogenesis study in
m ice. 219 I n a d r ink i n g wa t e r s t u d y, res u 1 t s we r e
positive for rats and mice. 220 "
Finally, it should be noted that pursuant to Section 110 of the
Superfund Amendments and Reauthorization Act (SARA), the Agency
for Toxic Substances and Disease Registry (ATSDR), in collabora-
tion with EPA, will be preparing a "Toxicological Profile" for
1,4-dioxane. Information on the availability of SARA section 110
profiles can be obtained from: Office of External Affairs, Agency
for Toxic Substances and Disease Registry, Chamblee 28 South,
1600 Clifton Road, Atlanta, Georgia 30333.
Immediately upon receipt of this Section 8(e) submission, the
Chemical Screening Branch sent copies of the provided information
to NIOSH, OSHA, CPSC, OW/EPA, OSWER/EPA, OAR/EPA, and to the
Regional Risk Guidance Staff (RRGS/ECAD/OTS/OPTS/EPA) for trans-
mittal to EPA'S Regional Offices. In addition, copies of the
submitted information was provided immediately to staff of the
Exposure Evaluation Division (EED/OTS/OPTS/EPA) for review.
a)
The Chemical Screening Branch will request Gelman to
submit complete copies of the actual protocols/methods
used by the company to analyze for l,4-dioxane.
b)
The Chemical Screening Branch will continue to review
the reported information in order to determine the need
for further OTS assessment of l,4-dioxane.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OW/EPA, OSWER/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA,
RRGS/ECAD/OTS/OPTS/EPA and EED/OTS/OPTS/EPAi copies of
th is repor t wi 11 be sent also to the TSCA Ass i stance
Office (TAO/OTS/OPTS/EPA) for further distribution.
-----------------------------------------------------------------
218 International Agency for Research on Cancer. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans.
Supplement 4. 292 pp. Lyon, France: IARC, 1982, pp. 121-122.
219 International Agency for Research on Cancer. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Vol. 11. 306 pp. Lyon, France: IARC, 1976, pp. 247-256.
220 National Cancer Institute. Bioassay of 1,4-Dioxane for
Possible Carcinogenici ty. Technical Report Ser ies No. 80. DHEW
Publication No. (NIH)78-l330. 108 pp. Bethesda, Maryland. 1978.
421
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
NOV - 9 1988
Page 1 of 4
SUBJECT:
Status Report* 8EHQ-1088-0762
David R. Williams~ction 8(e)
Chemical Screening BranchjECAD
APproved:r rtf::/ JI)o!yP
Coordinator
FROM:
TO:
James F. Darr, Section Head
Chemical Risk Identification SectionjCSBjECAD
Submission Description
The Amoco Corporation provided the following summary information
regarding the conduct and results of an acute inhalation study of
l-octanol vapor in rats:
"Two exposures to l-octanol were performed using two
groups of 10 rats (5 males and 5 females) each. The
rats were exposed via inhalation to l-octanol vapor for
either one hour at 6,400 mgjm3 or for four hours at
5,600 mgjm3. The l-octanol was heated to 3000C and the
animals were exposed to the resulting vapors. The rats
were held for up to seven days, sacrificed, and the
lungs [were] removed and processed for histological
examination.
"Three of [the] ten rats exposed to l-octanol (5,600
mgjm3) for four hours died within two days following
the exposure.
"Microscopic examination of the lungs of [the] exposed
animals was conducted. No microscopic abnormal i ties
were seen at any of the sacrifice periods in the lungs
of the animals exposed to 1- oc tano 1 [vapo r] f or one
hour (6,400 mgjm3), wi th the exception of minimal al-
veolar hemorrhage in one of the exposed males. However,
several treatment-related lesions were present in the
lungs of the animals exposed to l-octanol [vapor] for
four hours (5,600 mgjm3). These [lesions] included
bronchial epithelial necrosis, alveolar edema, accumu-
lation of alveolar macrophages, congestion, alveolar
====================================================================================
*
~OTE: T~is stat~s report is the result of a preliminary evaluation of
l~fo~atlon S~bmltted to EPA pursuant to Section 8(e), the substantial
rlsk lnformatlon reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
422
.~A 1'0- II" (lUV. 1-'81
-------
8EHQ-I088-0762
Page 2 of 4
hemorrhage, bronchial epithelial regeneration, and
alveolar epithelial hyperplasia. Severe epithelial
necrosis was seen in the bronchi of all lung lobes,
while alveolar edema and alveolar macrophage accumula-
tion were either diffuse or multi focal in distribution
and generally of mild severity. No necrosis of the
bronchiolar or alveolar epithelium was observed.
"The incidence of lung lesions (sexes combined) in the
4-hour exposure animals in relation to the day of death
or post-exposure sacrifice was as follows:
LESION
DAY 1 DAY 2 DAY 5 DAY 6
Alveolar edema 2/2
Accumulation of alveolar macrophages 2/2
Bronchial epithelial necrosis 2/2
Bronchial epithelial regeneration 0/2
Congestion 0/2
Alveolar hemorrhage 1/2
Alveolar epithelial hyperplasia 0/2
3/3
3/3
3/3
0/3
3/3
0/3
0/3
0/2
2/2
1/2
2/2
0/2
0/2
0/2
3/3
3/3
0/3
3/3
0/3
1/3
1/3
"Examination of these data indicated that the initial
lung lesion following [the 4-hour] l-octanol [vapor]
exposure consisted of necrosis of the bronchial epi-
thelium with alveolar edema and [an] accumulation of
alveolar macrophages. These changes were generally
seen one to two days after exposure. The predomi nant
lesions seen five and six days post-exposure were
regeneration of the bronchial epithelium and residual
alveolar edema with multi focal alveolar macrophage
accumulation. The epithelial regeneration and macro-
phage accumulation are indicative of reparative and
resolution processes, respectively: the regenerative
epithelium replaced the necrotic epithelium and the
macrophages removed the residual edema."
In its submission, Amoco provided the following information with
regard to the company's interpretation of the reported findings:
". [Amoco interprets] these results to indicate
that exposure to very high concentrations of i-octanol
vapor for an extended period of time is capable of
producing temporary lung damage. However, to produce
the vapors used in this study, it was necessary to heat
the sample to approximately 3000C (the boiling point of
i-octanol is 1960C). Given that the boiling point of
i-octanol is so high, the potential for human exposure
to the massive concentrations used in this study is
unl i kely. Also, in rats an exposure of gr ea ter tha n
one hour was required to produce the effects seen; it
is also unlikely that humans would be exposed for such
a long duration."
423
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8EHQ-I088-0762
Page 3 of 4
Submission Evaluation
Despite the fact that the l-octanol had to be heated to 3000C to
generate the vapors, the submitted data indicate that a 4-hour
exposure to 5600 mg/m3 in rats resulted in bronchial epithelial
necrosis, alveolar edema, accumulation of alveolar macrophages,
congestion, alveolar hemorrhage, alveolar epithelial hyperplasia
and bronchial epithelial regeneration. Although the submitting
company interpreted the study findings to indicate "temporary"
lung damage from exposure to high concentrations of l-octanol for
an extended period of time, EPA cannot agree that the toxicologic
concern for this chemical can be dismissed. Whi le EPA agrees
that a high temperature was required to generate the vapors for
an acute exposure, no information was submitted that predicts or
all udes to a lack 0 f chronic tox ici ty when there is long term
exposure to lower levels of l-octanol. Further, EPA' s concern
for chronic toxicity is not mitigated to any great degree by the
observed post-exposure regenerative/reparative activity.
It should be noted that the Registry of Toxic Effects of Chemical
Substances (RTECS) reports that l-octanol is a mild irritant when
applied to the skin of rabbits (500 mg) and has been shown to be
moderately toxic when administered orally to mice (LD50 of 1790
mg/kg), but does not present any information with regard to the
mammalian toxicity of l-octanol via inhalation.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for l-octanol (CAS No. 111-87-5), which is listed in
the initial TSCA Chemical Substance Inventory, has shown that 11
million to 60 million pounds were reported as manufactured and/or
imported in 1977. This production range information does not
include any information claimed as TSCA Confidential Business
Information (CBI) by the person(s) reporting for the initial TSCA
Inventory, nor does it i ncl ude any da ta tha t would compr omi se
TSCA CBI. All data reported for the initial TSCA Inventory,
including production range data, are subject to the limitations
in the initial TSCA Inventory Reporting Regulations (40 CFR 710).
The Condensed Chemical Dictionary (10th Edition), presents the
following information regarding the uses of l-octanol:
"Perfumery; cosmetics; organic synthesis; solvent;
manufacture of high-boiling esters; antifoaming agent;
flavoring agent."
Comments/Recommendations
a)
The Chemical Screening Branch will ask Amoco to submit
a full copy of the final report (including the actual
experimental protocol, results of gross/histopathologic
examinations, results of statistical analyses, etc.)
from the cited acute inhalation toxicity study in rats.
424
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8EHQ-I088-0762
Page 4 of 4
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Amoco will be asked
to describe the actions the company has taken or plans
to take to notify workers and others about the reported
information. In addition, Amoco will be requested to
describe the nature and results, if available, of all
studies (other than those reported already to EPA or
those cited in the open scientific literature) about
which Amoco is aware or that Amoco has conducted, is
conducting or plans to conduct that are designed to
determine the toxicity of I-octanol.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of I-octanol.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
425
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
DEC
8 1988
Page 1 of 6
SU8JECT:
Status Report* ~~~g=~~~~=~~~~ ~ ~~~~ Approved: ~
James F. Darr, Section Head f1.....,-r~
Chemical Risk Identificatio~~~tion/CSB/ECAD
12-)r/~
FRO..:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The Union Carbide Corporation claimed the exact identity of the
subject chemical to be TSCA Confidential Business Information
(CBI); the Information Management Division (IMD/OTS) will review
all Union Carbide correspondence relating to substantiation of
this CBI claim. In the "sanitized" version of this submission,
Union Carbide stated non-confidentially that the subject chemical
is an "alkylaminocarbonyl-substituted thiadiazole sulfonamide"
with the following internal designation: "UC77179."
Submission Description
Union Carbide provided the final reports from 14-day and 90-day
dietary feeding studies of UC77179 in rats and mice. The sub-
mitter's cover letter provides the following information with
regard to the conduct and results of these studies:
"Rat Study
"In a preliminary study, UC77179 was administered to
male and female Fischer 344 rats [(10/sex/group)] for 2
weeks at dietary concentrations of 0.0, 0.2, 0.4, 0.8,
1.6, or 3.2% (0,2000,4000,8000,16000, or 32000
ppm). Food uptake and body weights were reduced in a
dose-related manner for all treatment groups. Mortality
occur red in the males consuming 3.2% (8/10) and 1.6%
(4/10) UC77179 and in females (6/10) in the high dose
group. Death may have resulted from severely depressed
food uptake.
"In a subsequent 90-day study, male and female Fischer
344 rats [(30/sex/group)] were fed diets containing
0.0, 0.015, 0.03, 0.06, 0.1~, or 0.24% (0, 150, 300,
600, 1200, 2400 ppm) UC77179. Food uptake and body
weights were depressed in [the] males from the 0.24,
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information,.
426
I:~A ..0.... 11.. (lIIEV. 3-711
-------
Page 2 of 6
~.12 and ~.~6% UC77179 groups. Food uptake was reduced
for females at these same dietary concentrations. Body
weights for the females were significantly decreased in
a dose-related manner for all but the low dose group.
Treatment-related water consumption increases were
observed for all groups in both sexes. Corresponding
changes in urinalysis measurements including increased
urine volume, decreased specific gravity and decreased
protein concentrations were recorded. Other clinical
pathology alterations included a macrocytic anemia in
the high dose males and at all treatment levels for the
females. In addition, a dose-related increase in serum
chloride concentration was observed for both sexes.
Microscopic changes were seen in the kidneys of the
animals in the ~.24 and ~.12% UC77179 groups. These
[pathological] changes included mineralization of the
renal pelvis with associated hyperplasia of the transi-
tional epithelium. Thyroid adenomas were also observed
in 3 of 3~ male rats exposed to ~. 24% UC77179 for 90
days. Microscopic examinations on tissues from rats
fed lower concentrations of UC77179 were not conducted.
"Mouse Study
"In a preliminary two-week study, six groups of B6C3Fl
mice (10 mice/sex/group) were fed diets containing
UC77179 at concentrations of 0.~, ~.20, ~.40, 0.80,
1.60, or 3.20% for l4-days. The parameters measured
were: clinical observations, body weight, organ weight
(heart, lungs, liver, kidneys, testes, and brain) and
gross pathologic examination. For the highest dose
group, mortality occurred at a rate of 80% for both
sexes. [The] clinical signs for animals in the high
dose groups included lethargy, tremors, unkempt fur,
abdominal-urogenital wetness, and coldness to touch.
Time to death was approximately 5-to-6 days for both
sexes. Depressions in body weight and food consumption
were observed at UC77179 [dietary] concentrations of
0.80% and greater for males, and at 0. 4~% and greater
for females. Observed organ weight differences may
have been a manifestation of [the] body weight loss.
No treatment-related gross lesions were apparent at
necropsy.
"In the 90-day study, UC77179 was incorporated in the
diet of B6C3Fl mice (30 mice/sex/group) at concentra-
tions of 0.0, 0.015, 0.03, 0.06, 0.12, or 0.24%. The
0.0% and 0.12% groups contained ten additional mice per
sex that served as recovery groups maintained on [a]
control diet for an additional four weeks. Body weight
gain was reduced for males in the three highest dosage
groups and [for] females at the two highest concentra-
tions of UC77179 after 90 days. Clinical alterations
were restricted to hyperchloremia for females in all
427
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Page 3 of 6
[UC77l79] treatment groups after 90 days. There was no
treatment-related mortali ty. A no observable effect
level [(NOEL)] of 0.03% was established."
In its submission, Union Carbide stated that upon receipt of the
toxicologic findings from the 90-day UC77l79 feeding study in
rats, "all further studies with the chemical were abandoned"
including the concurrent 90-day feeding study in mice that was
ci ted prev iously. Accord i ng to Union Ca rb i de, "there were no
pathological examinations done on tissue from the [90-day] study
in mice."
In its submission, Union Carbide stated also that "rats appear to
be much more sensi ti ve than pr imates to the thyroid alterations
induced by suI fonamides and other goi trogens" and ci ted several
scientific articles and EPA documents on the observation and/or
interpretation (e.g., "threshold" phenomena) of toxic effects
(including certain oncogenic effects) induced by aromatic amines
including sulfonamides.
In a supplemental TSCA Section 8 (e) submission, Union Carbide
provided the final reports from a variety of in vitro and in vivo
genotoxicity studies of UC77179. According to the coverletter
from this supplemental submission, UC77179 caused gene mutations
in an Ames Salmonella typhimurium (bacterial) assay and produced
chromosomal damage in cultured Chinese Hamster Ovary (CHO) cells;
UC77l79 was reportedly negative in a Forward Gene Mutation Assay
in cultured CHO cells, a DNA Repair Assay in cultured rat hepato-
cytes, and an in vivo Bone Marrow Cytogenetics Assay in rats.
Finally, Union Carbide stated in its initial TSCA Section 8 (e)
notice that "there are other acute toxicity data available for
UC77l79" that were developed during the company's R&D activities
with this chemical, "none of which is indicative of substantial
risk."
Submission Evaluation
Overall, the major toxic effects induced by the subject chemical
after 90 days or less of dietary exposure appear to be thyroid
tumors, mineralization of the renal pelvis and macrocytic anemia.
It should be noted that although many sulfonamide-containing
compounds have been shown to exhibi t anti thyroid acti vi ty, this
activity is considered generally to be weak. Further, it could
be anticipated that the thiadiazole moiety would produce similar
effects considering that both aminothiazole and aminotriazole
have been reported to cause antithyroid effects. with regard to
tumor induction, however, the scientific literature indicates
that a number of sulfonamide-containing chemicals when tested for
oncogenic effects induced bladder tumors and not thyroid tumors.
Most interestingly, 2-p-methoxybenzenesulfonamido-l,3,4-thia-
diazole, which contains sulfonamide and thiadiazole moieties,
induced bladder tumors but not thyroid tumors in rats within 18
months at concentrations as low as 0.6% in the diet.
428
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Page 4 of 6
The observed adverse kidney effects are most likely due to the
sulfonamide portion of the subject chemical. Many sulfonamide-
containing compounds have been shown to cause direct damage to
the kidneys and N-acetylsulfonamide is known to precipitate in
the kidneys.
Many thiadiazole-containing compounds are effective hypoglycemic
agents; such a biologic activity could account for the clinical
signs (lethargy, tremors, coldness to touch) observed in the
exposed animals, especially those at the higher doses.
Considering that many sulfonamide-containing compounds have been
shown to cause hematopoietic disorders (including anemia), the
macro0ytic anemia detected in the submitter's 90-day study in
rats may have been due to a direct effect of the subject chemical
on the blood cells. It is also possible that the observed anemia
was secondary to kidney damage or adverse effects on the thyroid.
EPA has the following comments on Union Carbide's interpretation
of the findings from the performed studies. First, the Agency
disagrees with the statement that the deaths observed in the 14-
day rat study may have resulted from the "severely depressed food
intake." It is important to note that the time to death was 12-13
days for the male and female rats. EPA believes that this time
frame is much too short for the rats to have died from starvation
alone. This is especially true when one considers that the rats
were showing toxic signs/symptoms (e.g., lethargy, tremors).
Second, EPA di sagrees that a NOEL was establ ished in the 90-day
mouse study. It is an EPA scientific policy that a NOEL cannot
be established without a complete histopathologic examination;
such an examination was not conducted for the 90-day mouse study
because it was terminated immediately after the company learned
of the effects seen in the 90-day rat study. It is also important
to point out that the only tissues examined microscopically from
the 90-day rat study were those from animals in the two highest
UC77179 dose groups (0.12% and 0.24%).
Third, EPA bel ieves that on the basis of the provided data, the
observance of thyroid adenomas in 3/30 high-dose group rats after
only 90-days of exposure is both biologically and statistically
significant. An analysis of control Fischer 344 rats in long-
term biossays conducted by the National Toxicology Program (NTP)
shows that the incidence of this type of tumor in this strain of
rat is rare (22/2320 animals) even after two years of age.
Finally, EPA believes that the submitter's statements concerning
EPA's interpretation of and policy toward thyroid tumor induction
in experimental animals are incorrect. It is not EPA' s present
risk assessment policy to assume automatically that thyroid tumor
induction (even when a tested chemical substance or mixture that
adversely affects the thyroid is involved) represents a threshold
phenomenon. A threshold can be ascribed only after all available
evidence demonstrates conclusively that a chemical substance or
429
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Page 5 of 6
mixture that induces thyroid tumors acts solely by interfering
wi th those hormones regulating the thyroid. Further, it should
be noted that EPA does not believe that the present Section B(e)
submission presents any real evidence regarding the mechanism(s)
of action by which UC77179 induced thyroid tumors in rats.
With regard to the submitted genotoxicity studies, the Agency is
in agreement wi th the stated conclus ions. UC77179 was found to
be a direct acting mutagen (i.e., the chemical did not require
exogenous metabolic activation) in an Ames Salmonella typhimurium
(bacteria) assay and clastogenic (i.e., chromosome breaking) in
cultured Chinese Hamster Ovary (CHO) cells in the presence of
exogenous metabolic activation; UC77179 was found to be negative
in the in vitro CHO cell Forward Gene Mutation Assay, the rat
hepatocyte primary culture/DNA Repair Assay and the in vivo Bone
Marrow Cytogenetics Assay in rats. Overall, however, the positive
results in two of the performed studies do indicate that UC77179
has some degree of mutagenic potential.
Current Production and Use
Union Carbide reported non-confidentially that UC77l79, which
"was being studied as a possible candidate pesticide," has not
been assigned a Chemical Abstract Service (CAS) Registry Number
and is not on the TSCA Chemical Substance Inventory. with regard
to the potential for exposure to UC77l79, Union Carbide reported
that dur i ng the research and development (R&D) ac t i v i ties with
this chemical, "stringent handling and exposure protection and
precautionary practices were required to be followed. . . "
Comments/Recommendations
It is very important to note that even though a threshold for
tumor formation may be suspected and/or ultimately established
for a chemical substance or mixture during formal risk assessment
procedures, such threshold considerations should have no bearing
on a respondent's TSCA Section B(e)-applicability/reportability
decisions. The reader's attention is directed to the Agency's
TSCA Section B (e) policy document ("Statement of Interpretation
and Enforcement policy; Notification of Substantial Risk" 43 FR
11110; March 16, 1978) which explains that immediately reportable
"substantial risk" information includes any new evidence (e.g.,
evidence from an animal study) that offers reasonable support for
a conclusion that a TSCA-covered chemical substance or mixture
(including a chemical substance or mixture at the research and
development stage) is capable of producing cancer.
a)
The Chemical Screening Branch will ask Union Carbide to
describe the nature and results of all studies (other
than those reported in detail already to the Agency or
those cited in the published scientific literature)
about which Union Carbide is aware or that the company
has conducted to determine the toxicity of UC77l79.
430
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Page 6 of 6
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this alkylaminocarbonyl-substituted
thiadiazole sulfonamide.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA;
copies of this report will be sent also to the TSCA
Assistance Office (TAO/OTS) for further distribution.
431
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DA TI!:
DEC I 2 1988
Page 1 of 13
~ '~ft.f/?o
, .
SUIJECT:
Status Report* 8EHQ-l088-0764 S
FYI-OTS-l088-0645 S Approved:
James F. Darr, Section Head ~ ~~
Chemical Risk Identification(fs~~tion/CSB
'Ro..:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The Union Carbide Corporation has claimed the exact identities of
the subject chemical substances to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will review all incoming correspondence regarding Union Carbide's
substantiation of its CBI claims. In the "sanitized" versions of
the Section 8(e) and FYI notices, the following non-confidential
generic names were provided for three of the subject chemicals:
"tolylcycloalkenyl substituted alkyl ester" (UC55248), "xylyl-
cycloalkenyl substi tuted alkyl ester" (UC55304), and "cyanoalkyl
phosphorodi thioate" (UC70480). By phone, Union Carbide provided
the following non-confidential generic name for a fourth chemical
substance: "tolylcycloalkenyl substituted phosphorothioate ester"
(UC63l52) .
Submission Description
In its TSCA Section 8(e) submission, Union Carbide submitted the
final reports from teratologic studies of UC55248 (rabbits and
rats), UC55304 (rats), and UC63l52 (rats) as well as the final
report from a "Chernoff Assay" of UC55248 (mice and rats); these
studies had been conducted for Union Carbide by outside contract
laboratories. In its "For Your Information" (FYI) submission
(FYI-OTS-1088-0645 S), Union Carbide submi~ted final reports from
teratologic studies of UC55248 and UC70480 in rats; these studies
were conducted by Union Carbide at its own testing f,acility.
Finally, Union Carbide provided (in its Section 8(e) submission)
copies of two internal Union Carbide documents comparing the con-
duct and assessing the results of the UC55248 teratologic studies
that had been conducted inside and outside Union Carbide.
In the cover letter to its Section 8(e) submission, Union Carbide
provided the following information with regard to the conduct and
results of the studies conducted with UC55248:
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
.~A 1'0" II'" lltEV. ~7S1
432
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Page 2 of 13
"In the range-finding teratology study in rabbits. . .
[dosed orally by gavage at doses of 50, 130, 320, 800
and 2000 mg/kg/day on days 6-27 of gestation, the cqn-
tract laboratory] reported slight signs of maternal and
embryo toxicity at 320 mg/kg/day. In the [second con-
tractor-performed] teratology study in rats. .,
UC55248 administered in the diet at 50, 130, and 320
mg/kg/day [on days 6-19 of gestation for those females
scheduled for Cesarean section and continuing from day
0-21 of lactation for the females scheduled to deliver
pups for observation] apparently caused an increased
incidence of total malformations, primarily bent ribs
and tail abnormalities. The [contract laboratory's
final] report concludes: 'Treatment with UC55248
induced a teratogenic response in Charles River COBS CD
rats when administered in the diet at a dose level of
50 mg/kg/day or greater.' [In the third contractor-
performed teratology study, UC55248, UC55304 or UC63152
was administered via the feed to pregnant rats at doses
of 320 mg/kg/day (UC55 248), 5, 130 or 320 mg/kg/day
(UC55304) and 8, 20 or 50 mg/kg/day (UC63152) on days
6-19 of gestation.] ... [With regard to UC55248, the
con tr ac tor] repo rted increases only in bent ribs and
variations reflecting incomplete skeletal ossification,
but no teratogenic effects: 'In the absence of addi-
tional malformations, these data were considered [to
be] indicative of a retardation in fetal development
and not a tera togenic effect.' [Wi th regard to
the Chernoff Assay of UC55248, the contractor's final
report states that 'UC55248 produced extreme toxicity
resulting in morbidity and mortality in CD-1 mouse dams
exposed to 1,500.0 or 4,500.0 mg/kg/day, po [(gavage)],
on gd [(gestation days)] 6-15. Exposure to UC55248 at
50.0 or 100.0 mg/kg/day, po, on gd 6-15 resulted in no
evidence of maternal, fetal or neonatal mortality or
toxicity in CD-l mice. Exposure to UC55248 at 160.0 or
320.0 mg/kg/day, po, in CD rats on gd 6-19 produced
evidence of maternal and transient neonatal toxicity.'"
Further wi th regard to UC55248, the FYI submission cover letter
presents the following information about the conduct and results
of a rat teratology study of UC55248 conducted by Union Carbide
at its own testing laboratory:
"In th i s study [(which was conducted with UC55248 at
dietary dose levels of 0, 8, 20, 50, 130, or 320 mg/kg/
day on gestation days 6-20)], a statistically signifi-
cant (p < 0.05) reduction in fetal body weight per
litter at 20.0 and 8.0 mg/kg/day (two lowest doses) was
observed in the absence of statistically significant
ma terna 1 tox i ci ty - The fetal weights at these doses
were 94-95% of the control values; the maternal weight
gain for the gestation period (gd 0-20 - dosed feed was
available on gd 6-20) was also 93-95% of the control
433
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Page 3 of 13
value, but maternal weight gain depression was not
statistically significantly different (due to more
variability for maternal weights versus fetal weights).
Fetal weights were also reduced, to a greater extent,
at higher doses so the effect is clearly dose related.
"There were also caudal and anal defects [observed] in
the fetuses at doses (130.0 and 320.0 rng/kg/day - two
highest doses) which also produced maternal toxicity.
The incidence of the fetal defects was not signifi-
cantly increased, but these defects are not typical of
those observed in control [Charles River COBS] CD rats.
They are also not typical of rats exposed in utero to a
number of different agents causing maternal toxicity
and other indications of developmental toxicity such as
reduced fetal weight, . . . [as cited in reviews found
in the published scientific literature]."
In the cover letter to its Section B(e) submission, Union Carbide
provided the following summary information with regard to the
conduct and results of the contract laboratory's teratology study
of UC55304:
". . . [AS ci ted previously,] UC55304 was administered
in the diet of pregnant Charles River COBS CD rats at
50, 130, and 320 mg/kg/day [on days 6-19 of gestation].
. . . [The contractor] reported that UC55304 'caused a
dose-related trend in maternal toxicity at the 130 and
320 mg/kg/day levels.' In addition, . . . [the contrac-
tor] reported that 'UC55304 was fetotoxic at 50 mg/kg/
day and teratogenic at 130 and 320 mg/kg/day.'"
The "SYNOPSIS" section of the submitted final report from the
contract laboratory's teratology study of UC5524B, UC55304 and
UC63152 via the feed in rats presents the following information
with regard to UC63l52:
"In contrast to . [UC5524B and UC55304], UC63152
caused marked maternal toxicity at the highest dosage
level (50 mg/kg/day) but had no definite effect on any
of the Cesarean section parameters or on the occurrence
of malformations or variations at any dosage level.
Nine high dose rats died from gestation days 17 to 21.
Many of the rats which died had erosions and black or
brown material in the stomach. [The] mean maternal
body weights and mean maternal food consumption in the
high dose group were both moderately reduced relati ve
to the control group. A slight body weight inhibition
and a reduction in food consumption were the only test
article effects present at the 20 mg/kg/day [dosage]
level. In conclusion, . test article UC63152 had
no teratogenic effect at dosage levels of 50 mg/kg/day
and less."
434
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Page 4 of 13
The cover letter to Union Carbide's FYI submission presents the
following information regarding the conduct and results of an
internally conducted Union Carbide teratologic study in which
UC70480 was administered to pregnant Charles River COBS CD rats
by gavage at doses of 0.0, 5.0, 17.5 or 35.0 mg/kg/day on
gestation days 6-15:
"This [oral teratologic] study provides evidence of
reduced fetal ossification at a dose (5.0 mg/kg/day-
the lowest dose) which did not result in demonstrable
maternal toxici ty. This evidence of feto-
toxicity was not associated with any reductions in
fetal body weight or any other indication of develop-
mental toxicity and no evidence of teratogenicity-
There were no dose-related increases in fetal mal-
formations. ~he incidence of litters with one or more
fetuses with any malformations, categorized as total
malformations, was increased at 17.5 mg/kg/day, but not
at 35.0 mg/kg/day, and was not accompanied by any
increase in the incidence of individual, or pooled
external, visceral (including craniofacial) or skeletal
malformations. This finding [was] not considered [to
be] treatment related."
with regard to interpreting the results of the submitted
teratological studies, Union Carbide provided the following
information in the cover letter to the company's Section 8 (e)
submission:
"Two of [the tested] chemicals, UC55248 and
UC55304, have identical chemical structures, except
that the latter [(UC55304)] contains an additional
methyl group. Under the tes t cond i t ions, bo th com-
pounds readily liberate 2-ethylhexanoic acid [(CAS No.
149-57-5)], a chemical which has produced teratogenic
response[s] in laboratory animals.
"The sponsoring scientists conclude that the fetal
effects observed in the studies on UC55248 and UC55304
are attributable to the liberation of 2-ethylhexanoic
acid under [the] test conditions. This conclusion is
consistent with the fact that UC63152, which is chemi-
cally similar to [both] UC55248 and UC55304 but does
not contain or liberate 2-ethylhexanoic acid, did not
produce teratogenic responses in an identical con-
current test in the same [contract] laboratory."
[NOTE: The reader's attention is directed to the first
paragraph of the Comments/Recommendations section of
this status report for information wi th regard to the
ongoing assessment/testing-related activities for 2-
ethylhexanoic acid (2-EHA) in EPA's Office of Toxic
Substances (OTS).]
435
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Page 5 of 13
Finally, Union Carbide stated in its Section 8(e) submission that
one of the submitted internal Union Carbide documents compares
the conduct/resul ts of the UC55248 teratology studies performed
inside and outside Union Carbide. Union Carbide repor ted tha t
this particular corporate document notes that "because of the
maternal toxicity, UC55248 could not be termed a terat~gen,
according to . . . [the criteria published in 1975 by Staples and
Wilson in Chapter 4 ("Definition of Teratogenesis and Teratogen")
of Methods f or De tec t i on 0 f Envi ronmental Agents that Produce
Congeni tal Defects (Edi tors: T. Shephard, J. Mi ller, M. Maroi s;
North Holland Publishing Company; 1975)]." Union Carbide noted
also, however, that because the malformations observed in the
UC55248 studies "are not usually seen in studies where there is
maternal and/or fetal toxicity," the submitted internal corporate
report states that 'UC55248 produced these malformations not just
in the presence of, but in addition to, maternal and other fetal
toxicity-'"
Regarding the other submitted internal Union Carbide document,
the company reported that although this document "notes the
difficulties in interpreting the results of the various studies,"
the document "concludes that UC55248 appears to cause caudal and
anal defects."
Submission Evaluation
The following review does not include a detailed section on study
conduct for each indi vidual study submi tted. The reader should
assume, therefore, that a study was conducted using a generally
accepted protocol unless noted otherwise. The general study
des ign for a standard teratology (developmental toxici ty) study
is as follows: groups of pregnant animals (usually, one control
and three treated) are administered the test agent or vehicle
over the major period of organogenesis (usually days 6-15 of
gestation for rodents and 6-18 for rabbits). The standard number
of pregnant animals per group is 20 rodents and 12 rabbits. In a
range-finding study, more dose levels are added with fewer ani-
mals included per group. The pregnant animals are examined daily
for clinical signs and are weighed periodically; food consumption
is also measured periodically. The pregnant animals are sacri-
ficed just prior to term and subjected to necropsy. The uterus
is excised, usually weighed, and the following parameters are
asses sed: number of implanta t ion si tes, number of resorpt ions,
number of live/dead fetuses, number of corpora lutea, fetal body
weight and sex ratio. All fetuses are examined for external mal-
formations or variations. A portion of the fetuses are examined
for visceral malformations/variations and the remaining fetuses
are examined for skeletal malformations/variations. In a range-
finding study, only a limited number of parameters are evaluated
a t the time of sacr i f ice and the fetuses are no t exami ned fo r
visceral and skeletal effects.
The general study design for a "Chernoff Assay" (i.e., Chernoff/
Kavlock Assay (preliminary Developmental Toxicity Screen» is
436
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Page 6 of 13
similar to the standard teratology study up until the point of
sacrifice. Instead of sacrificing the pregnant animals prior to
term, in a Cher no f f /Ka v lock Assay, the animals are allowed to
deliver their offspring and the only measurements made usually
are weighing and counting the offspring on the day of birth (day
1 postnatally) and day 4 postnatally.
REVIEW OF RESULTS FOR UC70480
In the submi tted UC70480 study, there were no treatment-related
effects on maternal body weight and body weight gain. There was
an incr~ased incidence of perioral wetness in the 17.5 and 35
mg/kg/day groups. At sacr ifice there were no treatment-related
differences in maternal body weight, corrected body weight (body
weight minus gravid uterine weight), gravid uterine weight or
absolute or relative liver weight.
with regard to developmental effects, there was no effect on the
number of corpora lutea per dam, the total number of live/dead
implantations per litter, pre- and post-implantation loss, sex
ratio or fetal body weight. Further, there were no dose-related
differences in the incidence of external or visceral malforma-
tions/variations or skeletal malformations. However, there was a
dose-related statistically significant increase in the incidence
of skeletal variations across all treatment groups, largely in
the form of reduced ossification. In addition, there was a
statistically significant increase in the total malformations at
17.5 mg/kg/day, but not 35 mg/kg/day; this may be due to slight,
non-dose-related increases in the incidence of certain external
and visceral malformations.
REVIEW OF RESULTS FOR UC63152
Each group in the performed study consisted of 20 mated females,
all of which which were sacrificed on gestation day 20. The con-
trol and high dose groups included an additional 10 mated females
that were allowed to deliver and the offspring were maintained
for 4 weeks postweaning. The test article was administered in
the diet from day 6 through day 19 of gestation.
With regard to maternal effects, 9 rats died between days 17 and
21 of gestation. Prior to death, the animals were emaciated,
pale, inactive and cool to the touch. At necropsy, these animals
had black/brown material in and erosions of the stomach. There
was a dose-related decrease in maternal body weight and food con-
sumption (i.e., there was a significant decrease at 50 mg/kg/day
and a slight decrease at 20 mg/kg/day). There were significant
decreases in corrected body weight at 20 and 50 mg/kg/day.
In terms of developmental effects, there were no treatment-
related effects on parameters evaluated at the time of Caesarean
section nor were there any treatment-related effects on the
incidence of malformations and variations.
437
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Page 7 of 13
with regard to postnatal effects, 4 dams delivered 51 pups, 2 of
which were nonviable and 3 died by day 21. In addition, one pup
had loss of righting reflex. Further, there was a slight decrease
in litter weight on days 0 and 7 postnatally.
REVIEW OF RESULTS FOR UC55304
As in the case of the study on UC63152, each group in the UC55304
study consisted of 20 mated females which were all sacrificed on
day 20 of gestation. The control and high dose groups included an
additional 10 mated females which were allowed to deliver and the
offspring were maintained for 4 weeks postweaning. The test agent
was administered in the diet from day 6-19 of gestation.
with regard to maternal effects, there was an increased incidence
of clinical signs (hair loss; red or black anogenital staining)
in the 320 mgjkgjday group. There was a dose-related decrease in
in body weight, body weight gain and corrected body weight in the
130 and 320 mgjkgjday groups. In addi t i on, there was a sl i gh t
reduction in maternal body weight during the period of days 0-7
postnatally; however, these data were based on only two animals.
Further, there was a dose-related decrease in food consumption in
the 130 and 320 mgjkgjday groups.
In terms of developmental effects, at 320 mgjkgjday, 13 out of 17
gravid dams had total litter loss (resorptions or dead fetuses).
Consequently there was a significant increase in postimp1antation
loss and a significant decrease in the number of live fetuses.
Most of the deaths occurred as early resorptions. The exposure
to 130 mgjkgjday had a similar but less severe effect. Although
pos t impl a n ta tion loss and number of li ve fetuses were markedly
different from control values, the values were not statistically
different. Un1 i ke the high dose group, total 1 i tter losses did
not occur at 130 mgjkgjday. Further, there was a dose-related
decrease in fetal body weight with all treatment group values
being lower than the historical control range; however, only the
mid and high dose groups were found to be statistically signifi-
cantly different from the concurrent control values. The mean
numbers of corpora 1utea and total implantation sites were com-
parable across all groups. In addition, there was a dose-related
increase in the number of fetuses and Ii tters wi th fetuses wi th
bent ribs in all treatment groups and all values were higher than
those of the historical controls. All of the litters in the high
dose group were affected. In the 50 mgjkgjday group, one fetus
had bent bones and another a tail anomaly, while at 130 and 320
mgjkgjday, there was a dose-related increase in the incidence of
several malformations. These included anasarca, gastroschisis,
malpositioned limbs, bent tail, vertebral anomalies, fused ribs,
and sternoschisis. Nearly all incidences were beyond those of
the hi stor ical control ranges. All of the 1 i tters in the high
dose exhibited bent ribs, bent bones, anasarca and gastroschisis.
Although the sample size in the high dose group was small, as a
result of the high in utero mortality, the high incidence of
malformed fetuses (85:7%) and litters (100%) indicate that the
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Page 8 of 13
data have biological significance and are not likely to be due
merely to chance. All treated groups exh i b i ted a moder a te to
marked increase in the number of fetuses and litters with fetuses
with reduced skeletal ossification. The bones most frequently
involved were the sternebrae, vertebrae, pubis, and skull bones.
Al though there was not always a dose-related effect, these
effects are viewed as being biologically significant and the
reductions in ossification are undoubtedly treatment-related.
Wi th regard to postna tal effects, there were only 2 dams that
produced a total of 6 pups. Of the 6, 2 were nonviable at birth
and 2 died the day after birth. One of the nonviable pups had
gastro sch i s is. No body we i gh t compa r i sons were made on the
surviving 2 pups.
REVIEW OF RESULTS FOR UC55248
This section relates to the findings from the 3 standard studies
and the Chernoff/Kavlock Assay (all conducted in the rat), the
Chernoff/Kav10ck Assay conducted in the mouse, and the range-
finding study conducted in the rabbit.
RABBIT
with regard to the range-finding study in rabbits, each dose
group consisted of 5 artificially inseminated rabbits. Exposure
occurred during days 6-27 of gestation. Four animals in the 2000
mg/kg/day group and 2 animals in the 800 mg/kg/day group died; in
addition, one animal in the 800 mg/kg/day group was sacrificed in
extremi s. pr i or to dea th, these an ima 1 s were emac i a ted and
displayed reduced activity and anogenital matting of the fur, and
had reduced fecal material. At necropsy, there was evidence of
gastrointestinal irritation in 2 animals each in the 800 and 2000
mg/kg/day groups. Two addi tional animals in the 800 mg/kg/day
group aborted and displayed clinical signs. At both the 800 and
2000 mg/kg/day levels, there was marked maternal body weight loss
prior to death or abortion. There were no treatment related
maternal effects at the levels of 320 mg/kg/day and lower.
Regarding developmental effects, the following values were found
to be comparable across the 50, 130 and 320 mg/kg/day groups:
number of live fetuses, total implantations, and number of
corpora lutea. The single dam in the 800 mg/kg/day group that
had to be sacrificed and one dam in the 320 mg/kg/day group had
whole litter resorptions. There were 4 early resorptions of 6
total implantations in one dam in the 130 mg/kg/day group.
MICE
In terms of maternal effects, all of the mice exposed to 1500 or
4500 mg/kg/day were moribund or dead by the first or second day
of treatment and were sacrificed. There were no statistically
significant maternal effects for the animals exposed to 50 or 100
mg/kg/day.
439
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Page 9 of 13
with regard to developmental effects, there were no statistically
significant effects on the number of implantation sites, number
of live pups, or mean pup body weight on days 1 or 4 postnatally,
or on percent of prenatal or postnatal loss in the 50 and 100
mg/kg/day groups.
RATS (4 studies)
In terms of maternal effects, there was no maternal mortality.
There was reduced body weight, body weight gain, and food con-
sumption at 130 and 320 mg/kg/day. In addi tion, the study that
was conducted by Union Carbide's laboratory showed such decreases
at 50 mg/kg/day. Gravid uterine weight was reduced at 130 and
320 mg/kg/day.
With regard to developmental effects in general, there was no
effect on number of corpora lutea, total implantations, number of
live fetuses, or sex ratio. There was a statistically significant
reduction in fetal body weights found at all treatment levels.
The Union Carbide laboratory reported a reduction in crown-rump
length in all treated groups, as well. There was an increased
incidence of malformations in all treatment groups. The incidence
of bent ribs was increased at all dose levels (statistically sig-
nificantly in Union Carbide's laboratory study) and the incidence
of caudal and anal defects was increased in both the 130 and 320
mg/kg/day groups. The bent ribs and caudal/anal defects, while
not always statistically significantly increased, were markedly
above those of historical control values and were observed in
three different studies conducted by two different laboratories.
Therefore, the findings are considered by EPA to be biologically
significant. In addition, there were significant reductions in
skeletal ossification at all dose levels. Further, it should be
noted that Union Carbide's laboratory study showed a significant
increase in the incidence of several soft tissue variations,
specifically ecchymosis of the cranial region (significant at 320
mg/kg/day) and bi-lobed apex of the heart (s igni f ican tat both
130 and 320 mg/kg/day) .
With regard to postnatal effects, in the Chernoff/Kavlock assay,
there was a dose-related increase in the mean gestational length
wi th the va 1 ue from the 320 mg/kg/day group bei ng signi f icantly
higher than that of control animals. In the contractor's second
study, there was a dose-related increase in length of gestation
but it did not reach statistical significance due possibly to the
sma 11 numbe r 0 f animals (3-4) per group. In all three of the
postnatal studies, pup body weights were significantly reduced at
birth at levels of 130 mg/kg/day and greater. In the contractor's
second study, the pup body weights remained significantly reduced
throughout lactation and for four weeks postweaning in the 130
and 320 mg/kg/day dose groups. In the contractor's th i rd study,
pup body weights were decreased prior to weaning but were found
to be comparable to those of the control animals after weaning.
In the Chernoff/Kavlock Assay, body weights were significantly
decreased only for the female pups and only at 160 but not 320
440
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Page 10 of 13
mg/kg/day on day 4 postnatally (the only time other than the day
of birth that pup body weights were measured). The contractor's
second study showed a significant reduction in pup s~rvival index
on day 4 postnatally for the 320 mg/kg/day group.
OVERALL DISCUSSION
In reviewing the submitted studies, it became clear to EPA that
there are many areas that need further discussion other than the
presentation/evaluation of the results of the studies supplied.
SUMMARY OF THE DATA
Overall, the submitted data show that 1) UC55248 and UC55304 are
maternally and developmentally toxic, 2) UC63152 is maternally
toxic but not developmentally toxic, and 3) UC70480 is develop-
mentally toxic but not maternally toxic, al though there was an
increased incidence of perioral wetness observed in the maternal
animal. Considering that this was the only finding, it was not
considered biologically significant enough to characterize this
chemical (UC70480) as causing maternal toxicity.
Based on various data from the submitted studies, the lowest-
observed-adver se-e f fect-l eve I s (LOAELs) a nd the no- observed-
adverse-effect-Ievels (NOAELs) for each chemical are listed in
the following table. It should be noted that data from the
Chernoff/Kavlock Assay were not used to establish any NOAELs
because only a limited number of end points are evaluated in that
particular study; the study is designed merely to help prioritize
chemicals for further testing and is not designed to provide
"hard and fast" values for use in formal risk assessment.
Chemical
Maternal Toxicity
(mg/kg/day)
NOAEL
Developmental Toxicity
(mg/kg/day)
LOAEL
NOAEL
LOAEL
UC55304
50 NE* 50 NE
130 50 50 NE
20 8 >50 50
>35 35 5 NE
*NE: Not Established
UC55248
UC63l52
UC70480
The data on UC55304, UC63l52, and UC70480 were all derived from
one study each and in one species each. On the other hand, the
data on UC55248 were derived from two standard teratology studies
441
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Page 11 of 13
conducted in the rat performed at two different laboratories, one
teratology study in the rat conducted at only a single high dose
level, one Chernoff/Kavlock Assay conducted in the rat and mouse
and one range-finding teratology study conducted in the rabbit.
As a Union Carbide scientist noted in great detail in one of the
submitted internal company documents, there is great concordance
in the findings among the rat studies, regardless of study design
and site of study. Thi s serves to increase the conf idence EPA
has in the submitted data.
MATERNAL TOXICITY AND DEVELOPMENTAL TOXICITY
Over the years, there has been continued debate wi th regard to
the role of maternal toxicity on developmental toxicity. There
are a number of individuals who have taken the position that if a
chemical is developmentally toxic at a maternally toxic dose, the
substance should not be considered a developmental toxicant. It
is EPA's position, however, that developmental effects cannot be
dismissed as being secondary to maternal toxici ty. Furthermore,
currently available information is inadequate to allow one to
assume that developmental effects at maternally toxic doses
result only from maternal toxicity. In support of EPA's position
in this matter, it should be noted that numerous studies have
been conducted in which there was severe maternal toxici ty and
yet there was no evidence of developmental toxici ty. In fact,
the submitted study on UC63152 illustrates this point very well.
Although 9/20 mated rats died at the high UC63152 dose, and there
were significant effects on body weight at the mid and high dose
levels, there were no treatment-related effects observed for 1)
any developmental parameters evaluated at the time of Caesarean
section, or 2) the incidence of fetal malformations/variations.
DIFFERENCES IN INTERPRETATION OF FINDINGS
In the studies conducted with UC55248, there was much discussion
on the ques t i on 0 f whether ben t ribs should be class i f ied as
variations or malformations. (In two of the submi tted studies,
bent ribs are referred to as malformations, in another study,
they are referred to as variations, and in still another study,
they are referred to as both malformations and "deviations.")
The point remains, however, that this particular end point was
seen in three different studies and in a dose-related manner.
Further, it does not matter whether bent rib is classified as a
variation or a malformation because EPA regards both variations
and malformations as signs of developmental toxicity- This point
also comes into play in interpreting the results of the submitted
study on UC70480 where the only adverse effect observed was a
significant increase in the incidence of variations, specifically
decreased skeletal ossification. The FYI submission cover letter
refers to this finding as an indicator of fetal toxicity and goes
on to state there was no evidence of teratogenicity. EPA, on the
other hand, believes that no distinction should be made between
teratogenici ty and fetotoxici ty; ra ther, EPA regards these as
subsets of the broad term of developmental toxicity-
442
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Page 12 of 13
DEVELOPMENTAL TOXICITY DUE TO 2-ETHYLHEXANOIC ACID
In the cover letter to the Section 8(e) submission, it is stated
that the sponsors concluded that the developmental effects of
UC55248 and UC553~4 are due to the liberation of 2-ethylhexanoic
acid, a demonstrated developmental toxicant. In addition, this
cover letter states that UC63l52, which is structurally similar
to UC55248 and UC553~4 but does not contain nor liberate 2-ethyl-
hexanoic acid, does not produce "teratogenic responses." The
specific developmental effects caused by UC55248 and UC553~4 are
different than those seen in studies submi tted thus far to the
Agency on 2-ethylhexanoic acid; however, a different strain of
rat was used in those studies. In addi tion, it is important to
note that the effects caused by UC55248 and UC553~4 while similar
in some respects, were quite different in others. Therefore, it
is difficult for EPA to agree that 2-ethylhexanoic acid alone is
responsible for the observed effects; the possibility remains
that the parent compounds and/or other metabolites may be the
putative developmental toxicant(s). It is also interesting to
note that, in the Chernoff/Kavlock Assay, the length of gestation
was significantly increased for UC55248. Of the several hundred
chemicals that have been tested in this assay to date, the only
other chemicals shown to increase the length of gestation are
valproic acid (2-propyl pentanoic acid) and 2-ethylhexanoic acid.
Current Production and Use
In its TSCA Section 8 (e) and FYI submissions, union Carbide
reported non-confidentially that UC55248 (the tolylcycloalkenyl
substituted alkyl ester), UC553~4 (the xylylcycloalkenyl substi-
tuted alkyl ester), UC7~48~ (the cyanoal kyl phosphorod i th i oa te)
and UC63152 were exper imental pesticide chemicals. In addi tion,
Union Carbide reported non-confidentially that UC55248, UC553~4
and UC7~48~ do not have CAS numbers and are not listed on the
TSCA Chemical Substance Inventory. Union Carbide did not provide
any non-confidential information pertaining to the TSCA Inventory
status of UC63l52.
Comments/Recommendations
It is important to note that the Test Rules Development Branch
and the Risk Analysis Branch (TRDB and RAB/ECAD/OTS/OPTS/EPA)
have been reviewing available toxicologic and exposure data on 2-
ethylhexanoic acid (2-EHA), a chemical substance recommended by
the Interagency Testing Committee (ITC) for testing pursuant to
Section 4 of TSCA. Further, EPA has published TSCA Section 8(a)
and 8 (d) information gathering rules on 2-EHA. Also, EPA has
received a number of TSCA Section 8(e) and FYI notices on 2-EHA.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Union Carbide will be
asked to describe the actions the company has taken or
plans to take 1) to notify workers and others about the
443
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Page 13 of 13
reported findings, and 2) to reduce/eliminate exposure
to the subject chemical substances. Union Carbide will
be asked also to describe the nature and results, if
ava i lable, of all stud ies (other tha n those repor ted
already to the Agency or those ci ted in the published
scientific literature) about which Union Carbide is
aware or that the company has conducted, is conducting
or plans to conduct that are designed to determine the
toxicity of the subject chemical substances.
b)
Staff of the Chemical Screening Branch will review the
reported information in order to determine the need for
further OTS assessment of the subject chemicals.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA, and TRDB and
RAB/ECAD/OTS/OPTS/EPA; copies of thi s report wi 11 be
sent also to the TSCA Assistance Office (TAO/OTS) for
further distribution.
444
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
DEC I 9 1988
SUBJECT:
Status Report* BEHQ-llB8-0765 S Approved:
James F. Darr, Section Head ~~~
Chemical Risk Identificatio~~~ion/CSB
~ /zji1CO
!"ROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will review all incoming correspondence relating to the company's
substantiation of these CBI claims. In the "sanitized" version
of the submission, the company stated non-confidentially that the
subject chemical substance is an "aryl oxime."
Submission Description
The submitting company provided the following information with
regard to the conduct and preliminary results of a "pilot" oral
teratology study of this aryl oxime in rats:
"In this study, the aryl oxime was administered by
gavage to 6 groups of mated female rats at dose levels
of 0, 75, 150, 250, 500 and 1000 mg/kg/day during ges-
tation days 6-15. Surviving dams were sacrificed on
gestation day 20. Fetuses were removed, weighed, sexed
and examined for possible external malformations.
"All B animals at 1000 mg/kg/day and 1/8 animals at 500
mg/kg/day died during the study. Maternal weight gain
was substantially decreased at 500 and 250 mg/kg/day
and slightly decreased at 150 mg/kg/day. There were no
viable fetuses in the living dams at 500 mg/kg/day. An
increase in post-implantation loss and a decrease in
fetal weights were noted at >150 mg/kg/day. In addition
3 fetuses from 2 litters at- 250 mg/kg/day exh i b i ted
rare limb defects (short legs, short and/or missing
fingers). These defects were observed in fetuses tha t
were extremely light in weight but the reduced fetal
weight is not believed to have contributed to the
defects." .
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
II~A 'OMI ..... I"EV. 1-711
445
-------
8EHQ-1188-0765 S
Page 2 of 3
Submission Evaluation
An EPA eva 1 ua t i on of the overall signi ficance of the reported
findings should be possible upon EPA's receipt of a full copy of
the final report from the oral "pilot" teratology study cited in
the company's submission. In the interim, however, it should be
noted that the submitted summary information, which includes
several data tables, does provide evidence for the maternal and
developmental toxicity of this aryl oxime.
All maternal animals in the highest dose (1000 mg/kg/day) group
died before the end of the study. Although only one animal died
at the next highest dose (500 mg/kg/day), no animals at this dose
level produced any viable fetuses. At 25~ mg/kg/day, 6/8 maternal
animals did have viable fetuses. A trend for decreased maternal
weight gain with increasing dose was apparent at all dose levels
and statistical significance was reached for overall changes and
for several specific time intervals at 250 and 500 mg/kg/day.
In the 150, 250 and 500 mg/kg/day dose groups, there were trends
for dose-dependent decreases in fetal viability and increases in
early resorptions and post-implantation loss. At the two higher
doses (250 and 500 mg/kg/day), the early resorptions and post-
implantation loss represented statistically significant changes.
Fetal weights were significantly reduced at 150 and 250 mg/kg/day
with a trend extending to the 75 mg/kg/day dose group; as stated
previously, there were no live fetuses in the 500 and 1000 mg/kg/
day groups.
External malformations were seen in 3 fetuses from 2 litters at
250 mg/kg/day. These external malformations included micromelia,
brachydactyly, microphthalmia and/or anophthalmia, adactyly and
open eye lid (s) . As expected for a typical "pilot" teratology
study, no examination appears to have been performed for fetal
soft tissue or skeletal abnormalities.
Current production and Use
In view of the submi tter' s TSCA CBI claims, no information wi th
regard to the TSCA Chemical Substance Inventory status or use(s)
of the subject chemical will appear in this status report. The
submi tter reported non-confidentially, however, that th i s aryl
oxime" i s currently bei ng manufactured and used exclus i vely for
R&D [(research and development)] purposes."
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submitter to
ensure that EPA receives a complete copy of the final
report (including the actual experimental protocol,
results of gross and histopathological examinations,
results of any statistical analyses, etc.) from the
"pilot" oral teratology study in rats that was cited in
the company's Section 8(e) submission.
446
-------
8EHQ-1188-0765 S
Page 3 of 3
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the actions the company has taken or
plans to take 1) to notify workers and others about the
reported information, and 2) to reduce or eliminate
exposure to this aryl oxime. In addition, the submitter
will be asked to describe the nature and results. if
available, of all studies (other than those reported
already to EPA or those cited in the open scientific
literature) about which the company is aware or that
the company has conducted, is conducting or plans to
conduct that are designed to determine the toxicity of
this aryl oxime.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
447
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
DEC '9 1988
status Report* 8EHQ-1188-13766 S Approved:~
James F. Darr, Section Head ~ r ~
Chemical Risk Identification Section/CSB
t1Jt1 (t6
SU8JECT:
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name and the e~act
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will review all incoming correspondence concerning the company's
substantiation of these TSCA CBI claims. In the "sanitized"
version of the submission, the company stated non-confidentially
that the subject chemical is a "heteroaryl alkyl ether."
Submission Description
The submitting company provided the following information with
regard to the conduct and preliminary results of a "pilot" oral
teratology study of this heteroaryl alkyl ether in rats:
"In this [teratology] study, the heteroaryl alkyl ether
was administered by gavage to 6 groups of mated female
rats at dose levels of 13, 513, 11313, 1513, 2513, and 4513
mg/kg/day during gestation days 6-15. Surviving dams
were sacrificed on gestation day 213. [The] fetuses
were removed, weighed, sexed and examined for possible
external malformations.
"Three of e i gh t females at 4513 mg/kg/day died dur ing
the study and there were no viable fetuses in the
surviving animals. Decreased maternal weight gain and
an increase in post-implantation loss was observed at
dose levels> 11313 mg/kg/day. Fetal weights were
reduced in all-treated groups. External malformations
were also noted in all treated groups. The defects
observed at the higher dose levels included umbi 1 ical
hernias and omphalocele."
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should ta~e into account
the fact that the report may be based on incomplete information.
448
I[~A "0'"' u'" (lU:V. 1-711
-------
8EHQ-1188-0766 S
Page 2 of 3
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a compl~te copy
of the final report from the oral "pilot" teratology study cited
in the company's TSCA Section 8(e) submission. In the interim,
however, it must be noted that the submitted summary information,
which includes a number of data tables, does provide evidence for
the maternal and developmental toxicity of this heteroaryl alkyl
ether.
In the high dose group (45~ mg/kg/day), 4 maternal animals died
or were' sacrificed in a moribund condition prior to scheduled
necropsy. Of the 4 remaining animals, none had any viable
fetuses. Further, there were statistically significant decreases
in gestational weight gain for maternal animals at l~~, 15~, 25~
and 45~ mg/kg/day.
The number of viable fetuses per litter was inversely related to
dose. These decreases were statistically significant at all
doses except the lowest dose (5~ mg/kg/day). In addition, there
were corresponding dose-dependent increases in early and late
resorptions as well as post-implantation loss. The frequencies
of both the early resorptions and post-implantation loss were
statistically significant at the 3 highest dose levels (i.e.,
l5~, 25~ and 45~ mg/kg/day). Further, the fetal weights were
significantly (p<~. ~l) reduced from control values at all doses
tested except the high dose (as there were no viable fetuses in
the high dose group).
Several types of external fetal abnormalities were observed, most
notably umbilical herniation of the intestines and omphalocele.
The frequencies of , umbilical herniation at different doses were
as follows: 2 fetuses from 2 litters at l~~ mg/kg/day, 1 fetus
from I litter at 15~ mg/kg/day, and 2 fetuses from 2 litters at
25~ mg/kg/day. Omphalocele was observed in 2 fetuses from I
litter at l~~ mg/kg/day, 9 fetuses from 5 litters at 15~ mg/kg/
day (statistically significant at p<~.~5), and 4 fetuses from 3
lit ter sat 2 5~ mg/kg/day. As expec ted for a typical "pi lot"
teratology study, no examination appears to have been conducted
for fetal soft tissue or skeletal abnormalities.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information about
the TSCA Chemical Substance Inventory status or use (s) of th i s
heteroaryl alkyl ether will appear in this status report. The
submitting company reported non-confidentially, however, that
this heteroaryl alkyl ether "is currently being manufactured
exclusively for R&D [(research and development)] purposes."
449
-------
8EHQ-1188-0766 S
Page 3 of 3
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submitter to
ensure that EPA receives a complete copy of the final
report (including the actual experimental protocol, the
results of gross/histopathological examinations, the
results of statistical analyses, etc.) from the "pilot"
oral teratology study in rats cited in the company's
TSCA Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the actions the company has taken or
plans to take 1) to notify workers and others about the
reported information, and 2) to reduce or eliminate
exposure to this heteroaryl alkyl ether. In addition,
the submitter will be asked to describe the nature and
results, if available, of all studies (other than those
reported already to the Agency or those cited in the
open scientific literature) about which the company is
aware or that the company has conducted, is conducting
or plans to conduct that are designed to determine the
toxicity of this heteroaryl alkyl ether.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
450
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DEC I 9 ,]88
Page 1 of 3
DATE:
SUBJECT:
Status Report* 8EHQ-1188-0767 S A d
pprove :
James F. Darr, Section Head ~ 1: ~
Chemical Risk IdentificatioJ7;~;ion/CSB
aIt IJ-!Iq !f(
, 0'
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will be reviewing all incoming correspondence from the submitting
company regarding substantiation of these CBI claims. In the
"sanitized" version of its Section 8(e) notice, the submitting
company stated non-confidentially that the subject chemical is a
"haloalkyl heterocycle."
Submission Description
The submitting company provided the following information with
regard to the conduct and preliminary results of a "pilot" oral
teratology study of this haloalkyl heterocycle in rats:
II In this [teratology] study, the haloalkyl heterocycle
was administered by gavage to 6 groups of mated female
rats at dose levels of 0, 50, 100, 2013, 4130 and 800
mg/kg/day during gestation days 6-15. Surviving dams
were sacrificed on gestation day 20. [The] fetuses
were removed, weighed, sexed and examined for possible
external malformations.
"All eight females at 800 mg/kg/day died during the
study- No maternal mortality occurred at 4013 mg/kg/day
but dams at this level exhibited significant weight
loss and/or reduced weight gain. No maternal toxici ty
was evident at 200 mg/kg/day.
===================================================================================:
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
451
I:~A I'OMI "... uuv. J-nl
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8EHQ-1188-0767 S
Page 2 of 3
"post-implantation loss was moderately increased at 2@@
mg/kg/day and substantially increased at 4@@ mg/kg/day.
Reduced fetal weights were also evident at both of
these dose levels. Umbilical hernias were noted in one
fetus at l@@ mg/kg/day and 8 fetuses (4 litters) at 2@@
mg/kg/day. The l@ viable fetuses at 4@@ mg/kg/day did
not exhibit any external malformations."
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a complete copy
of the final report from the oral "pilot" teratology study cited
in the company's submi ss ion. In the inter im, however, it should
be noted that the submi tted summary information, which includes
several data tables, does provide evidence for the maternal and
developmental toxicity of this haloalkyl heterocycle.
All maternal animals treated with 8@@ mg/kg/day died during the
study. Although all maternal animals in the 4@@ mg/kg/day dose
group survived, they had significant weight loss or reductions in
weight gain. No apparent maternal toxicity was observed after
treatment with doses of ~2@@ mg/kg/day.
At 4@@ mg/kg/day, only 1 dam produced viable fetuses; 3 animals
at this dose were nongravid and 4 had resorptions. At 2@@ mg/kg/
day, there was a statistically significant (p<@.@S) decrease in
mean fetal weight. In addition, post-implantation loss was found
to be increased among the litters at 2@@ mg/kg/day (a mean of
2.4/litter as opposed to 1.0/litter in the controls).
At 2@0 mg/kg/day, 8 fetuses from 4 li tters were found to have
umbilical herniation of the intestines. This same defect was
seen in 1 fetus at the next lowest dose (l@@ mg/kg/day) but not
in any of the control or low dose (S@ mg/kg/day) fetuses. As
expected for a typical "pilot" teratology study, no examination
appears to have been performed for fetal soft tissue or skeletal
abnormalities.
Current Production and Use
In view of the submitter's TSCA CBI claims, no information about
the TSCA Chemical Substance Inventory status or use (s) of this
haloalkyl heterocycle will appear in this status report. The
submitter stated non-confidentially, however, that this haloalkyl
heterocycle "is currently being manufactured exclusively for R&D
[(research and development)] purposes."
452
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8EHQ-1188-0767 S
Page 3 of 3
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submitter to
ensure that EPA receives a complete copy of the final
report (including the actual experimental protocol, the
results of gross and histopathological examinations,
the results of statistical analyses, etc.) from the
"pilot" oral teratology study in rats that was cited in
the company's TSCA Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a. voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the actions the company has taken or
plans to take 1) to notify workers and others about the
reported information, and 2) to reduce or eliminate
exposure to this haloalkyl heterocycle. In addi ti on,
the submitter will be asked to describe the nature and
results, if available, of all studies (other than those
reported already to the Agency or those ci ted in the
open scientific literature) about which the company is
aware or that the company has conducted, is conducting
or plans to conduct that are designed to determine the
toxicity of this haloalkyl heterocycle.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, N~P,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
453
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 4
DATE:
DEC 29 1988
SU8JECT:
Status Report*
8EHQ-1188-0768 S
Approved: I~ #~
DEC 2 9 1988
FROM:
~.-.--'-R~~~
James F. Darr, Section Head
Chemical Risk Identification Section/CSB
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The Eastman Kodak Company has cla imed the exact ident i ty of the
subject chemical to be TSCA Confidential Business Information
(TSCA CBI); the Information Management Division (IMD/OTS) will be
reviewing all incoming correspondence pertaining to the company's
substantiation of this CBI claim. According to the "sanitized"
(i.e., non-confidential) version of the Section 8(e) submission,
the subject chemical is an "inorganic potass i urn hal ide comp.lex."
Submission Description
The Eastman Kodak Company provided the final report of an acute
oral toxicity study of this inorganic potassium halide complex in
rats. The company's cover letter presents the following informa-
tion with regard to the conduct and results of the study:
"In an acute oral toxicity study, estimated oral LD50
values of 769 mg/kg and 544 mg/kg were obtained in male
and female rats, respectively. All animals receiving
doses of 1250 mg/kg or more died before scheduled study
termination. A dose of 625 mg/kg was also lethal to a
portion of the treated animals.
"At the 1250 mg/kg dose level, gross treatment-related
changes in [those] animals dying within three days of
treatment included hemorrhage, edema, and necrosis of
the glandular gastric mucosa, green contents in the
small intestines and cecum, pale kidneys, enlarged and
discolored livers, and yellow discoloration of the in-
guinal hair. [The] microscopic lesions in the kidneys
====================================================================================
*
NOTE: This status report is'~he result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
454
K~A 1'0"" U.. (IilEV. ..nl
-------
8EHQ-1188-0768 S
Page 2 of 4
included diffuse necrosis of the proximal convoluted
epithelium, granular and epithelial casts in the proxi-
mal and distal tubules, and granular casts in the
glomerulus (females only). Microscopic 1 i ver 1 e s ion s
included diffuse necrosis, hemorrhage (males only), and
lipoid degeneration (males only) of the centrilobular
or mid-zonal hepatocytes.
"A t 612 mg /kg, [the] gross treatment-related changes
seen in one or more animals dying within three days of
treatment included hemorrhage in the glandular gastric
mucosa, yellow, enlarged, mottled livers, dark, en-
larged adrenal glands, and hydroperitoneum in the
abdomi nal cav i ty - Microscopic 1 i ver lesions i nc 1 uded
diffuse necrosis, hemorrhage, and lipoid degeneration
of the centrilobular or mid-zonal hepatocytes. Lesions
of the adrenal glands, seen in one fema le [rat] only,
included diffuse necrosis and hemorrhage in the zona
fasciculata. No kidney lesions were observed. Treat-
. ment-related changes in the four males and two females
which survived the 14-day observation period consisted
of pale (2/4 males, 1/2 females) and enlarged (1/2
females) kidneys.
"The only treatment-related change in the 312 and 156
mg/kg dose groups consisted of pale kidneys in one 312
mg/kg male. All animals in these two groups survi ved
the 14-day observation period.
"Animals in the 625 and 312 mg/kg dose groups which had
gross treatment-related lesions and which survived the
14-day observation period showed regeneration of the
proximal convoluted tubule epithelium."
In its submission, Eastman Kodak also provided the final results
of an acute dermal toxicity study in rats, an acute dermal irri-
tation study in rabbits, an acute eye irritation study in rabbits
and a dermal sensitization study in guinea pigs. The submitted
cover letter provides the following information regarding the
results of these additional acute toxicity studies:
"When applied to the skin, the test article had an
estimated acute lethal dose of greater than 2000 mg/kg
for rats and did not produce abnormal clinical signs.
The test article was, at most, a slight skin irritant
[in rabbits], and it was not a skin sensitizer [in
g u i n e a pig s] . Wh e n p 1 ace din the [r a b bit] eye, the
test article produced strong irritation. Immediate
irrigation of the eye following exposure to the test
article was beneficial and significantly reduced the
irritation."
Eastman Kodak also provided the following information summarizing
the results of all of the submitted acute toxicity studies:
455
-------
8EHQ-1188-0768 S
Page 3 of 4
"In summary, the test article produced liver and kidney
damage at moderate to high oral doses which were also
assoc ia ted wi th gastr ic damage. High dermal doses of
the test article did not result in similar effects. The
test article was not a skin sensitizer and was only a
slight skin irritant, but it may cause strong eye irri-
tant if not promptly washed out of the eye."
Submission Evaluation
Based on the reported acute rat oral L050 values of 769 mg/kg
(males) and 544 mg/kg (females), the subj ect chemica 1 wou Id be
classified as being moderately toxic. Of particular concern in
the submi tted acute oral tox ic i ty study are the adverse effects
on the kidney, liver and adrenal glands. The oral administration
of 612 mg/kg resulted in hemorrhage in the glandular mucosa, en-
larged, mottled livers and dark, enlarged adrenal glands. Micro-
scopically, the observed liver lesions included diffuse necrosis,
hemorrhage and 1 ipo id degenera ti on of the centr i lobular or mid-
zonal hepatocytes. These effects were seen in one or more of the
animals that died during the study. It should be noted also that
although no adverse kidney effects were observed in any 612 mg/kg
dose group animals that died during the study, such effects were
found in surviving animals from that dose group (pale kidneys in
2/4 males and 1/2 females; enlarged kidneys in 1/2 females). All
animals receiving 312 or 156 mg/kg survived until study termina-
tion and only 1 male (in the 312 mg/kg group) was found to have
treatment-related effects (pale kidneys). In addition, it should
be noted that although proximal convoluted tubule epithelial
regeneration was observed in the animals that survived the 312
and 625 mg/kg dose levels in this acute oral study, EPA's overall
concern for kidney toxicity is not mitigated. While it is quite
beneficial for EPA to know that repair can occur following kidney
injury caused by acute exposure, there is no currently available
evidence that consecutive short-term exposures or a long-term
exposure would yield similar regenerative activity. until such
evidence is presented, EPA's concern for kidney toxicity remains.
with regard to the other reported toxicity studies, the subject
chemical appears to be a slight skin irritant, a non-sensitizer
and a strong ocular irritant.
Current Production and Use
In view of the submitter's TSCA CBI claim, no information with
regard to the TSC~ Chemical Substance Inventory status or use(s)
of the subject chemical will appear in this status report. In
its Section 8(e) submission, Eastman Kodak provided the following
non-confidential information concerning the manufacture of and
the potential for workplace exposure to this inorganic potassium
halide complex:
456
-------
8EHQ-1188-0768 S
Page 4 of 4
"This substance has been synthesized and used only in
small quantities for research and development purposes.
It is being evaluated for potential limited (less than
10 kg/yr) use in the manufacturing operations within
the company- . [The Eastman Kodak Company is] not
aware of any adverse health problems ass oc i a ted with
its manufacture or its use to make the final product.
The chemical was originally evaluated as health hazards
unknown. Such a rating is accompanied by a statement
tO,avoid all contact. Based on the acute toxicity
testing, employees will be required to wear company-
supplied clothing, gloves, and safety glasses when
working with this material. ,r:.. hood, glove box, or
vented enclosure will be used to weigh out material."
Comments/Recommendations
In its submission, Eastman Kodak reported non-confidentially that
the company 1) is considering the need for further toxicological
testing of the subject chemical, and 2) has updated the Material
Safety Data Sheet (MSDS) to reflect the reported acute toxicity
findings. A non-confidential version of this updated MSDS was
included in Eastman Kodak's submission.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity/exposure data, Eastman Kodak will be asked to
describe the nature and results, when available, of all
studies (other than those reported already to EPA) that
the company conducts to determine the toxicity of this
organic potassium halide complex.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA; copies of
this report wi 11 be sent also to the TSCA As s i stance
Office (TAO/OTS/OPTS/EPA) for further distribution.
457
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
DEC
9 1988
Page 1 of 2
SUBJECT:
Status Report* 8EHQ-1188-0769 Approved: ~
James F. Darr, Section Head 12~~ ~~
Chemical Risk Identificatioi7;~~~ion/CSB/ECAD
/19/ &f>
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAO/OTS/OPTS
Submission Description
The ClBA-GEIGY Corporation provided a written followup report
concerning an incident that occurred in late October 1988, and
involved a release of polychlorinated biphenyl (PCB; CAS No.
1336-36-3) oil (44% Aroclor 1260) from a transformer at the
company's plant site in Toms River, New Jersey. According to
CIBA-GEIGY, the release occurred "after an unrelated electrical
fire in the proximity" of the transformer and was reported by
phone and/or in writing under a number of mandatory State and
Federal authorities (including CERCLA (i.e., "Superfund") and
Section 8 (e) of TSCA) "before the amount and extent of the PCB
leakage were fully known." CIBA-GEIGY stated further that the
release was determined later to have involved less than one (1)
gallon of PCB oil and "occurred at the ceramic bushings that had
apparently gotten hot from the heat of the electr ical fire and
cracked when subjected to cold water used to put out the fire."
CIBA-GEIGY stated also that "some" of the PCB oil "mixed with a
large volume of standing water which resul ted from fighting the
unrelated electrical fire." CIBA-GEIGY stated further that
although "there was no environmental release outside of the
plant,". . "a small amount of PCB-contaminated water entered
the process wastewater sewer line which leads to the plant's
wastewater treatment facility." ClBA-GEIGY reported that an
appropriate notice was given to the New Jersey Department of
Environmental Protection (NJDEP) under the conditions of a NJDEP-
issued permit. with regard to clean-up, CIBA-GEIGY reported that
the contamination was contained and cleaned up by the next day by
a contractor and arrangements were made by CIBA-GEIGY for "proper
disposal of all PCB wastes."
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
458
E~A "0'"" 11.. IREV. 3-111
-------
8EHQ-1188-0769
Page 2 of 2
with regard to required reporting of this PCB-related incident,
CIBA-GEIGY noted that the quanti ty of PCBs released was deter-
mined ultimately to be less than the ten (10) pound "Reportable
Quantity" (RQ) that would trigger a mandatory phone report to the
National Response Center (NRC) pursuant to Section 302 of CERCLA.
Further wi th regard to required reporting of this PCB release,
C IBA-GE IGY sta ted that in "in retrospect, . thi s incident
should not have been reported under TSCA Section 8(e) because:
"1.
The quantity [of PCBs] spilled
was minor;
"2.
The PCB release was promptly contained and
cleaned up;
"3.
There was no environmental release outside of
the plant. ....; [and]
"4.
Appropriate Federal, [New Jersey]
local authorities were notified."
State and
Finally, the CIBA-GEIGY Corporation re-emphasized the fact that
"the PCB transformer was not involved in the electrical fire."
Comments/Recommendations
Considering various criteria including but not limited to the
reported amount, pattern and extent of this PCB release, it is
EPA's initial opinion that this incident did not warrant formal
reporting to EPA as an "Emergency Incident of Environmental
Contamination" (EIEC) under Section 8 (e) of TSCA. It should be
noted, however, that EPA's opinion in this matter is based solely
on the summary information provided in writing by CIBA-GEIGY and
does not take into account any other information that may have
been con s i dered by CIBA-GEIGY on a prospect i ve basi s (e.g., as
this PCB-related incident was occurring) in deciding to report
the incident under Section 8(e) of TSCA. For further information
on the reporting of EIECs under TSCA Section 8(e), the reader's
attention is directed to Part V(c) of EPA's March 16, 1978 TSCA
Section 8 (e) policy statement ("Statement of Interpretation and
Enforcement policy; Notification of Substantial Risk" 43 FR
11110). In addition, it should be noted that Part VII of the
Section 8(e) policy statement explains that information need not
be submitted under Section 8(e) of TSCA if the information has
been reported to EPA pursuant to mandatorYJreporting requirements
under TSCA or any other authority that is administered by EPA
(e.g., CERCLA).
The Chemical Screening Branch will transmit copies of this status
report to NIOSH, OSHA, OSWER/EPA, OW/EPA, OAR/EPA, EPA Region II
and CRB/EEO/OTS/OPTS/EPA; copies of this status report will be
sent also to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
459
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
DEC 2 3 1988
Status Report* 8EHQ-1188-0770 S APproved:oU
James F. Darr, Section Head L1~~~~
Chemical Risk Identification~~;~ion/CSB
/z/VfJ/ir
.
SU8JECT:
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will review all incoming correspondence relating to the company's
substantiation of these CBI claims. In the "sanitized" version of
its Section 8 (e) notice, the company stated non-confidentially
that the subject chemical is a "heterocyclic acetal."
Submission Description
The submi tting company provided the following information about
the conduct and preliminary results of a "pilot" oral teratology
study of this heterocyclic acetal in rats:
"In this [teratological] study, the heterocyclic acetal
was administered by gavage to 6 groups of mated female
rats at dose levels of 0, 50, 150, 250, 500 and 1000
mg/kg/day during gestation days 6-15. Surviving darns
were sacrificed on gestation day 20. Fetuses were
removed, weighed, sexed and examined for possible
external malformations.
"The only maternal death in this study was a single
animal at 50 mg/kg/day. Substantial weight loss
occurred during gestation days 6-9 in darns at 1000 mg/
kg/day. Slight losses in weight during days 6-9 were
noted in darns from the 250 and 500 mg/kg/day groups. A
slight, but not statistically significant, increase in
post-implantation loss, and early resorptions and a
modera te decrease in fetal we ight were no ted at 1000
mg/kg/day. External malformations were noted in 1
fetus from the control and 250 mg/kg/day groups and in
2 fetuses from the 1000 mg/kg/day group."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
460
II~A '0"'" II" IltEv. 3-711
-------
8EHQ-1l88-0770 S
Page 2 of 3
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a full copy of
the final report from the oral "pilot" teratology study cited in
the submission. In the interim, it should be noted that the sub-
mitted summary information, which included several data tables,
does provide evidence for the maternal and developmental toxicity
of this heterocyclic acetal.
Only 1 maternal animal died prior to scheduled sacrifice; this
was in the 5~ mg/kg/day group. Two animals were non-gravid (1 in
the 5~ mg/kg/day group and 1 in the 15~ mg/kg/day group. Treat-
ment with the heterocyclic acetal had a substantial effect on the
maternal body weight gain. Over gestation days 6-9, animals in
the 3 highest dose groups (25~, 5~~ and l~~~ mg/kg/day groups)
lost weight. These changes were statistically significant (to
the p< ~. ~ 5 or 13. ~ 1 level). Reduced body weight ga in over the
entire gestation period, or just over the treatment period, was
statistically significant (p<~.~1) only at 1131313 mg/kg/day.
There were no clear treatment-related increases observed in the
frequencies of any specific or total external abnormalities. An
increased frequency of early resorption (3.2X controls) and an
increased frequency of post-implantation loss (3.8X controls) was
observed at 1~13~ mg/kg/day. The mean fetal weight for the 1~~~
mg/kg/day group was reduced from controls by ~.7 grams. Although
none of these changes were reported as statistically significant,
it is not clear from the submitted information that statistical
analyses were performed on the fetal data.
It should be noted that the lowest dose group (5~ mg/kg/day) does
appear to be anomalous. This particular dose group had fewer
viable fetuses/litter, fewer implantation sites and higher pre-
implantation loss than any of the other dose groups. Based on
the provided summary information, these deviations from control
values do not appear to be related to treatment.
In summary, maternal toxicity was clearly demonstrated after
treatment with the test article at doses of 2513, 5~13 and 1~~13
mg/kg/day. This maternal toxicity was evidenced by statistically
significant reductions in weight gain. Developmental toxicity at
a dose of l~~~ mg/kg/day was evidenced by increased resorption
and by fetal growth retardation. As expected for a typical
"pilot" teratology study, no examination appears to have been
performed for fetal soft tissue or skeletal abnormalities.
Current Production and Use
In view of the company's CBI claims, no information on the TSCA
Chemical Substance Inventory status or use(s) of the heterocyclic
acetal appears in this status report; the company did report non-
confidentially, however, that the chemical is "being manufactured
exclusively for R&D [(research and development)] purposes."
461
-------
8EHQ-1188-0770 S
Page 3 of 3
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submi tting
company to ensure that the Agency receives a full copy
of the final report (including the actual experimental
protocol, results of gross/histopathological examina-
tions, results of any statistical analyses, etc.) from
the "pilot" oral teratology study in rats cited in the
company's TSCA Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the actions the company has taken or
plans to take 1) to notify workers and others about the
reported information, and 2) to reduce or eliminate
exposure to this heterocyclic acetal. In addition, the
submitter will be asked to describe the nature and
results, if available, of all studies (other than those
reported already to the Agency or those cited in the
open scientific literature) about which the company is
aware or that the company has conducted, is conducting
or plans to conduct that are designed to determine the
toxicity of this heterocyclic acetal.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORO/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i s ta nce Off ice (TAO/OTS/OPTS/EPA) for
further distribution.
462
-------
UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
DEC 2 3 1988
SU8JECT:
Status Report* 8EHQ-1188-0771 S APproved:~
James F. Darr, Section Head Ll~o~ ~~
Chemical Risk Identificatio~:~~ion/CSB
lz(tbP
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
The submitting company has claimed its company name and the exact
identity of the subject chemical to be TSCA Confidential Business
Information (CBI); the Information Management Division (IMD/OTS)
will be reviewing all incoming correspondence pertaining to the
company's substantiation of these CBI claims. In the "sanitized"
version of its Section 8 (e) submission, the company stated non-
confidentially that this chemical is an "alkyl aryl ether."
Submission Description
The submitting company provided the following information with
regard to the conduct and preliminary results of a "pilot" oral
teratology study of this alkyl aryl ether in rats:
"In this [teratology] study, the alkyl aryl ether was
administered by gavage to 6 groups of mated female rats
at dose levels of 0, 50, 125, 250, 500 and 1000 mg/kg/
day during gestation days 6-15. Surviving dams were
sacr i f iced on gestat ion day 20 . . . [and the] fetuses
were removed, weighed, sexed and examined for possible
external malformations.
,
"Two of the eighf animals at 1000 mg/kg/day died during
the study. Substantial reductions in maternal weight
g a i n were ev i dent at 250 mg/kg/day. Maternal weight
gain appeared to be slightly reduced at 125 mg/kg/day
as well. No viable fetuses were produced at 500 or 1000
mg/kg/day. Substantially increased post-implantation
loss was also evident at 125 and 250 mg/kg/day. Mean
fetal weight was also decreased at these latter 2 dose
levels. A single fetus at 125 mg/kg/day exhibited
several external malformations. However, this fetus was
extremely light and came from a mother which exhibited
substantially decreased weight gain."
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e). the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
463
.~" 1'0"" "'" uu:v. 1-711
-------
8EHQ-1188-0771 S
Page 2 of 3
Submission Evaluation
An EPA evaluation of the overall significance of the reported
findings should be possible upon EPA's receipt of a complete copy
of the final report from the oral "pilot" teratology study cited
in the company's submission. In the interim, however, it should
be noted that the submitted summary information, which included a
number of data tables, does provide evidence for the maternal and
developmental toxicity of this alkyl aryl ether.
Two maternal animals died in the highest dose group (1000 mg/kg/
day) be fore scheduled necropsy. One of these animals was non-
gravid. Two animals at 250 mg/kg/day and 1 each at 125 and 500
mg/kg/day were non-gravid as well. Statistically significant
(p<0.01) decrements in weight gain over the entire gestation
period were observed in the 250, 500 and 1000 mg/kg/day dose
groups. A trend for decreasing weight gain with increasing dose
could be identified even at the 2 lower dose groups (50 and 125
mg/kg/day).
There was a clear and striking reduction in fetal viability with
increasing dose. The control litters averaged 14.4 fetuses, the
50 mg/kg/day litters averaged 14.0 fetuses, the 125 mg/kg/day
litters averaged 10.0 fetuses, the 250 mg/kg/day litters averaged
4.2 fetuses and there were no fetuses in either the 500 or 1000
mg/kg/day dose groups. There were no la te resorpt ions in any
dose group, hence all post-implantation loss was due to early
resorption. The frequency of post- implantati on loss increased
with increasing dose; a dose-dependent trend was evident even at
the lowest dose (50 mg/kg/day). The frequencies of implantation
sites, corpora lutea and pre-implantation loss did not appear to
have been affected by treatment with the test article. The mean
fetal weights were reduced from control values by about 1 gram
for the 125 and 250 mg/kg/day dose groups. It should be noted
that it is not clear from the submitted information that any
statistical analyses were performed on the fetal data. Only 1
fetus (from the 125 mg/kg/day dose group) was reported to have
external malformations.
In summary, clear evidence of maternal toxicity was provided by
statistically significant decreases in gestational weight gain at
the 3 highest dose levels (250, 500 and 1000 mg/kg/day). The
dose-dependent trend for decreased weight gain was evident for
the 2 lowest dose levels (50 and 135 mg/kg/day). Developmental
tox ic i ty was seen at all dose levels, i ncl uding the lowest dose
level (50 mg/kg/day). Developmental toxicity was evidenced by
increased fetal tox ic i ty and by feta 1 growth reta rda t i on. As
expected for a typical "pilot" teratology study, no examination
appears to have been performed for fetal soft tissue or skeletal
abnormalities.
464
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"b)
8EHQ-1188-0771 S
Page 3 of 3
Current production and Use
In view of the submitter's TSCA CBI claims, no information about
the TSCA Chemical Substance Inventory status or use (s) of this
alkyl aryl ether will appear in this status report. The company
did report non-confidentially, however, that the subject chemical
"is currently being manufactured exclusively for R&D [(research
and development)] purposes."
Comments/Recommendations
a)
The Chemical Screening Branch will ask the submitting
company to ensure that the Agency receives a full copy
of the final report (including the actual experimental
protocol, results of gross/histopathological examina-
tions, results of any statistical analyses, etc.) from
the "pilot" oral teratology study in rats cited in the
company's TSCA Section 8(e) submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, the submitter will be
asked to describe the actions the company has taken or
plans to take 1) to notify workers and others about the
reported information, and 2) to reduce or eliminate
exposure to this alkyl aryl ether. In add i t i on, the
submitter will be asked to describe the nature and
results, if available, of all studies (other than those
reported already to the Agency or those cited in the
open scientific literature) about which the company is
aware or that the company has conducted, is conducting
or plans to conduct that are designed to determine the
toxicity of this alkyl aryl ether.
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch wi 11 transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
465
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 4
OATE:
JAN - 4 1989
SUBJECT:
status Report* 8EHQ-1188-0772 Approved:
James F. Darr, Section Head f1/W1h r ~
Chemical Risk Identificatio~~ec~ion/CSB
[)JJl l/tf/?1
, r
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Hoechst Celanese Corporation provided the following summary
information regarding the conduct and preliminary results of a
mortality study of workers at the company's Celriver cellulose
triacetate (CAS No. 9012-09-3) fiber production plant located in
Rock Hill, South Carolina:
"A cohort of 1,271 employees who worked in the prepara-
tion and/or extrusion departments for at least three
months between January 1, 1954 and June 1, 1977 was
followed through September 1, 1986. Four deaths due to
cancer of the liver and biliary passages were reported.
Less than one (0.69) was expected. The standardized
mortality ratio [(SMR)] was 5.8 with a 95% Confidence
Interval [(CI)] of 1.8 to 14. All [of] the deaths from
liver or biliary tract cancer occurred among people
with greater than 10 years employment who died at least
20 years after they were hired. The observed deaths
for all causes were 123, with 121 expected, and deaths
for all malignant neoplasms were 28, with 33 expected.
"The current preliminary status of this [mortality]
study is typical of cohort studies with small popula-
tions which are still relatively early in a potential
latency period. The diagnoses from the death certifi-
cates require verification before final conclusions can
be drawn and a final report issued. Followup of the
cohort will be continued."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
466
E~" FORM II" (REV, ),711
-------
8EHQ-1l88-0772
Page 2 of 4
In its submission, Hoechst Celanese reported that this study "is
an extension of . . . [an] earlier study of workers at the.
[cellulose] triacetate plant (Ott et al., Scandinavian Journal of
Work Environment and Health, 1983)." Hoechst Celanese stated
also that methylene chloride (CAS No. 75-09-2) exposure had been
the "motivating factor" for this earlier study. Finally: Hoechst
Celanese stated that the [cellulose] triacetate fiber production
process at the company's Rock Hi 11, South Carol i na faci 1 i ty was
"shut down in 1986."
Submission Evaluation
The present Section 8 (e) notice pertains to a followup of an
or ig inal cohort of 1,271 workers exposed to methylene chlor ide;
the results of this initial study were published by Ott et ale in
1983. The or ig ina1 study cons i sted of all workers employed for
longer than 3 months in the cellulose triacetate production and
extrusion areas of the Rock Hill, South Carolina plant where
there was exposure to methylene chloride as well as acetone. The
"exposed" group was compared to a "referent" group of workers at
another fiber production plant where there was exposure only to
acetone (CAS No. 67-64-1). The findings from this original cohort
study were statistically significant risks for "all causes" of
mortal i ty, di seases of the ci rcu1a tory system and all "external
causes" for white males among the exposed group. No differences
in risk were detected among white females and there was no
elevation overall in cancer deaths.
The present Section 8(e) submission adds 10 years of fo110wup to
the or i g i nal cohort and reports excess 1 i ver and bi 1 i ary tract
cancer deaths among the exposed cohort. No other individual
causes of death were ci ted, and the overall mortali ty and total
cancer deaths were reported to be not statistically elevated.
The original (1983) cohort study had a number of problems that
should be considered when evaluating the conclusions of that
earlier study as well as the results reported in the present TSCA
Section 8(e) submission. The original study had a maximum of 22
years of followup; however, 55% of the exposed group left employ-
ment between 1954 and 1977 (the original study dates were from
January 1, 1954 to June 1, 1977), and the vital status could not
be ascertained on 18% of this group. The referent group (i.e.,
those worker s exposed to acetone only) had 29% of its workers
leave employment between 1954 and 1977 and 12% were lost for
fur ther fo 11 owup. Al though the present study adds another 10
years of followup, the submitted summary does not present any
additional information on the vital status ascertainment for the
exposed or referent groups.
A number of differences exist between the exposed and referent
populations. The sex and race distributions between the two
groups were different in that the exposed cohort had more women
(57% versus 26% in the referent group) and more non-wh i tes (13%
versus <1% in the referent group). The referent group had more
467
-------
8EHQ-1188-0772
Page 3 of 4
white males (73% versus 38% in the exposed group). In the
or ig i nal study, non-wh i te females were not analyzed because no
deaths occurred among the 108 non-white females (105 exposed, 5
referent). In addition, the white males in the referent group
were younger than those in the exposed group. Also, there are
geographic differences between the exposed and referent plant
sites; the referent plant site is located in a mountainous, rural
area while the exposed plant site is in a flat, urban area.
Although the primary focus of the first study was cardiovascular
disease deaths, total mortality, cancer deaths and deaths from
external causes were also reviewed. Overall, the general mor-
tality of the exposed and referent groups was similar to the
mortality experience of the general U.S. population; however,
excess deaths due to external causes were observed in each sex-
race group for both the exposed and referent cohorts. None of
these excess deaths appeared to be related to methylene chloride
or acetone exposures. Further, there were only 7 cancer deaths
each in the exposed and referent groups; this number of cancer
deaths is similar to the expected values although the white males
in the referent group had much lower observed cancer dea ths (5
versus 10 expected).
In the followup cohort study, which is the subject of the present
TSCA Section 8(e) submission and encompasses the time period from
June 1977 to September 1, 1986, overall mortality was found to be
similar to the general U.S. population (Standard Mortality Ratio
(SMR) =102) and total deaths from all malignant neoplasms was 28
with 33 expected. Of interest is the fact that the "healthy
worker effect" does not seem to be operating in the exposed
cohort. It should be noted that it is not unusual to find SMR
values in the 80's for a group of workers; such values reflect a
healthier population than the general U.S. population.
In the present submission, there were 4 deaths due to cancer of
the 1 i ver and bi 1 i ary passages reported for the worker sin the
exposed cohort. This number of deaths is significantly different
than 0.69, the expected number of deaths for this cause (p<0.~5;
95% Conf idence Interval (CI) of 1. 8 to 14). The submi t ter notes
that all deaths occurred in people who worked for more than 10
years at the exposed plant and who died at least 20 years after
they were hired. All of these liver and biliary cancer deaths
occurred in the post-1977 10-year followup period.
The submitter did not specify sex or race differences in cancer
mortality and no information was given on cancer deaths in the
referent group. Further, the submitter did not provide any
information about followup ascertainment or enumerate other types
of malignant neoplasms found. Also, considering that the original
study classified chemical exposure in areas within the plants as
being low, intermediate or high, it would be of interest to know
the exposures that were associated with the workers who died of
liver and biliary tract cancer despite the fact that the low
number of deaths precludes intensive analysis.
468
-------
8EHQ-1l88-0772
Page 4 of 4
It is difficult to evaluate the meaning of the reported excess
deaths without more information on the followup status, the
experience of the referent group and the sex-race distributibn of
the liver and biliary tract cancer deaths.
Comments/Recommendations
Considering the potential impact of the reported findings on
previous and ongoing Agency assessments of methylene chloride as
well as natural and man-made fibers, the Chemical Screening
Branch immediately sent full copies of the incoming Section 8(e)
submissio~ to the Test Rules Development Branch (TRDB/ECAD/OTS),
Risk Analysis Branch (RAB/ECAD/OTS), Health and Environmental
Review Division (HERD/OTS), Chemical Control Division (CCD/OTS),
Exposure Evaluation Division (EED/OTS) and Carcinogen Assessment
Group (CAG/ORD). Further, the reader's attention is directed to
the "Health Assessment Document for Dichloromethane (Methylene
Chloride) - Final Report" published in March 1985 by EPA's Office
of Health and Environmental Assessment (OHEA/ORD). It should be
noted also that under Section 110 of the Superfund Amendments and
Reauthorization Act (SARA), the Agency for Toxic Substances and
Disease Registry (ATSDR), in collaboration with EPA, is in the
process of preparing "Toxicological Profiles" on a number of
chemical substances, including methylene chloride. Information
on the public availability of SARA 110 chemical profiles can be
obtained from: Office of External Affairs, Chamblee 28 South,
1600 Clifton Road, Atlanta, Georgia 30333.
a)
The Chemical Screening Branch will ask Hoechst Celanese
to ensure that EPA recei ves a full copy of the f i na 1
report (including protocols, data, all statistical
analyses, etc.) from the company's ongoing followup
study. In addition, the company will be asked to keep
EPA apprised of any further significant findings from
that ongoing followup study.
b)
staff of the Chemical Screening Branch will review and
distribute the reported information to appropriate EPA
offices and other agencies.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH; OSHA; CPSC; FDA; NTP; ATSDR;
OW/EPA; OSWER/EPA; OAR/EPA; ORD/EPA; OPP/OPTS/EPA;
CCD, HERD and EED/OTS; RAB and TRDB/ECAD/OTS; copies of
th i s repor t wi 11 be sent also to the TSCA Ass i stance
Office (TAO/OTS) for further distribution.
469
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
DEC I 9 1988
SU8JECT:
Sta tus Report* 8EHQ-12 8 8-077 3 Approved:
James F. Darr, Section Head L -;-: ~
Chemical Risk Identificatiob7~ection/CSB
311ft- i~j;o/ ~
I
FRO..:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Amoco Oil Company provided the following summary
with regard to the conduct and preliminary results
designed to determine the tumor promotion potential
Resid Hydroprocessing Unit (RHU) Middle Distillate:
information
of a study
in mice for
"Groups of 30 male mice received a single dermal appli-
cat ion of ei ther 50 ul acetone or 50 ul of a 1 mg/ml
(w/v) solution of 9,10-dimethyl-l,2-benzanthracene
(DMBA) in acetone. The initiated mice were rested for
two weeks and then treated via dermal application twice
weekly for 25 weeks with 50 ul of [the] undiluted Resid
Hydroprocessing Unit (RHU) Middle Distillate. A third
group [of mice], initiated with DMBA, received sham
promotion treatment (i.e., identical treatment but
without any test article). All study groups were
terminated after 28 weeks on test. All [of the] mice
underwent gross necropsy, and the application site skin
and associated masses were collected, fixed, stained,
and examined microscopically.
"These studies indicate that RHU Middle Distillate
possessed tumor promotion potential. Tumor incidence
of RHU Middle Distillate was significantly increased in
the DMBA-initiated/test article-promoted group (8/313)
compared to the acetone-initiated controls (0/313) and
DMBA-initiated sham controls (13/30). The tumors were
squamous cell papillomas and one keratoacanthoma.
Tumor latencies were also significantly shortened in
the DMBA-initiated/test article-promoted group. ...
[Amoco interprets] these results to indicate that RHU
Middle Distillate has the potential to promote skin
tumors."
====================================================================~===============
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should ta~e into account
the fact that the report may be based on incomplete information.
470
E~A "OMI II" tREV. 1-711
-------
8EHQ-1288-0773
Page 2 of 3
Submission Evaluation
Although Amoco interprets the reported positive findings to mean
that RHU Middle Distillate is a tumor promoter, this type of
study alone is insufficient to determine if RHU Middle Distillate
is only promoting the DMBA-initiated cells or if RHU Middle
Distillate itself is initiating. Further, despite the fact that
only benign tumors were reportedly found, the length of the study
may have been too short (Le., 28 weeks) to allow the detection
of malignant tumors; it is also possible that the dosage employed
was too low. Amoco should be asked to ensure that EPA receives
a full copy of the final report from this study. In addition, it
would be of interest to know if Amoco is conducting or plans to
conduct a study in which RHU Middle Distillate serves as the
potential initiator.
Current Production and Use
Amoco reported non-confidentially by phone that the CAS Registry
Number for the company's RHU Middle Distillate is 64741-76-0.
Appendix A of the first printed edition of the Agency's initial
TSCA Chemical Substance Inventory reports that CAS No. 64741-76-0
refers to heavy hydrocracked petroleum distillates and identifies
this material as follows:
"A complex combination of hydrocarbons from the distil-
lation of the products from a hydrocracking process. It
consists predominantly of saturated hydrocarbons having
carbon numbers in the range of C15 through C25, and
bo i 1 i ng in the range of approximately 2600C to 4000C
(5000F to 7520F)."
Although the "[CAS] REGISTRY NUMBER UPDATE" section of Volume I
of the 1985 Edi t ion of the pr inted TSCA Inventory repor ts tha t
CAS No. 64741-76-0 is no longer listed in the TSCA Inventory,
staff of the Information Management Division (IMD/OTS) stated
that 1) the deletion of CAS No. 64741-76-0 was inadvertent, and
2) CAS No. 64741-76-0 is still in the TSCA Inventory.
A review of the production range (includes importation volumes)
statistics for CAS No. 64741-76-0, which is listed in the initial
TSCA Chemical Substance Inventory, showed that over 1 billion
pounds were reported as manufactured and/or imported in 1977.
This production range information does not include any data
claimed as TSCA Confidential Business Information (TSCA CBI) by
the person(s) reporting for the initial TSCA Inventory, nor does
it include any information that would compromise TSCA CEL All
of the information reported for the initial TSCA Inventory,
including the production range information, is subject to the
limitations contained in the initial TSCA Inventory Reporting
Regulations (40 CFR 710).
471
-------
8EHQ~1288~0773
Page 3 of 3
Amoco did not submi t any information wi th regard to the current
production or use(s) of the tested material nor was such informa-
tion located in the secondary literature sources searched by EPA.
Comments/Recommendations
In its submission, Amoco reported that
Material Safety Data Sheet (MSDS) and
revi sed to reflect the results of the
study.
the RHU Middle Distillate
product label are being
company's tumor promotion
EPA's Office of Toxic Substances has received and evaluated many
TSCA Section 8(e) and "For Your Information" (FYI) submissions
containing toxicologic and/or exposure information on a wide
variety of coal-, shale- and petroleum-derived oil products,
process streams, and/or waste materials.
a)
The Chemical Screening Branch will request Amoco to
ensure that EPA receives a full copy of the final
report (including the actual experimental protocol,
results of gross and histopathological examinations,
results of statistical analyses, etc.) from the tumor
promotion study cited in the submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Amoco will be asked
to describe the nature and results, if available, of
all studies (other than those reported already to EPA
or those cited in the open scientific literature) about
which Amoco is aware or that the company has conducted,
is conducting or plans to conduct that are designed to
determine the toxicity (especially the tumor initiation
potential) of or the exposure to RHU Middle Distillate.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of RHU Middle Distillate.
c)
The Chemical Screeni ng Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
472
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
Page 1 of 3
DATE:
DEC 2 I 1988
SU8JECT:
Status Report* 8EHQ-1288-0774 Approved:
James F.Darr, Section Head ~ ~ ~
Chemical Risk Identificatio(!section/CSB
0Jk- /Z)Mjrr
!'ROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Amoco Oil Company provided the following summary information
with regard to the conduct and preliminary results of a study
designed to determine the tumor initiation potential in mice for
Resid Hydroprocessing Unit (RHU) Light Vacuum Gas oil:
"Groups of 30 male mice were treated dermally once a
day [(number of days not specified)] with 50 ul of
Resid Hydroprocessing Unit (RHU) Light Vacuum Gas Oil.
The exposed mice, along with 60 sham control mice, were
rested for two weeks and then dosed twice weekly for 25
weeks wi th 50 ul (0.1 mg/ml) of phorbol-12-myr i sta te-
13-acetate (PMA) in acetone as a promoter. All study
groups were terminated after 28 weeks on test. All
mice underwent gross necropsy, and the application site
skin and associated masses were collected, fixed,
stained, and examined microscopically.
"These studies indicate that RHU Light Vacuum Gas oi 1
possessed initiation tumorigenic potential. Tumor
incidence of RHU Light Vacuum-Gas Oil (21/30) was sig-
nificantly increased compared to sham controls (8/60),
and tumor latepcy (17.4 weeks) was significantly
different from sham controls (23.1 weeks). All [of
the] induced tumors were squamous cell papillomas or
keratoacanthomas. [Amoco interprets] these
results to indicate that RHU Light Vacuum Gas Oil has
the potential to initiate skin tumors."
Submission Evaluation
Based on the provided summary information, RHU Light Vacuum Gas
Oil appears to be a very active tumor initiator (21/30 animals
with skin tumors observed within a very short time period (17.5
====================================================================================
* NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
473
E~" "OM! """ IREV. 1-711
-------
8EHQ-1288-0774
Page 2 of 3
weeks» . Although all of the tumors found were reported to be
benign, one needs to consider the short duration of and the low
dose of material used in this study. Amoco should be asked to
ensure that EPA receives a complete copy of the final report from
the company's tumor initiation study of RHU Light Vacuum Gas Oil.
Current production and Use
Amoco reported non-confidentially by phone that the CAS Registry
Number for the company's RHU Light Vacuum Gas Oil is 64741-75-9.
Appendix A of the printed 1985 Edition of EPA's initial TSCA
Chemical Substance Inventory reports that CAS No. 64741-75-9
refers to hydrocracked petroleum residues and identifies this
material as follows:
"A complex combination of hydrocarbons produced as the
residual fraction from distillation of the products of
a hydr oc rack i ng pr ocess. It consi sts of hydrocarbons
having carbon numbers predominantly greater than C20
and boiling above approximately 3500C (6620F)."
A review of the production range (includes importation volumes)
statistics for CAS No. 64741-75-9, which is listed in the initial
TSCA Chemical Substance Inventory, has shown that over 1 billion
pounds were reported as manufactured and/or imported in 1977.
This production range information does not include any informa-
tion claimed as TSCA Confidential Business Information (TSCA CBI)
by the person(s) reporting for the initial TSCA Inventory, nor
does it include any information that would compromise TSCA CBI.
All data reported for the initial TSCA Inventory, including the
production range data, are subject to the limitations contained
in the initial TSCA Inventory Reporting Regulations (40 CFR 710).
Amoco did not submi t any information wi th regard to the current
production or use(s) of RHU Light Vacuum Gas oil nor was such
information located in the secondary literature sources searched
by EPA.
Comments/Recommendations
The Amoco Oil Company stated that the RHU Light Vacuum Gas Oil
Material Safety Data Sheet (MSDS) and label are being revised to
reflect the findings from the company's tumor initiation study.
EPA's Office of Toxic Substances has received and evaluated a
number of TSCA Section 8 (e) and "For Your Information" (FYI)
submissions containing toxicologic and/or exposure information on
coal-, shale- and petroleum-derived oil products, process streams
and/or waste materials.
a)
The Chemical Screening Branch will request Amoco to
ensure that EPA receives a full copy of the final
report (including the actual experimental protocol,
474
-------
8EHQ-1288-0774
Page 3 of 3
results of gross and histopathological examinations,
results of any statistical analyses, etc.) from the
tumor initiation study of RHU Light Vacuum Gas Oil
cited in the submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Amoco will be asked
to describe the nature and results, if available, of
all studies (other than those reported already to EPA
or those cited in the open scientific literature) about
which Amoco is aware or that the company has conducted,
is conducting or plans to conduct that are designed to
determine the toxicity of or the exposure to RHU Light
Vacuum Gas Oil.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of RHU Light Vacuum Gas Oil.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Assistance Office (TAO/OTS/OPTS/EPA) for
further distribution.
475
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE:
JAN 2 3 1989
Page 1 of 4
SUBJECT:
Status Report* 8EHQ-1288-0775 Approved:
James F. Darr, Section Head ~r-k
Chemical Risk Identificatio6fsection/CSB
rJfJIt t/~7/~
FRO..:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Amoco Oil Company provided the following summary information
regarding the conduct and preliminary results of a chronic mouse
skin application study of Amoco NT-45 Process Oil, a hydrotreated
middle distillate (CAS No. 64742-46-7):
"Two groups of 50 male mice were used in the study.
One group was treated dermally twice weekly for 104
weeks wi th 50 microli ters of undiluted test material.
The second group of 50 mice served as sham controls,
and were treated the same as the test-article group
except that no material was applied to the skin. All
mice underwent gross necropsy, and the application site
sk in and other organs were collected, fixed, sta ined ,
and examined microscopically.
"preliminary histopathological examination indicates
tha t five mi ce in the test-art icle treated group had
histologically confirmed tumors. Four of those mice
had squamous cell carcinomas, one mouse had a squamous
cell papi lloma, and one of the mice wi th a carc i noma
also had a keratoacanthoma. The mean latency period
was 97.7 weeks. Tissues from the sham control group
have not yet been processed histologically, so tumor
information on this group is incomplete. This study
indicates that the test material possessed weak
tumorigenic potential. ....
.. [Amoco interprets] these resul ts to indicate
that this hydrotreated distillate has the potential to
induce skin tumors following lifetime exposure."
In its submission, Amoco also reported that "previous studies
have shown that the test material is not a tumor initiator, but
that it does possess weak tumor promoting activity."
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
476
I!~A "0- 1J211~' (REV. 1-711
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8EHQ-1288-0775
Page 2 of 4
It should be noted that in a previously received supplemental
TSCA Section 8(e) submission (8EHQ-1087-06!34 Supplement), the
Amoco Corporation provided a full copy of the final report from a
CD-l mouse tumor initiation study of a number of Amoco products
including Amoco NT-45 Process Oil. The "SUMMARY" section of that
final report presents the following information with regard to
the conduct and results of the initiation study:
"Dermal tumorigenicity bioassays were conducted to
assess the initiation potential of Amoco NT-45 Process
O~l . .. Groups of 313 male [CD-l] mice were topically
dosed once a day for 5 days with 513 ul of the undiluted
test article. The initiated mice, along with 613 sham
con tro 1 mi ce, were rested for 2 weeks and then dosed
twice weekly for 25 weeks wi th 513 ul (13.1 mgjml) 0 f
phorbol-12-myristate-13-acetate (PMA) in acetone as a
promoter. ....
"No significant differences in tumor incidence were
detected between [the] groups treated with Amoco NT-45
Process oil. . . and the sham controls."
The reader's attention is directed also to the status report that
was prepared by EPA in response to another previously received
TSCA Section 8(e) submission (8EHQ-028!3-0333). In this previous
Section 8(e) submission, the Kerr-McGee Corporation reported that
Kermac 6!30W (also CAS No. 64742-46-7) was found to be mutagenic
in an Ames Salmonella typhimurium (bacteria) assay.
Submission Evaluation
An EPA evaluation of the overall significance of the reported
oncogenicity findings should be possible upon EPA's receipt of
full copies of the final reports from the chronic mouse skin
application study and the previously conducted tumor promotion
study cited in the present Amoco submission; EPA's evaluation
will also include the Amoco NT-45 Process Oil tumor initiation
study and Kermac 6!3!3W Ames test submitted previously to EPA.
Current Production and Use
Appendix A of the printed 1985 Edition of EPA's initial TSCA
Chemical Substance Inventory reports that CAS No. 64742-46-7
refers to "hydrotreated middle distillates (petroleum)" and
identifies this material as follows:
"A complex combination of hydrocarbons obtained by
treating a petroleum fraction with hydrogen in the
presence of a catalyst. It consists of hydrocarbons
having carbon numbers predominantly in the range of Cll
through C25 and boiling in the range of approximately
205°C to 4000c (40l~ to 752°F) ."
477
-------
8EHQ-1288-0775
Page 3 of 4
A review of the production range (includes importation volumes)
statistics for CAS No. 64742-46-7, which is listed in the initial
TSCA Chemical Substance Inventory, has shown that over 1 billion
pounds were reported as manufactured and/or imported in 1977.
This production range information does not include any informa-
tion claimed as TSCA Confidential Business Information (TSCA CBI)
by the person(s) reporting for the initial TSCA Inventory, nor
does it include any information that would compromise TSCA CBI.
All data reported for the initial TSCA Inventory, including the
production range data, are subject to the 1 imi tations contained
in the initial TSCA Inventory Reporting Regulations (4@ CFR 7l@).
In the present TSCA Section 8(e) submission, Amoco reported that
Amoco NT-45 proces s 0 i 1 is "sold as a highly pur i f ied mineral
seal oil." It should be noted also that in a previous TSCA
Section 8(e) notice (8EHQ-@28@-@333), the Kerr-McGee Corporation
reported that one of its customers may have used Kerr-McGee's
mineral seal oil product (Kermac 6@@W; CAS No. 64742-46-7) in the
formulation of printing inks. Kerr-McGee also stated, however,
that the company no longer produced or sold Kermac 6@@W and had
replaced the Kermac 6@@W with Kermac 6@@ (CAS No. 64741-44-2).
According to Kerr-McGee, Kermac 6@@ is similar to Kermac 6@@W in
composition, constituents and physical characteristics and is the
petroleum feed-stock from which the Kermac 6@@W was produced via
hydrotreating.
Comments/Recommendations
In the present Section 8 (e) notice, Amoco stated that although
the current Amoco NT-45 Process Oil Material Safety Data Sheet
(MSDS) already contains a warning about possible tumorigenic
effects, Amoco is revising that MSDS to reflect the findings from
the company's new chronic mouse skin application study.
EPA's Office of Toxic Substances has received and evaluated a
number of .TSCA Section 8 (e) and "For Your Information" (FYI)
submissions containing toxicologic and/or exposure information on
coal-, shale- and petroleum-derived oil products, process streams
and/or waste materials.
a)
The Chemical Screening Branch will ask Amoco to ensure
that EPA receives complete copies of the final reports
(including the actual experimental protocols, results
of gross and histopathological examinations, results of
any statistical analyses, etc.) from the chronic mouse
skin application study and the previously conducted
tumor promotion study cited in the submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Amoco will be asked
to describe the nature and results, if available, of
all studies (other than those reported already to EPA
478
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8EHQ-1288-0775
Page 4 of 4
or those cited in the open scientific literature) about
which Amoco is aware or that Amoco has conducted, is
conducting or plans to conduct that are designed to
determi ne the tox ic i ty 0 f or the expo su re to hyd r 0-
treated middle distillate.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of hydrotreated middle distillate.
c)
The Chemical Screening Branch wi 11 transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWERjEPA, OWjEPA, OARjEPA, ORDjEPA and OPPjOPTSjEPA.
In addition, copies of this status report will be sent
to the TSCA Ass i s ta nce Off ice (TAOjOTSjOPTSj EPA) for
further distribution.
479
-------
UNITED STATES ENV'IRONMENTAL PROTECTION AGENCY
OA TE:
JAN 2 4 1989
Page 1 of 4
SU8JECT:
Status Report*
Approved:
Darr, Section HeadLT~
Risk Identificati~'section/CSB
8EHQ-1288-~776
(Pk.
;Pl fi~j
.
FROM:
James F.
Chemical
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Note
In its TSCA Sect ion 8 (e) submi ss ion, the Amer ican Telephone and
Telegraph Company (AT&T) reported that the subject chemical sub-
stance is Bordon Chemical Compound 9MKUl~l~8R, an "acrylate
coating compound." AT&T also reported, however, that AT&T "is
not at liberty to disclose the formulation."
Submission Description
AT&T submitted a full copy of a draft final report from a mouse
Micronucleus Test (MNT) of the acrylate coating compound (test
material 22~). The "SUMMARY" of the provided report presents the
following information with regard to the conduct and results of
this study and a preliminary study:
"In a preliminary Dose-Range-Finding Study, test
material 22~ was administered intraperitoneally to 6
g r 0 ups 0 f CD -1 m ice at do s e level s 0 f 5 ~ ~ , 1 ~ ~ ~ , 1 7 5 0 ,
25~~, 3100 and 3700 mg/kg of body weight prior to
dosing. Due to mortali ty at 3700 mg/kg and pharmaco-
toxic signs observed in the study and in discussion
wi th the sponsor [(AT&T)], 3100 mg/kg was selected as
the high dose for the MNT.
"In the MNT, three groups of mice were given single
doses of test material 220 by intraperitoneal injection
at 3100 mg/kg and sacrificed at 24, 48 or 72 hours post
dosing. Two additional groups of mice were administered
310 and 1500 mg/kg and sacrificed 24 hours later. Three
groups of mice [that were] administered the vehicle
control, dimethylsulfoxide/corn oil (DMSO/CO), were
evaluated concurrently at each sacrifice interval. An
------------------------------------------------------------------------------------
------------------------------------------------------------------------------------
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting orovision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
I:~A "0- 11.6 (RIEV. 3-76'
480
-------
8EHQ-1288-0776
Page 2 of 4
additional group of mice was administered triethylene-
melamine (TEM) at a dose of 0.5 mg/kg and sacrificed at
24 hours, serving as the positive control. Slides were
[then] prepared from the bone marrow of the femurs and
s ta i ned . Coded sl ides were scored for the number of
polychromatic erythrocytes (PC E) with micronuclei in
1000 PCE/animal. The ratio of polychromatic to normo-
chromatic erythrocytes (NCE) per 1000 erythrocytes was
determined for each animal.
IIStatistical analyses of the data indicated a
significant increase in the number of micronucleated
PCEs in the 3100 mg/kg dose group (24 hour sacrifice
time) versus the vehicle control group. Statistically
significant depression in PCE/NCE ratios were noted at
doses of 310 mg/kg and 1500 mg/kg at 24 hour sacrifice
time and also [at] 3100 mg/kg at the 48 hour sacrifice
time, as compared to their respective controls.
IIIn conclusion, test material 220 is deemed positive at
[the] 3100 mg/kg dose level of the 24 hour sacrifice
time under the experimental conditions of this [mouse
MNT] protocol. II
I nth e co v e r 1 e t t e r to its T S CAS e c t ion 8 (e) s u bm i s s ion, AT & T
presented the following information with regard to the company's
interpretation of the reported genotoxicity findings:
liThe study revealed a statistically significant
positive response in the [mouse] micronucleus test
conducted at the highest dose level of the [acrylate]
compound administered (3100 mg/kg). The conclusion
reached as a result of these findings is that the
compound is a weak inducer of micronucleated poly-
chromatic erythrocytes, which in the context of the
full test results is only suggestive that the compound
may exhibit clastogenic activity. While statistically
significant reductions in the ratio of polychromatic
to normochromatic erythrocytes were observed in the 24
hour test animals exposed to the test compound at
levels of 310 mg/kg and 1500 mg/kg, and in the 48 hour
test animals exposed to the test material at 3100 mg/
kg AT&T notes that an Ames/Salmonella plate incorpora-
tion assay for the same material was negative.1I
In the cover letter to its submi ss ion, A T& Tal so pr ov i ded the
following summary information regarding pharmacotoxic signs that
were observed in the dose-range-finding study as well as the
actual mouse micronucleus assay:
II. Animals were observed immediately and at 24,
48 and 72 hours after administration [of the acrylate
coat i ng compound] for signs of mortal i ty and pharmaco-
toxic signs. [The] control group animals recei ved an
481
-------
8EHQ-1288-0776
Page 3 of 4
i ntr aper i tonea 1 [in j ecti on] dose of DMSO/Corn Oi 1 at a
volume of 10 ml/kg body weight. [The] pharmacotoxic
signs reported for the vehicle control group were that
most animals exhibited writhing immediately following
dosing. Twenty-four hours after dosing, several
animals exhibited decreased body tone. Abnormal gait
was also recorded for one male mouse at this time. At
48 and 72 hours post dosing, several male and female
mice in the vehicle control group were noted to have
decreased body tone. All [0 f] these find i ngs are con-
sistent with pharmacotoxic findings reported in the
literature for exposure to Dimethyl Sulfoxide, DMSO.
Most animals dosed with the test compound not only
exhibited similar pharmacotoxic signs to those observed
in the vehicle control group but also exhibited addi-
tional signs including piloerection, decreased activity
and abnormal stance. A few of the animals dosed wi th
the acrylate [coating] compound were also reported to
have exhibited pharmacotoxic signs of ptosis. While
these findings may be considered to be indicative of
the compound presenting some neurotoxic effects, based
upon the neurotoxic signs observed for the vehicle
control group, it is difficult to effectively assess
the true neurotoxicity of this substance."
Submission Evaluation
In this MNT study, a statistically significant increase in the
micronucleated PCEs was detected at the 24-hour high dose (3100
mg/kg; 0.01
-------
8EHQ-1288-0776
Page 4 of 4
a)
The Chemical Screening Branch will request AT&T to
submi t a full copy of the final report (i ncl ud i ng the
actual experimental protocols, results of gross and
histopathological examinations, results of statistical
analyses, etc.) from the dose-range-finding study cited
in the company's submission. In addition, AT&T will be
asked to submit a full copy of the Ames test cited also
in the company's submission.
The Chemical Screening Branch will request the Bordon
Chemical Company to report the exact chemical identity
(including the CAS Number, if known) and amount of each
component in Bordon Chemical Compound 9MKU10108R.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, both companies will
be asked to describe the actions they have taken or
plan to take 1) to notify workers and others about the
reported information, and 2) to reduce or eliminate
exposure to the subj ect acrylate coati ng compound. In
addition, both companies will be asked to describe the
nature and results, if available, of all studies (other
than those reported already to the Agency or those
cited in the open scientific literature) about which
the companies are aware or that they have conducted,
are conducting or plan to conduct that are designed to
determine the toxicity (especially the potential
neurotoxicity) of or the exposure to this material.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of this acrylate coating compound.
c)
The Chemical Screening Branch will transmi t copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWERj EPA, OWjEPA, OARjEPA, ORDjEPA, OPP jOPTSjEPA,
CCDjOTSjOPTSjEPA and TRDBjECADjOTSjOPTSjEPA; copies of
this report will be sent also to the TSCA Assistance
Office (TAOjOTSjOPTSjEPA) for further distribution.
483
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DA TE:
DEC 2 9 1988
SUBJECT:
Status Report* 8EHQ-l288-0777 Approved:.&~ (Jl~ I~
James F. Darr. Section Head ll.~ r: k DEC 29 1988 I
Chemical Risk Identificatio(T~;;tion/CSB
FROM:
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Amoco Chemical Company submitted the following summarized
information regarding the conduct and preliminary results of a
study designed to determine the rat respiratory sensitization
potential of isopropylidenebis(phthalic anhydride) (IPAN):
"One group of 10 male and 10 female Sprague-Dawley rats
was exposed to IPAN at a target concentration of 50 ug/
m3 for 6 hours/day for 5 days. Two addi tiona1 groups
were exposed to filtered air. Following a 3-week rest
period, [the] IPAN-exposed [rats] and one group of
filtered air-exposed rats were challenged with the same
concentration of IPAN for 6 hours. The second filtered
air-exposed group served as a non-challenged control.
"Serum IgG antibody levels were significantly elevated
in the IPAN-treated females and combined males/females
compared to the challenged and non-challenged controls.
There were no other effects of treatment associated
with the increased serum IgG. Lung foci, absolute lung
weight, and relative lung weight were not significantly
different in IPAN-treated animals compared to controls.
". . . [Amoco interprets] these results. to indicate that
there is evidence to support the conclusion that IPAN
is a potential respiratory sensitizer at concentrations
of 50 ug/m3 for 6 hours/day for 5 days."
Submission Evaluation
An E PAr e vie w 0 f the 0 v era 11 s i g n i f i can ceo f the s u bm i t t e d
toxicologic findings should be possible upon EPA's receipt of a
full copy of the final report from the cited rat respiratory
sensitization study.
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting orovision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
484
E~A '0'"" IUI~' 'REV. )-711
-------
8EHQ-1288-0777
Page 2 of 2
Current production and Use
The Amoco Chemical Company reported non-confidentially by phone
that IPAN has the following Chemical Abstracts Service (CAS)
Registry Number: 1779-17-5. A review of the non-confidential
computerized version of the initial TSCA Chemical Substance
Inventory has shown that CAS No. 1779-17-5 is not listed on the
TSCA Inventory.
The Amoco Chemical Company did not provide any information in its
submission regarding the use(s) of IPAN nor was such information
located in the secondary literature sources consulted by EPA.
Comments/Recommendations
In its submission, the Amoco Chemical Company reported that the
IPAN product label and Material Safety Data Sheet (MSDS) were
being updated to reflect the reported toxicologic findings.
a)
The Chemical Screening Branch will ask Amoco to ensure
that EPA receives a complete copy of the final report
(including the actual experimental protocol, results of
gross and histopathological examinations, results of
any statistical analyses, etc.) from the respiratory
sensitization study cited in the company's submission.
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure information, Amoco will be asked
to describe the nature and results, if available, of
all studi es (other than those repor ted al ready to EPA
or those cited in the open scientific literature) about
which Amoco is aware or that Amoco has conducted, is
conducting or plans to conduct that are designed to
determine the toxicity of or the exposure to IPAN.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of the subject chemical substance.
c)
The Chemical Screening Branch will transmit copies of
this status report to NIOSH, OSHA, CPSC, FDA, NTP,
OSWER/EPA, OW/EPA, OAR/EPA, ORD/EPA and OPP/OPTS/EPA.
In addition, copies of this status report will be sent
to the TSCA Ass i stance Office (TAO/OTS/OPTS/EPA) for
further distribution.
485
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
JAN 3 I 1989
Page 1 of 6
0" TE:
Status Report*
8EHQ-1288-0778
,I\Dproved: L~~f)/;./ -1'1/ ry
SU8JECT:
FROM:
~ 'f. ~ ~ wdh.oML.7 ~
James F. Darr, Section Head
Chemical Risk Identification Section/CSB
TO:
Frank D. Kover, Branch Chief
Chemical Screening Branch/ECAD/OTS/OPTS
Submission Description
The Eastman Kodak Company provided the final report from an oral
developmental toxicity probe study of 2-ethyl-l,3-hexanediol (CAS
No. 94-96-2) in rats. The submi tter' s cover letter presents the
following information regarding the conduct and results of this
study:
"In a developmental toxicity probe [study], pregnant
rats received doses of . [0, 500, 1000, 2000 or
4000] mg/kg by gavage on the 6th through the 15th days
of gestation. At 2000 and 4000 mg/kg, mortality was
observed in 1/8 and 7/8 rats, respectively. The eighth
rat at the high dose level was euthanatized due to its
moribund condition. No mortality was observed at the
500 or 1000 mg/kg dose levels. Clinically observable
changes seen in the one animal dying at 2000 mg/kg and
in animals at 4000 mg/kg included weakness, respiratory
difficulty, sialorrhea, gait disturbances, nasal dis-
charge, porphyrin tears, and unkempt haircoats. At 4000
mg /kg, hypo therm i a, pa r t i ally closed eyes, excess i ve
tearing, and piloerection were also seen. No clinical
abnormalities were seen at the 500 or 1000 mg/kg dose
levels. Mean relative liver weight was significantly
increased for the 2000 mg/kg dams. Necropsy changes,
seen only in dams dying or euthanatized prior to [the]
scheduled study termination, included necrosis of the
glandular gastric mucosa, excessive mucus in the cecum,
and atrophy of the thymus and [the] adipose tissue. No
necropsy lesions were seen at the 500 or 1000 mg/kg
dose levels.
"An increase in post-implantation losses and an
increase in the incidence of malformed fetuses were
seen in [the] dams treated with 2000 mg/kg of the test
====================================================================================
*
NOTE: This status report is the result of a preliminary evaluation of
information submitted to EPA pursuant to Section 8(e), the substantial
risk information reporting provision of the Toxic Substances Control
Act (TSCA). The statements made in this report should not be regarded
as expressing final EPA policy or intent with respect to the subject
chemical(s). Any review of this status report should take into account
the fact that the report may be based on incomplete information.
486
E~" 1"0"" U" (REV. J-711
-------
8EHQ-1288-0778
Page 2 of 6
article. Malformations at the 2000 mg/kg dose level
included rudimentary (filamentous) tails, missing
tails, abnormal curvature of the hindlimbs, arthro-
grypos is, shortened trunk, and umbi 1 ical hern ia. [The]
malformations at the lower dose levels were restricted
to the tail. One fetus at 500 mg/kg and two fetuses,
each from a different li tter, in the 1000 mg/kg dose
group had rudimentary tails.
"In summary, the test chemical produced maternal
toxici ty and lethal i ty at oral doses of 2000 and 4000
mg/kg. Significant fetal toxici ty and teratogenici ty
were evident at a maternally toxic dose (2000 mg/kg),
whi le only one fetus in the 500 mg/kg and two fetuses
in the 1000 mg/kg group had malformations."
In its TSCA section 8(e) submission, Eastman Kodak also provided
a report summarizing the conduct and final results of a number of
Eastman Kodak acute toxicity studies on the subject chemical.
The company's cover letter presents the following information
regarding the results of these acute studies:
"In the acute oral toxicity study, the oral LD50 values
were grea ter than 5000 mg/kg in both male and female
rats. When applied to the skin, the test article had
an estimated acute lethal dose of greater than 20 ml/kg
for rats and did not produce abnormal clinical signs.
The test article was, at most, a slight skin irritant
[in guinea pigs], and it was not a skin sensitizer [in
guinea pigs]. When placed in the [rabbit] eye, the
test article produced moderate irritation. Immediate
irrigation of the eye following exposure to the test
article was beneficial and significantly reduced the
irritation."
Eastman Kodak also submitted a copy of the company's 2-ethyl-
1,3-hexanediol Material Safety Data Sheet (MSDS) that had been
revised to reflect the results of the reported developmental
toxicity probe study. The submitted MSDS presents the following
summary information taken from published l-ethyl-l,3-hexanediol
studies:
"Skin absorption studies: Skin absorption has been
demonstrated in the hairless dog
"Inhalation study: Rats exposed to a fog generated at
700C with a nebulizer at a concentration estimated to
be 4800 ppm for 8 hours all survived. ....
"Feeding study: Rats fed 700 mg/kg/day in the diet for
90 days did not grow as well as the controls. but
apparently suffered no organic [organ ?] injury. At
480 mg/kg/day, growth was normal and no adverse effects
were noted. ...."
487
-------
8EHQ-1288-0778
Page 3 of 6
Submission Evaluation
Oral administration of 2-ethyl-1,3-hexanediol to pregnant rats
during the major period of organogenesis produced both maternal
toxicity and lethality at doses of 2000 and 4000 mg/kg/day. The
Maternal toxicity seen was in the form of increased incidence of
clinical signs, pathological findings and increased liver weight.
Al though the mean maternal body weight ga i n was less than the
controls in all treated groups during the period of days 6-9 of
gestation, the differences were not statistically significant.
Thus, there were no significant maternal effects observed at 500
or 1000 mg/kg/day. It should be noted that Eastman Kodak's cover
letter states that the results of an acute oral toxicity study
indicate the LD50 values to be greater than 5000 mg/kg/day in
both male and female rats. In the developmental tox i city probe
study, on the other hand, all of the maternal animals in the 4000
mg/kg/day group either died or had to be sacrificed following
several days of exposure. Therefore, the possibility exists that
pregnant animals represent a uniquely sensitive population.
Oral administration of 2-ethyl-l,3-hexanediol to pregnant rats
during the major period of organogenesis produced developmental
toxicity at all dose levels administered, Le., 500, 1000 and
2000 mg/kg/day; at 4000 mg/kg/day there were no live dams to
evaluate. Developmental toxicity was in the form of increased
incidences of external malformations and variations at all dose
levels, and, at 2000 mg/kg/day, a signi f icant increase in post-
implantation loss and a significant decrease in the fetal body
weight. At 2000 mg/kg/day, there was a statistically significant
increase (indicated by an *) in the total and several specific
incidence(s) of external malformations. These malformations
included: rudimentary or filamentous tails (15 fetuses in 4
litters, 15/4*), missing tails (11/3*), small tail (1/1), curly
tail (1/1), edematous or hemorrhagic tails (2/2), cyst on tail
(1/1), abnormal curvature of the hindlimbs (13/4*), arthrogry-
posis (3/3), shortened trunk-lumbar region (5/3), umbilical
hernia (4/2). There was also a statistically significant increase
observed in the incidence of a variation, hematomas (9/4*). In
the 1000 mg/kg/day dose group, 2 fetuses in 2 Ii tters had rudi-
mentary or filamentous tails and 1 fetus had a hematoma. At 500
mg/kg/day, 1 fetus had a rudimentary or filamentous tail; no
external malformations or variations were observed in the control
animals. while the values from the 500 and 1000 mg/kg/day groups
do not represent a stat i st ica lly sign i f icant increase, the fact
remains that the malformations observed were of the same nature
(Le., tail malformations) as those observed at significantly
increased levels at 2000 mg/kg/day. Therefore, EPA regards those
malformations seen at 500 and 1000 mg/kg/day as being indicators
of developmental toxicity. This is in contrast with the probe
study report which states that the significance of the effects
seen at the low doses is obscured by the small number of control
fetuses available for examination. The number of fetuses/litters
at 1000 mg/kg/day was not much larger (i.e., 38/3, 75/6, 45/4 and
66/6 for 0, 500, 1000 and 2000 mg/kg/day, respectively).
488
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8EHQ-1288-0778
Page 4 of 6
It must be kept in mind that this Eastman Kodak study is merely a
probe study in which a I imi ted number of animals were used per
dose group and a limited number of developmental parameters were
evaluated (i.e., visceral and skeletal examinations were not
conducted). Despite the limited nature, however, the study is of
sufficient design to clearly identify 2-ethyl-I,3-hexanediol as a
maternal and developmenta I tox i cant. As ind icated in the probe
study, a definitive developmental toxicity study would need to be
conducted to further characterize the toxicity of this chemical.
Further, and considering the fact that the submitted MSDS reports
that 2~ethyl-1,3-hexanediol has been shown to be absorbed through
the skin, it would be of interest to know if Eastman Kodak is
conducting or plans to conduct a full developmental toxicity
study in rats exposed to the subject chemical via the skin.
The structural similarity between 2-ethyl-I,3-hexanediol and 2-
ethylhexanol (2-EH), which is metabolized to 2-ethylhexanoic acid
(2-EHA) in vivo, should be noted. In addition, it should be noted
2-ethyl-T, 3-hexanediol could be metabolized to a hydroxylated
analogue of 2-EHA. 2-EHA has been tested by members of the
chemical industry for potential developmental toxicity in rabbits
and rats pursuant to a "test rule" under TSCA Section 4. While
the industry-conducted TSCA Section 4 study of 2-EHA in the rat
demonstrated clear signs of developmental toxicity, the specific
developmental findings reported in the present Eastman Kodak TSCA
Section 8(e) notice (i.e., the high incidence of malformations of
the tail) do not mimic those seen in the Section 4 study of 2-EHA
in rats. However, there was a significant decrease observed in
the number of caudal segments in the Section 4 study of 2-EHA in
rats. A possible explanation for the lack of externally observed
rat tail malformations could be due to strain differences; the
strain of rats used in the 2-EHA Section 4 study was Fischer 344,
whereas, the rat strain used by Eastman Kodak in its study of 2-
ethyl-I,3-hexanediol was CD Sprague Dawley.
Some support for this theory comes from preliminary findings from
an EPA-sponsored testing program (EPA' s Heal th Effects Research
Laboratories is conducting studies on the potential developmental
toxicity of a series of short-chain carboxylic acids and has been
using CD Sprague Dawley rats). According to a recently released
progress report, preliminary data from this EPA-sponsored testing
program show a dramatic increase in the incidence of no tailor
vestig ial tail (nine pups, four li tters) assoc ia ted with 2 - EHA
treatment at 900 mg/kg. In addition, a published study (Ritter
et al.; 1987) on the teratogenicity of di (2-ethylhexyl)phthalate
(DEHP), 2-EH, 2-EHA and valproic acid in wistar rats reported
tail malformations for all of the compounds following treatment
on day 12 of gestation. Also, a recent Union Carbide Corporation
Section 8(e) submission (8EHQ-1088-0764 S) reported malformations
of the tai I or caudal region of CD Sprague Dawley rat fetuses
after prenatal exposure to two chemicals which, according to the
company, are metabolized to 2-EHA. With all of these studies,
there has been an increased incidence of pre- or early postnatal
death as well as a decrease in fetal or neonatal body weight.
489
-------
8EHQ-1288-0778
Page 5 of 6
It is not pos s ibl eat this time to determine whether there is
consistency with the results of other specific developmental
tests because the Eastman Kodak study of 2-ethyl-l,3-hexanediol
is a probe study, and, as such, did not include any visceral or
skel et al analyse s of the f et u se s. The structural s imi lari ty
among these agents and the similarity in test results, however,
are quite interesting and raise further concern regarding the
number of untested substances that are themselves short-chain
carboxylic acids or may be metabolized to short-chain carboxylic
acids or their analogues.
The reader's attention is directed to the second paragraph of the
Comments/Recommendations section of this status report for more
information about current OTS chemical assessment/testing-related
activities for 2-EH and 2-EHA. The reader's attention is directed
also to the "Status Report" prepared by EPA in response to the
recently received TSCA Section 8(e) submission (8EHQ-l088-0764 S)
in which Union Carbide reported that anal and caudal defects were
seen in oral rat teratology studies of two chemicals that yield
2-ethylhexanoic acid as a metabolite.
Current Production and Use
A review of the production range (includes importation volumes)
statistics for 2-ethyl-l,3-hexanediol (CAS No. 94-96-2), which is
1 i s ted in the i ni tial TSCA Chemical Substance Inventory, shows
that no 1977 manufacture/importation of the chemical was reported
or that all of the manufacturing and/or importation data reported
were claimed as TSCA Confidential Business Information (CBI) by
the person(s) reporting for the initial Inventory and cannot be
disclosed (Section l4(a) of TSCA; U.S.C. 26l3(a)). All of the
data that have been submitted for the initial TSCA Inventory,
including the product ion range data, are subj ect to the 1 imi ta-
tions that are contained in the initial TSCA Inventory Reporting
Regulations (40 CFR 710).
The 10th Edition of the Condensed Chemical Dictionary reports
that 2-ethyl-l,3-hexanediol has the following uses: "Insect
repellent; cosmetics; vehicle and solvent in printing inks;
medicine; chelating agent for boric acid."
In its Section 8(e) notice, Eastman Kodak provided the following
information regarding the potential for exposure to 2-ethyl-l,3-
hexanediol at Eastman Kodak:
"Potential exposure to this material from Eastman Kodak
Company ac t i vi ties comes from two sources. Approxi-
mately 100 kg have been manufactured in essentially
closed equipment for evaluation by customers. A maximum
of 12 employees have been involved during the synthesis
and laboratory development work during which good
labora tory prac t ices were used. Approx imately 40 kg
have been sampled to one customer. In addition, the
substance has been purchased and repackaged for sales
490
-------
8EHQ-1288-0778
Page 6 of 6
as a laboratory reagent with sales of less than 10 kg
i n 1 9 8 8 . . [E as tm an K 0 d a k is] not a war e 0 fan y
adverse human health problems associated with.
manufacture or use [of 2-ethyl-l,3-hexanediol]."
Comments/Recommendations
In addition to modifying the 2-ethyl-l,3-hexanediol MSDS to
reflect the reported developmental toxicity probe study findings,
Eastman Kodak stated that the company is considering the need for
further toxicologic testing of this chemical substance.
Considering that 2-ethyl-l,3-hexanediol is structurally similar
to 2-ethylhexanol (2-EH; CAS No. 104-76-7), a chemical substance
that metabolizes rapidly to 2-ethylhexanoic acid (2-EHA; CAS No.
149-57-5), the Chemical Screening Branch immediately provided
copies of this Section 8(e) notice to the Test Rules Development
Branch (TRDB/ECAD/OTS) and Risk Analysis Branch (RAB/ECAD/OTS)
for inclusion in their ongoing review of available toxicologic
and exposure data on 2-EH and 2-EHA. Further, the Agency has
published TSCA Section 8(a) and 8(d) information gathering rules
for 2-EHA and a TSCA Section 8(d) information gathering rule for
2-EH. In addition, EPA has published TSCA Section 4 "test rules"
covering 2-EH and 2-EHA. Finally, EPA has recieved several TSCA
Section 8(e) and "For Your Information" (FYI) notices on 2-EH, 2-
EHA and chemicals that metabolize to yield those substances.
a)
In view of EPA's general interest in corporate actions
taken on a voluntary basis in response to new chemical
toxicity or exposure data, Eastman Kodak will be asked
to de sc r i be the nature and results, if avai lable, of
all studies (other than those reported already to EPA
or those published in the open scientific literature)
about which Eastman Kodak is aware or that the company
has conducted, is conducting or plans to conduct that
are designed to determine the toxicity of 2-ethyl-l,3-
hexanediol, especially the developmental toxicity of
the chemical via dermal exposure.
b)
The Chemical Screening Branch will review the reported
information in order to determine the need for further
OTS assessment of 2-ethyl-l,3-hexanediol.
c)
The Chemical Screening Branch will send copies of this
status report to NIOSH, OSHA, CPSC, FDA, NTP, OW/EPA,
OSWER/EPA, OAR/EPA, ORD/EPA, OPP/OPTS/EPA, and TRDB and
RAB/ECAD/OTS/OPTS/EPA; copies of this status report
will be provided also to the TSCA Assistance Office
(TAO/OTS/OPTS/EPA) for further distribution.
REf'ERENCE
Ritter et al.; Teratology; Vol. 35, pg. 41-46; 1987
491
-------
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AŁfftilllX A
THURSDAY, MARCH 16, 1978
PART V
ENVIRONMENT AL
PROTECTION
AGENCY
.
TOXIC SUBSTANCES
CONTROL ACT
Statement of Interpretation and
Enforcement Policy; Notification
of Substantial Risk
492
-------
11110
[6560-01 ]
ENVIRONMENT AL PROTECTION
AGENCY
[FRL 849-2]
TOXIC SUBSTANCES CONTIOl ACT
Notlflcotlon of Sub,tontlo. II,k Undo,
Sedlon ICo)
AGENCY: Environmental Protection
Agency.
ACTION: Statement of interpretation
and enforcement policy.
SUMMARY: This action states EPA's
interpretation of. and enforcement
polley concerning, section S(e> of the
Toxic Substances Control Act (TSCA>
(90 Stat. 2029. 15 U.S.C. 2607>. The
provisions of that section went into
effect on January 1. 1977.
Section S(e> states that "any person
who manufactures. processes. or dis-
tributes in commerce a chemical sub-
stance or mixture and who obtains in-
formation which reasonably supports
the conclusion that such substance or
mixture presents a substantial risk of
injury to health' or the environment
shall immediately inform the Adminis-
trator of such Information unless such
person has actual knowledge that the
Administrator has been adequately in-
formed of such Wormation."
DATES: The policy expressed in this
document Is in effect as of the date of
publ1cation.
FOR FURTHER INFORMATION
CONTACT:
Frank D. Kover. Assessment Divi-
sion, Office of Toxic Substances
(WH-557>. Environmental Protec-
tion Agency, 401 M Street SW..
Washington. D.C. 20460, 202-755-
2110.
SUPPLEMENTARY INFORMATION:
On September 9. 1977, the Agency pro-
posed guidance (42 FR 45362> on its in-
terpretation of and policy concerning
the provisions of section See). Al-
though the proposed "guidance" was
an interpretive rule and statement of
policy exempt from the notice and
public comment provisions of the Ad-
ministrative Procedure Act (5 U.S.C.
553), the Agency solicited comments
on several issues to make more in-
formed decisions. On October 11. the
Comment period was extended from
Octc,ber 15 to October 31. 1'977 (42 FR
54857). On November 4, 1977, a supple-
mental notice to the proposed guid-
ance was published (42 FR 57744>, de-
letil1i the November 15 date for re-
porting certain Information obtained
before 1977 and stating that a new
date would be established In the final
&,uldance.
In developing this policy statemed,
two meetings have been held (Ft:.bru-
NOTICES
ary I, 1977. and October 26, 1977) with
selected representatives of Industry
and environmental and other Inter-
ested groups. Comments submitted
pursuant to the February 1 meeting
were addressed in the preamble to the
September 9 proposal. Over 100 writ-
ten comments have been submitted
pursuant to the September 9 proposal
from trade associations. businesses, en-
vironmental groups. labor unions.
State and Federal agencles, and other
interested parties. Appendix B de-
scribes significant Issues raised In
these comments and the Agency's re-
sponse to them.
The major modiflcatlons to the Sep-
tember 9 proposal are summarized in
points 1 through 7 below.
(1) Pursuant to some question over
the definition and nature of "guid-
ance," this document Is now described
more accurately as a "policy state-
ment." It Is exempt from the notice
and public comment provisions of the
Administrative Procedure Act. as well
as provisions concerning delayed effec-
tive dates.
(2) Many commenters expressed the
view that to apply these requirements
to officers and employees of a business
organization would result in Ul-consid-
ered. premature reports and would un-
fairly subject employees to conflicting
responsib!l!ties as individual respon-
dents and as corporate aaents. Other
commenters expressed support for the
view that certain employees have a re-
sponsib!l!ty to report pertinent Wor-
mati on, and felt that the phrase "ca-
pable of appreciating pertinent infor-
mation" appropriately described those
employees.
The September 9 proposal would
have applied section See) requirements
to commercial establishments as well
as to employees capable of appreciat-
ini pertinent information. but stipu-
lated enforcement priorities intended
to encourage corporate processing and
centralized reporting of such informa-
tion (42 FR 45363>. The intent was to
ensure that pertinent information ob-
tained by employees Is promptly and
appropriately considered. while mini-
mizing duplicative or !ll-consldered
submissions.
The Agency now feels that these ob-
jectives would best be served by allow-
ing commercial establishments-under
certain conditions designed to ensure
full disclosure-to assume exclusive re-
sponsiblllty for reportini to EPA any
substantial-risk Information obtained
by Individual officers or employees.
Accordingly, this pOltey statement
stipulates that individual officers and
employees wUl have fully discharged
their section 8( e) obligations once they
have notified the designated responsi-
ble company supervisor or official of
pertinent information. provided, that
the employing company or flrm has
established. Internally publicizes. and
afflrmatively Implements procedures
governing such notifications. These
procedure.>, at a minimum. must: (I)
Specify the information that must be
reported: (2) indicate how the notifica-
tions are to be prepared and submit-
ted: (3) note the Fpderal penalties for
falling to report: and (4) provide a
mechanism for promptly notifying of-
flcers and employees who have submit-
ted reports of the company's disposI-
tion of those reports, including wheth-
er or not they were submitted to EPA
(and if not, informing employees of
their right to report to EPA, as pro-
tected by TSCA section 23>. EPA be-
lieves these four criteria will ensure
prompt and appropriate processing of
pertinent information.
Establishment of such procedures
notwithstanding, all officials responsi-
ble and having authority for the orga-
nization's execution of Its section See)
obligations retain personal liability for
ensuring that substantial-risk informa-
tion is reported to EP A.
(3) The September 9 proposal stated,
in Part III, that a person obtains in-
formation when he is aware that it
"may suggest" substantial risk. Nu-
merous commenters questioned the
Administrator's authority to compel
the reporting of information which
"may suggest" substantial risk. The
Administrator agrees that section 8<1')
addresses information that "reason-
ably supports the conclusion" of sub-
stantial risk and has deleted the "may
suggest" provision, but emphasizes
that "reasonablY supports the conclu-
sion" of substantial risk Is not Identi-
cal to a conclusive demonstration of
substantial risk. The former typically
occurs. and must be reported, at an
earlier stage. Part VI in this policy
statement provides Agency interpreta-
tion of the types of information that
"reasonably support" sucn a conclu-
sion.
(4) Numerous commer'lters requested
clarification of different aspects of
Part V of the September 9 proposal
("Information Which Reasonably Sup-
ports a Conclusion of Substantial
Risk"). partIcularly concerning envi-
ronmental effects, and suggested dif-
ferent interpretations of what consti-
tutes a "substantiai risk". The Agency
continues to focus in this policy state-
ment on the effects set forth in the
September 9 proposal. but clarifies
that the substantiality of a risk is a
function of both the seriousness of the
effect and the probability of its occur-
rence (see Part V).
(5) Numerous commenters main-
tained that section 8< e) on ly applies
prospectively to information obtained
after January I, 1977. The Agency dis-
agrees, as explained in the preamble
to the September 9 proposal. This
polley statement continues to apply
section 8( e) to information obtained
before 1977 of which a person hIU
FEDEIAL REGISTEI. VOL 43. NO. 52-THUISDAY, MAICH 16, 197.
493
-------
been aware since January 1. 1977. In
response to requests for clarification,
the statement defines what constitutes
such awareness. In this manner, EPA
Intends to limit the need for searches
of historical records and files.
(6) This policy statement now pro-
vides that any Information publlshf'd
In scientific literature, In any lan-
guage, is exempt If It is referred to in
abstracts published by specified ab-
stracting services.
(7) This policy statement describes
In a new Part X how to submit claims
of confidentiality.
Accordingly, the Administrator's In-
terpretation of and policy towards sec-
tion 8(e) is set forth below.
Dated: February 24, 1978.
DOUGLAS COSTLE
Administrator.
I. DEFINITIONS
The definitions set forth in TSCA
section 3 apply to these requirements.
In addition, the following definitions
are provided for purposes of this
policy statement:
The term "manufacture or process
'for commercial purposes' " means to
manufacture or process: (1) For distri-
bution in commerce, including for test
marketing purposes, (2) for use as a
catalyst or an Intermediate. (3) for the
exclusive use by the manufacturer or
processor, or (4) for product research
and development.
The term "person" includes any nat-
ural person, corporation, firm, com-
pany, joint-venture, partnership, sole
proprietorship, association, or any
other business entity, any State or po-
litical subdivision thereof, any munici-
pality, any Interstate body and any de-
partment. agency, or Instrumentality
of the Federal Government.
The term "substantial-risk Informa-
tion" means lnIormation which rea-
sonably supports the conclusion that a
chemical substance or mixture pre.
spnts a substantial risk of injury to
healtil CJr the environment.
11. PERSONS SUBJECT TO THE
REQUIREMEJfT
Persons subject to section 8(e) re-
Quirements Include both natural per.
sons and business entities engaged in
manufacturing, processing, or distrib-
uting In commerce a chemical sub-
stance or mixture. In the case of busi-
ness entities, the president, chief ex-
ecutive officer, and any other officers
respon&ible and having authority for
the organization's execution of Its sec.
tlon 8(e) obHgations must ensure that
the organization reports substantial-
risk information to EPA. The business
organization Is considered to have ob-
tained any InIormation which any of-
ficer or employee capable oC appreciat-
Ing the significance of that inCorma-
tion has obtained. It is therefore in-
NOTICES
cumbent upon business organizations
to establish procedures for expedi-
tiously processing pertinent Informa-
tion In order to comply with the
schedule set forth In Part IV.
Those officers and employees of
business organizations who are capa-
ble of appreciating the significance of
pertinent information are also subject
to these reporting requirements. An
employing organization may reHeve its
Individual officers and employees of
any responsibility for reporting sub-
stantial-risk Information directly to
EP A by establishing. Internally pubH-
cizing, and affirmatively implementing
procedures Cor employee submission
and ~orporate processing of pertinent
Information. These procedures, at a
minimum, must: (1) Specify the Infor-
mation that officers and employees
must submit; (2) indicate how such
submissions are to be prepared and
the company official to whom they are
to be submitted; (3) note the Federal
penalties for failing to report; and (4)
provide a mechanism for promptly ad.
vising officers and employees in writ-
ing of the company's disposition of the
report. Including whether or not the
report was submitted to EPA (and If
not Informing employees of their right
to report to EP A, as protected by
TSCA section 23). An employee of any
company that has established and
publicized such procedures, who has
internally submitted pertinent Infor-
mation in accordance with them, shall
have discharged his section 8(e) obll.
gation. Establishment of such proce-
dures notwithstanding, all officials re-
sponsible and having authority for the
organization's execution of Its section
8(e) obligations retain personal Ilabil-
ity for ensuring that the appropriate
substantial-risk lnIormation is report.
ed to EPA.
Business organizations that do not
establish such procedures cannot reo
lIeve their Individual officers and em-
ployees of the responslbllty for ensure
ing that substantial-risk Information
they obtain Is reported to EP A. While
officers and employees of such organi.
zatlons may also elect to submJt sub-
stantial-risk Information to their supe-
riors for corporate processing and re-
porting, rather than to EPA directly.
they have not discharged their Individ-
ual section 8(e) obligation until EPA
has received the Information.
NOTl!:.-Irrespective of a business organiza-
tion's decision to establish and publicize the
procedures descrltx.ct above. It ill responsible
for becoming cognizant of any substantial.
risk Information obtained by Its officers and
employees, and for erusurtni that such infor.
matlon ill reported to EPA within 15 work-
Ing days.
III. WHEN A PERSON WILL BE REGARDED
AS HAVING OBTAINf.:D INFORMATION
A person obtains substantial-risk. In-
formation at the time he first comes
lllll
Into possession of or knows of such in-
formation.
Non.-Thill Includes Inlonnatlon of
which a prudent person similarly situated
could reasonably be expected to p05Sess or
have knowledge.
An establishment obtains Informa.
tlon at the time any offIcer or em-
ployee capable of appreciating the sig-
nificance of such Information obtains
It.
IV. REQUIREMENT THAT A PERSON "1M.
MEDIATELY INFORM" THE ADMINISTRA-
TOR
With the exception oC Information
on emergency Incidents of environ-
mental contamination [see Part V(C)]
a person has "Immediately Informed"
the Administrator If information Is reo
celved by EPA not later than the 15th
working day after the date the person
obtained such Information. Supple-
mentary lnIormation generated after a
section 8( e) notification should, If ap-
propriate. be immediately reported.
For emergency incidents of environ-
mental contamination, a person shall
report the incident to the Adminlstra.
tor by telephone as soon as he has
knowledge of the Incident (see Part IX
for appropriate telephone contacts).
The report should contain as much of
the Information required by Part IX
as possible. A written report in accor-
dance with Part IX (a) through (f) Is
to be submitted within 15 days.
InIormation currently In the posses.
slon of a person who Is subject to reo
porting must be reported within 60
days of publication of this policy state.
ment.
V. WHAT CONSTITUTES SUBSTANTIAL
RISKS
A "substantial risk of Injury to
health or the environment" is a risk of
considerable concern because of (a)
the seriousness of the effect [see Sub.
parts (a),
These two criteria are differentially
weighted for different types of effects.
The human health effects listed In
Subpart (a) below, for example. are 80
serious that relatively little weight Is
given to exposure; the mere fact the
Implkated chemical Is In commerce
constitutes sufficient evidence of expo.
sure. In contrast, the remaining ef-
fects listed in Subparts (b) and (c)
below must involve, or be accompanied
by the potential for. significant levels
of exposure (because of general pro-
duction levels. persistence, typical
uses, common means of disposai, or
other pertinent factors).
Note that: (i) The effects outlined
below should not be reported if the reo
fiDUAL UGISnR, VOL 43, NO. 52-THURSDAY, MARCH 16, 1971
494
-------
11112
spondent h8.'l actual knowledge that
the Administrator is already Informed
of them.
(II) Information respecting these ef-
fects can be obtained either directly,
by observation of their occurrence, or
inferred from designed studies 8.'1 dis-
cussed In Part VI.
The Agency considers effects for
which substantial-risk information
must be reported to Include the fol-
lowing:
(a) Human health e/!ecU-(l) Any
Instance of cancer. birth defects. mu-
tagenicity, death. or serious or pro-
longed incapacitation, Includinl the
loss of or inability to use a normal
bodily function with a consequent rel-
atively serious irnpalrment of normal
activities. 11 one (or a few) chemlcal(s)
Is strongly implicated.
(2) Any pattern of effects or evi-
dence which reasonably supports the
conclusion that thc chemical sub-
stance or mixture can produce cancer.
mutation. birth defects or toxic effects
resulting in death, or serious or pro-
longed incapacitation.
(b) Environmental et!ecu-(l> Wide-
spread and previously unsuspected dis-
tribution In environmental media. aa
indicated In studies (excluding materl-
ala contained within appropriate dis-
posal facilities).
(2) Pronounced bioaccumulation.
Measurements and indicators of pro-
nounced bioaccumulation heretofore
unknown to the Administrator (lnclud.
ing bioaccumulation in fish beyond
11,000 times water concentration in a
30-day exposure or having an n-oc-
tanol/water partition coetticient
greater than 25,000) should be report-
ed when coupled with potential for
widespread exposure and any non-triv.
ial adverse effect.
(3) Any non-trivial adverse effect,
heretofore unknown to the Admillia-
trator, associated with a chemical
known to have bioaccumulated to a
pronounced degree or to be wide-
spread in environmental media.
(4) Ecologically significant changes
in species' interrelationships; that Is,
changes In population behavior,
growth, survival, etc. that In turn
affect other species' behavior, growth,
or survival.
Examples include: (I) Excessive stim-
ulation of primary producers (algae,
macrophytes) in aquatic ecosystems,
e.g., resulting in nutrient enrichment,
or eutrophication, of aquatic ecosys-
tems.
Interference with critical bloreo-
chemical cycles, such as the nitrogen
cycle.
(5) Facile transformation or degra-
dation to a chemical having an unac-
ceptable risk as defined above.
(c) Emergency incident. 01 environ.
mental contamination-Any environ-
mental contamination by a chemical
substance or mixture to which any of
NOTICES
the above adverse effects has been &s-
cribed and which because of the pat-
tern. extent. and amount of contami-
nation (1) seriously threatens humans
with cancer, birth defects. mutation.
death, or serious or prolonged Inca-
pacitation, or (2) seriously threatens
non-human organisms with large-scale
or ecologically significant population
destruction.
VI. NATURE AND SoURCES OF INFORMA-
TION WHICH "REASONABLY SUPPORTS
THE CONCLUSION" OF SUBSTANTIAL
RISK
Information attributing any of the
effects described In Part V above to a
chemical substance or mixture is to be
reported If It is one of the types listed
below and It It Is not exempt from the
reporting requirement by reason of
Part VII of this policy statement. A
person Is not to delay reporting until
he obtains conclusive information that
a substantial risk exists. but Is to im-
mediately report any evidence which
"reasonably supports" that conclusion.
Such evidence will generally not be
conclusive 8.'1 to the substantiality of
the r1ak; It should. however. reliably
ascribe the effect to the chemical.
Information from the followinl
sources concerning the effects de.
scribed in Part V will often "reason-
ably support" a conclusion of substan-
tial risk. Consideration of corrobora-
tive information before reportinl can
only occur where It Is indicated below.
(1) De8i~c1, controlled ,tudtu. In
assessing the Quality of information,
the respondent Is to consider whether
It containB reliable evidence ascribing
the effect to the chemical. Not only
should final results from such studies
be reported. but also prellminary reo
sults from incomplete studies where
appropriate. Designed. controlled stud-
ies include:
(1) In vivo experiments and tests.
(Ii) In vitro experiments and tests.
Consideration may be given to the ex-
Istence of corroborative Information, It
necessary to reasonably support the
concluaion that a chemical presents a
substantial risk.
(Iii) Epidemiological studies.
-------
(b) Any information the contents of
which a person has been alerted to by
date received after January 1. 1977, In-
cluding any Information concerning a
chemical for which the person Is pres-
ently assessing health and environ-
mental effects;
Cc) Any other information of which
the person has actual knowledge.
IX. REPORTING REQUIRDIDTS
Notices shall be delivered to the
Document Control Officer, Chemical
Information Division, Office of Toxic
Substances CWH-557), Environmental
Protection Agency; 401 M Street SW.,
Washington, D.C. 20460. (****)
A notice should:
(a) Be sent by certified mall, or In
any other way permitting verification
of Its receipt by the Agency,
(b) State that It Is being submitted
In accordance with section S(e),
(c) Conta1n the Job title, name, ad-
dress. telephone number, and signa-
ture of the person reporting and the
name and address of the manufactur.
ing, processing. or diatributlng estab.
lJahment with which he Is associated,
(d) IdentifY.the chemical substance
or mixture (Including, if known, the
CAS Rea1stry Number).
(e) Summarize the adverse effects
being reported, describing the nature
and the extent of the rtak Involved.
and
(f) Contain the specific source of the
information together with a summary
and the source of any available sup-
porting technical data.
For emergency incidents of environ-
mental contamination (see Part V(c».
a person shall report the incident to
the Adm1nJstrator by telephone as
soon &8 he has knowledge of the inci-
dent (see below for appropriate tele-
phone contacts), The report should
conta1n &8 much of the information re-
quired by instructions (b) through (!)
above as possible. A written report, In
accordance with instructions Co.)
through (!) above, Is to be submitted
within 15 days. Twenty-four hour
emergency telephone numbers are:
Rel10n I (Maine, Rhode Island. Connecti-
cut. Vernont. MassachU8etta. New Hamp-
Ihlre),817-223-7265.
Rel10n II (New York, New Jersey, Puerto
Rico, Vlrrtn Islands>, 201-548-8730.
Re810n III (PennaylvuUa, Welt Vlrrtnla,
Vlrrtnla, MarYland, Delaware, District of
Columbia>, 215-597-118118.
R~on IV (Kentucky, Tennessee, North
Carolina, South Carolina, Geor'ala. AIa-
bama, Mlaalaalppl, Florida>, 404-881-4082.
Re810n V (Wisconsin, Illinola. Indiana,
MlchlPl' Ohio, Minnesota>, 312-353-
2318.
Rerlon VI (New Mexico, Texu, Oklahoma,
Arkanaal, Louisiana>, 214-749-3840.
Rel10n VII (Nebruka, Iowa, Mlaaouri,
Kanau>, 816-374-3778.
Rel10n VIII (Colorado, Utah, Wyomlna.
Montana. North D&kota. South D&kota).
303-837 -3880.
Re810n IX (California, Nevade.. Arizona.
HawaII, Quam). 415-556-6254.
NOTICES
Region X (Washington, Oreron, Idaho,
Alaska), 206-442-1200.
X. CONFIDENTIALITY CLAUD
co.) Any person submitting a notice
to EPA under section 8Ce) of TSCA
may assert a business confidentiality
claim covering all or part of the infor-
mation contained In the notice. Any
Information covered by a claim will be
disclosed by EPA only to the extent,
and by means of the procedures. set
forth In 40 CFR Part 2 (41 FR 36902.
September 1. 1976).
Cb) If no claim accompanies the
notice at the time It Is submitted to
EP A. the notice will be placed In an
open file to be available to the pubUc
without further notice to the submit-
ter.
.. WHAT JfD:D IfOT 811: REPORTED AS All
DUIIGDCY INCIDENT
Information contained In notification of
spills under section 311 (b)( 5 > of the Federal
Water Pollution Control Act (FWPCA>.
(For a complete list of exemptions to report-
ing, see Part VII.>
c. WBEIf A1m WHERI TO aEPORT DlERGElfCY
INCIDDTI
Emergency Incidents of environmental
contamination are to be reported immedi-
ately by telephone to the appropriate EPA
Rei10nal 24-hour telephone emergency line
llated below.
Rel10n I CMalne, Rhode Island, Connecti-
cut. Vennont. Massachusetts. New Hamp-
Ihlre >, 617-223-7265.
Rel10n II (New York. New Jersey, Puerto
Rico, VlrI1n Islands>. 201-548-8730.
Rei10n III (Pennsylvania, West Vlrl1nJa,
VlrrtnJa, Maryland, Delaware. District of
Columbia>, 215-5117-98118.
Rel10n IV (Kentucky, Tennessee, North
CarolJna, South Carolina, Georgia, Ala-
bama, Mlaalaslppl, Florida>, 404-881-4062.
Rei10n V (Wlaconsln. Illinois. Indiana,
Mlchlp,n, Ohio. MInnesota>, 312-353-
2318.
Rel10n VI (New Mexico, Texu. Oklahoma,
Arkanau. Louisiana>. 214-749-3840.
Rel10n VII (NebrukA. Iowa, MJasouri.
F(anaaa>, 818-374-3778.
Rel10n VIII (Colorado, Utah, Wyoming,
Montane.. North Dakota, South Dakota),
303-837-3880.
Rei10n IX (California, Nevada, Arizone..
Hawaii. Quam>. 415-556-3254.
Rei10n X (Wa.W1naton, Orevon, Idaho.
-Al.....laJ, ~4{2-1200.
In addition. a written report. In accord-
ance with irultructlona (a> through (t) of
Part IX. Ia to be lubmltted within 15 days to
the Document Control Ottlcer. Chemical In-
formation Division, Ottlce of Toxic Sub-
stancel (WH-557), 401 M Street SW., Wash.
Inrton. D.C. 20460.
AJ'PElfDIX B-SIGIfIrICAIfT COKIIJ:IfTS A1f1)
RESPONSES
A. PERIOIfI SUBJECT TO THIS& UQUIRDIJ:IfTI
C~ 1: Employeel cannot be hl'ld
subject to thes~ requirements, since:
-------
nut
Re$fJon$e: The Agency ronslders that dU-
ferent sections of TSCA. having different
purposes. are appropriately directed to dif-
ferent respondents. In the case of section
8(1"), officers and employeea who a.re capable
or appreciating the significance of informa-
tion have a legitimate responsibility to be
alert to and report substantial-risk Informa-
tion. The guidance haa been modUled 110
that natural persons and business entities
can fuUill their section 8(1') obligations In
different ways. Most otflcers and employees
can dtscharie their section 8<1') obllutlons
by submlttlni pertinent information to cor-
porate superiors. provided that the com-
pany has established the risk-evaluation
procedures characterized In Put II. In the
case of a business organization. Its presl.
dent. chief executive otflcer. and other oW.
cials responsible and havlni authority for
the business organization's execution of Its
section 8(1') obligations must ensure that
the organization reports substantial-risk in-
formation to EPA.
Comment 2: Even if employees can be held
subject to these requirements. they should
not be. To do so would force employees and
employers into conflicting positions. inviting
internal corporate dissension and over- re-
porting. Further, individuals often do not
have the overview necessary to reach con-
sidered. well-supported decisions. Corporate
reporting by designated otflclala will pro.
vide EPA with more reliable data.
ResfJonse: The Agency considers that em.
ployees have a legitimate role In risk report.
tni: it Is imperative that risk Information
obtained by employees be appropriately
considered. Officers and employees can ful.
fill their role In the reportini of substantial.
risk Information. without the dlsadvantaies
described above. by reportlni Information
to superiors for corporate consideration.
and. having done so. wUl have dlscha.ried
their obligation to EPA. Thla Is contiIlient
upon the establishment by the business or.
ganlzatlon of certain procedures for rlsk-
evaluation. thereby assurtni the appropri-
ate consideration of such reports. Those of.
fleers responsible and hal'lng authority for
the organization's execution of Its section
8(1') obligations must ensure that the orga.
nization reports substantial-risk Informa.
tion to EPA.
Comment J' Clarify which employees are
covered. and the extent of their obligation.
Are employees "capable of appreciating per.
tlnent Information" by virtue of rank. or
knowledg-e? Are rank and file employees
subject to these requirements. or Just super.
visory and managerial pe rIIOnn 1'1. company
toxicologists. etc.? Is an employee absolved
of further respansi bllity If he reports to his
lupervlsor?
ResfJQrue: The Agency considers that the
phrase "capable of appreciating the signlfl.
cance of per\.inent Information" appropri.
ately describes those officers and employees
who have a responsibility to be alert to and
report substantlaJ-risk Information. Includ.
tng not only relatively senior corporate offi-
cen; but also many corporate employees.
The pollry statement modUles the Septem.
ber 9 proposal. In response to the concerns
expressed in Comments 2 and 3. to permlt
most offtcers and employees to dlscharlle
their obligation by submlttlni Information
to corporate supenors. subject to the condi-
tion.'> described In Part II.
Comment 4' Cornultants and Indl'~ndent
lab!; should not be subject to these require-
ments.
Re$pon.st: Contractors and Independent
labs are not responsible for reportll111 Infor.
NOTICES
matlon they have obtained directly to EPA;
rather. their client manufli.cturenl. proces-
sors and distributors are respornible for
reportln& such Information.
I. THZ "OnAllfllfO" or IN1ORMATION
Comment 5: The "may suggest" criterion
In Part III of the proposal serves to compel
further examination of Information that by
Itself ill not subject to section 8<1') require-
ments. The statutory lani'Uaie caliini for
"reuonable support" does not support thill.
Further. rlak usessment often requires &nY-
where from months to several years of
Itudy after prel1m.ina.ry results "sunest"
risk. far exceedlna the 15-day compliance
period.
Rt6J/On.st: The Aaency does not Intend to
compel under section 8(e) examination of
information that by ItseU ill not lubJect to
section 8(e) requirements &nd has deleted
the "may sunest" provision. provldlna Its
Interpretation of what constitutea evidence
that "reallOnably supports the conclusion"
of substantial risk In a new Part VI.
Comment 6: Section 8(1') oblliatlons a.re
Incurred upon obtaln1na conclusory substan-
tial-risk information.
RtsJ/On$e: The Agency disaaTees. &nd con.
siders that "reallOnable support" of a con-
clusion of substantial risk ill not Identical to
the conclusion itsel1. The former typically
occurs. and must be reported. at an ea.rUer
ltace.
Comment 7: The statement. In Put In of
the propoaal that a person has obtained in-
formation if he" . . should know of the ex-
ilItence of such Information not In hill pos.
_Ion but which would be delivered to him
on request." tendl to compel an active
aearch for lubstantial-rlsk Information
rather th&l1 the reportlnr of subaitantial-rlak
Information a perllOn "obtains." Thla ill of
particular concern to Importel'll wtth limited
access to Information possessed by their
suppliers.
RUJ)0n6t: The Arency consldenl that sec.
tion 8(1') applies to Information which a
person possesses or of which he kno,*s. It ill
not intended to compel aearches for infor-
mation or extraordinary efforts to acQuire
information. The Aaency further considers.
however. that "known" information In.
cludes information whl~h a prudent person
similarly situated could reasonably be ex-
pected to know. Nerllrence or intentional
avoidance of information does not abllolve a
person of hil section 8Orly chosen examples of precursor
Iymptoma. Deletini these eXlLmples will
avoid unduly emphasizing them when other
Iymptoma may be more Important, yet will
not eliminate the obligation to report them
U they a.re suspected precursors.
Re$JIOf1.&t.' The Agency agrees.
Comment 14: How a.re reportable data dis.
tlniUilIhed from routine tests Includlni
r&nIe teats such as W."s?
&IIJ/01l.6e.' This policy statement directs
the reportlna of specified effects when un.
known to the Administrator. Many !'outlne
teat.l a.re based on a knowled,e of toxicity
associated with a chemical; unknown effects
occurrlna during such a ranie test may have
to be reported 11 they are those of concern
to the Alency and U the information me..ts
the criteria set forth In P&.rt.8 V &nd VI.
Comment 15: The most widespread "in
vitro" test ill the Ames test. which is 5ubJett
to considerable debate. Clarify the circum-
stances under whIch positive results of In
vitro tests must be reported.
RUJ/On$e: Put VI cla.rlfles that the re-
portlnll of In vitro tests will d{'pend upon
the exilltence of corrobora.tive Inlormatlon
U necessary to reallOnably suppo) t the con.
cluslon of substantial risk.
Comment 16: The description of "extrf'me
persistence" &8 a substantial mk is an exam-
ple of the need to redefine Part V
-------
~3pon3e: Part V now clarifies those ef-
fecta for which reporting depends upon a
.I&'nlflca.nt exposure potential. Persislence
by Itself is no longer Itemized as a report-
able effect but rather is considered to be a
component of exposure. potential; it ma,v
also underlie the measurementa described in
Part V(b)( 1>. Laboratory Indicators of pro-
nounced bioaccumulatlon are to be reported
when coupled wllh potential for widespread
exposure and any non. trivial adverse effect.
Comment 17: The n-octanol/water parti-
tion coefficient addresses a physico-chemi-
e&I property. not blologie&l effects. and is
not alone an Indicator of substantial risk;
further. the values stated for the coefficient
and the bloaccumulatlon factor In fish do
not correspond.
Ruporue: The Agency acknowledges the
numerie&l error and has amended the values
to correspond. This policy statement now
d1recta the reportlnc of an experimental
meuurement of bloaccumulation when
coupled with an adverse effect and potential
for widespread exposure.
Com~t 1 B: The requirement that Infor-
mation which "linJr.s" an effect to a chemi-
cal be reported is too broad and contradicts
the statutory laniUage of "reasonably
.upports".
~,porue.' The Agency has provided In a
new Part VI Ita interpretation of "reason-
ably supports".
Comment 19: A determination that infor-
mation "reasonably supports the conclu-
8100" of substantial risk cannot be made in-
dependently of considerations of use since
the method and manner of using a chemical
may 1nfiuence the occurrence of an effect;
In particular. the criteria should reflect a
distinction between normal and abnormal
UIeI of chemJcats.
RupofUe.' The Aa'ency considers that the
appropriate componenta of a "substantial
rtat" with respect to a chemical are (a) the
aeriouaI1eaa of the effect. and (b) total expo-
.ure potential. The method and manner of
usinl a chemJe&I is one of several factors de-
termlnlnl Ita exposure potential. As de-
acrlbed In Part V. the Importance of expo-
.ure potential as a component of "substan-
tial risk" depends upon the kind of effect of
concern. Thus. the effecta described In Part
Via) are 110 serious that relatively little
well'ht is given to exposure: the effects de-
acribed In Parts V (b) and (c) Involve a sig.
nillca.nt exposure or exposure potential.
The Aa'ency further considers that a defl.
nltlon of "normal" use for a particular
chemle&l will often depend upon a knowl-
edl'e of the risu associated with the
chemical.
&. IIfPOIUlATIOK THAT IfJ:ED KOT 81 REPORTED
Com~t 20: Information published In
aclentlfic literature In laniUaces other than
English should be exempted If published In
summary form by abstracting services. Can
the accuracy of English language abstracts
and commercial translations of foreign lit.
erature be assumed?
Ruponlle: This policy statement now pro.
vides that Information published in scien.
tlfic literature. whether In English or an-
other laniUaae. is exempt from reporting If
published In summary form by certain
specified abstract services.
Comment 21: Information exchange sys.
tema with other Federal agencies should be
Immediately established so that rE'spondents
need not report to EPA Information already
reported to other Agencies. and vice versa.
Such duplicative reports are unduly burden.
s<>me.
NOTICES
Rrsponse: EPA is coordlnatln&' this pro-
gram with other agencies now. When this
coordination is successlully completed. the
policy statE'ment will be amended to exempt
from the reporting requirement Inlormatlon
that has been submitted to other specified
agencies. In the meantime. substantial-risk
information must be reported directly to
EPA; such a report does not discharie any
reporting obligation to other acencles.
F. INFORKATION FIRST RECEIVED PRIOR TO THII:
UP'ECTiVE DAn OF TSCA
Comment ZZ: The tense of the verb "ob-
tains" reveals that section 8(e) wa.a Intended
to be applied prospectively to Inlormatlon
newly acquired after January 1. 1977. Utilize
section 8(d) or other rules to acquire Inlor.
matlon obtained before then.
Response: As discussed In the preamble to
the September 9 proposal. the Aiency con.
siders section 8(e) to apply to rIsIt Inlorma.
tion possessed by or known to a person
before. on. or alter January 1. 1977. Con-
cerning information first obtained before
1977. this policy statement continues to re-
Quire reportlnl' of Information received If a
person has been aware of It since January 1.
1977. for the reasons discussed In the Sep-
tember 9 preamble.
Comment 23: The term "aware" is too
vague to be of any help In respondlnl' to
these requirements. Since many corporate
employees are potentially subject to these
requirements. and given uncertainty over
the extent to which they oUiht to be aware
of pre-1977 In!ormatlon. this provision tends
to compel the very tile search It was Intend.
ed to avoid. The term "aware" should be
further defined. possibly In terma of actual
Irnowledge.
Ruponse: The Agency In Part VIII of this
policy statement now defines the pre-1977
information of which a person is considered
to be aware.
G. COKFIDENTIAL 110001UlATIOI'I
Comment 24: EPA should delay iUldance
untll procedures are published governln&'
the treatment of confidential sublIililllions.
Com~nt 25: EPA should treat allsubmis-
slons as confidential until the In!ormation is
verified.
Comm.e11t 26: EPA should automatically
publish section 8( e) notices.
Response to Comme1lt.! Z4 through 26:
EPA has included a new Part X which de.
scribes how to submit a claim of conflden.
tlallty and states that any or all of the In-
formation submitted may be claimed as con.
fidentlal. Such information will be disclosed
by EPA only to the extent. and by means of
the procedures. set forth in 40 CFR Part 2,
H. MISCELLA1fl:OUS
Comment 27: What is the statutOry basis
or need for guidance? What Is Ita exact
status under the Administrative Procedure
Act?
Response: This pollcy statement sets forth
EPA's Interpretation of and policy concern.
Ing TSCA section 8(e). As an Interpretive
rule and statement of policy It Is not subject
to the comment period and delayed effec.
tive date provisions of the Administrative
Procedure Act (5 U.S.C. 553). Although
TSCA does not mandate a policy statement.
the Agency of necessity must develop the
cnterla which wl1l govern enforcement ac-
tivities. Trade associations and businesses
WE're among those who previously expressed
interest In such a statement to guide their
compliance.
11115
Comment 28: Clarify whether these reo
QUirements apply to chemlcais previously
but no lonl'er manulactured. processed. or
distributed In commerce by a person.
&SJKJn3e.' Information obtained before
1977 must be reported if the person hu
been aware of it since January 1. 1977. u
prescribed by Part VIII. Concerning cheml.
cals which a person has discontinued manu-
facturinl'. processln&'. or distributing since
January 1. 1977. In!ormatlon obtained
before the time of discontinuation Is subject
to these requirements. It Is expected that
the acquisition of information after that
time will be minimal; however. should addi-
tional Inlormatlon be acquired. It may trlg-
I'er the reporting described In Part VIII.
Comment 29: Clarify the meaning of "sub-
stantial risk" relative to other risu ad-
dressed by TSCA.
Response.' A substantial risk is defined In
Part V(a) of this policy statement as a risk
of considerable concern because of (a) the
seriouaI1eaa of the effect. and (b) the fact or
probability of Ita occurrence. As opposed to
other risks addresaed by TSCA. economic or
social beneflta of use. or costs of restrtctlDl'
use. are not to be considered In determining
whether a risk is "substantial".
Comment 30: To what extent are "users"
of chemlcais subject to these requirements?
Rupo1Ue.' The Aa'ency considers that
many Industrial uses of chemicals actually
fall within the scope of "proceastn&''' cheml.
cats. A manufacturer. processor. or distribu-
tor who obtalns substantial-risk In!ormatlon
concemina' chemlcais he handles should be
alert to the possibility he may have to
report It,
Com~t 31: Are chemicals manufac.
tured. proceased and 'dlstributed In com-
merce In small Quantities IIOlely for purposes
of research and development subject to
these requirements?
RespofUe.' In I'eneral. the Aa'ency consld.
ers that much manufactur1nl'. processing.
and distribution In commerce of chemicals
In small Quantities IIOlelY for purposes of re-
search and development is conducte(l for
"commercial purposes", Such purposes
would Include the we and distribution of
such materials. as well as their use by the
manufacturer or processor In activities (for
example. product research and development
and studies asaeaslnc the feasibility and
safety of uslnl chemicals) preceding his or a
cllent's commercial use of such materials or
others on a l&r8'er scale.
As deacribed In Part V. the Agency consid-
ers that "substantial risks" depend in part
upon an exposure potential. Thus. the oc-
currence of the effecta described In Part
V(a) presuppose exposure to the chemical
and must be reported: reportlDl' of the
other effects will depend upon a potential
for significant levels of exposure.
Comment 32: Are raw materials. Interme-
diates. and Inert Ingyedients produced or
used In the manufacture of a pesticide sub-
Ject to TSCA?
Resporue: The Administrator considers
that raw materials. intermediates and Inert
Innedlents produced or used In the manu-
facture of a pesticide are substances or mix-
tures which can be reiUlated under TSCA.
In order to be considered a pesticide. I
substance must be Intended for use as a pes-
ticide. Raw materials. intermediates. and
Inert ingredients produced or used In the
manufacture of a pesticide are not them-
selves regulated under FIFRA (unless they
happen to be pesticides themselves) and.
therefore. are subject to TSCA. The pest!.
FEDERAL REGISTER, VOL 43, NO. 52-THUUDAY, MAICH 16, 1971
498
-------
11116
clde regulations at 40 CFR 182.4 are cons la-
tent with thla view.
Commnlt 33: Are Intermediates and cata-
lysts Intended solely tor UIIe In the produc-
tion ot a tood. tood additive. drur, cosmetic.
or device subject to TSCA?
Re!pon!t: The AdmlniBtnitor consldel'll
that intermediates and catalY8U intended
solely for use in the production ot a tood.
tood additive. drur, cosmetic. or devtce are
excluded trom regulation under TSCA. The
definitions of the FFDCA provide that
chemical substances which are intended for
use as a component ot a food. food additive.
drui. cosmetic. or device are encompassed
within the meanlni of 8uch terms. respec-
tively. The FDA considers Intermediates
and catalysts to be such componenu. There-
tore. they are subject to regulation under
the FFDCA. Any such substance Is excluded
trom reaulatlon under TSCA Insofar as It Ia
actually manufactured. processed, or dis-
tributed in commerce solely tor use In the
NOTIaS
production of a food. tood additive. drui.
cosmetic. or device.
Comment 34: EmplOyee8 should have the
option to submit reporU anonymously.
Re!po~e: EPA considers that any person
may report intormatlon to EPA under
TSCA. Those who are required to do so
under section 8(e) are persons who manu-
tacture. process, or dlatrlbute in commerce
chemical 8ubstances or mixtures. Includini
not only buslnelil entities but also such em-
ploYeei as described In Part II. In order to
establish that such persons have discharged
their obligations. and In order to encourage
responsible review ot the quality of Informa-
tion and the substantiality ot risks. EPA be-
lieves that notlflers should Identify them-
selves. Section 23 will adequately protect
employees trom discrimination pursuant to
notifications they have made under section
S(e).
[FR Doc. 78-7064 Filed 3-15-78; 8:45 am]
NOTE
According to technical amendments published
by EPA in the May 29, 1~ 8 7 FEDERAL R~G I ~TER
(52 FR 20083), TSCA SectIon 8(e) submIsSIons
are to be addressed to the Agency as follows:
Document processing Center (TS-790)
(Attn: Section 8(e) Coordinator)
Office of Toxic Substances
U.S. Environmental Protection Agency
401 "M" Street, S.W.
Washington, D.C. 20460
PlDERAllEGISUl, VOL 43, NO. 52-THUISDAY. MAICH 16, 1978
499
-------
APPENDIX B:
CAS NUMBER:
58-08-2
SUBMISSION .: 8EHQ-0587-0672 S
CAS NUMBER:
58-08-2
SUBMISSION .: 8EHQ-0587-0672 S
CAS NUMBER,
67-63-0
SUBMISSION .: 8EHQ-I088-0760 S
CAS NUMBER:
67-63-0
SUBMISSION .: 8EHQ-I088-0760 S
CAS NUMBER, 67-64-1
SUBMISSION .: 8EHQ-1088-0759
U1
0 CAS NUMBER, 67-64-1
0
SUBMISSION .: 8EHQ-I088-0759
CAS NUMBER: 67-66-3
SUBMISSION .: 8EHQ-I088-0759
CAS NUMBER: 67-66-3
SUBMISSION .: 8EHQ-I088-0759
CAS NUMBER: 75-00-3
SUBMISSION .: 8EHQ-0188-0713
CAS NUMBER: 75-09-2
SUBMISSION .: 8EHQ-U88-0772
STATUS REPORTS BY CAS NUMBER
CHEMICAL NAME: CAFFEINE
CHEMICAL NAME: IH-PURIHE-2,6-DIONE, 3,7-DIHYDRO-l,3,7-TRIMETHYL-
CHEMICAL NAME: ISOPROPANOL
CHEMICAL NAME: 2-PROPANOL
CHEMICAL NAME: ACETONE
CHEMICAL NAME: 2-PROPANONE
CHE~ICAL HAME: CHLOROFORM
CHEMICAL NAME: METHANE, TRICHLORO-
CHEMICAL NAME: ETHANE, CHLORO-
CHEMICAL NAME: METHANE, DICHLORO-
-------
APPENDIX B:
CAS HUMBER: 75-09-2 CHEMICAL NAME: METHYLENE CHLORIDE
SUBMISSION .: 8EHQ-1l88-0772
CAS NUMBER: 75-15-0 CHEMICAl NAME: CARBON DISULFIDE
SUBMISSION .: 8EHQ-I088-0759
CAS HUMBER: 75-69-4 CHEMICAL HAME: METHAHE, TRICHLOROFLUORO-
SUBMISSION .: 8EHQ-1088-0759
CAS NUMBER: 78-30-8
SUBMISSION .: 8EHQ-0788-0744 S
CAS NUMBER: 78-79-5 CHEMICAL NAME: 1, 3-BUTADIEHE, 2-METHYl-
SUBMISSION .: 8EHQ-0887-0689 II
CAS HUMBER: ]8-79-5 CHEMICAL HAME: ISOPREHE
(Jl
0 SUBMISSION .: 8EHQ-0887-0689 II
f--'
CAS HUMBER: ]8-93-3 CHEMICAl HAME: 2-BUTAHOHE
SUBMISSION .: 8EHQ-I0BB-0759
CAS NUMBER: ]8-93-3
SUBMISSIOH .: 8EHQ-I0BB-0759
CAS HUMBER: 78-95-5
SUBMISSION .: 8EHQ-0387-0660
CAS HUMBER: 78-97-7
SUBMISSION .: 8EHQ-09BB-0754
STATUS REPORTS BY CAS NUMBER
CHEMICAL HAME: PHOSPHORIC ACID, TRIS(2-METHYLPHEHYL) ESTER
CHEMICAL NAME: METHYLETHYLKETOHE (MEK)
CHEMICAL HAME: 2-PROPAHONE, l-CHLORO-
CHEMICAL HAME: PROPAHEHITRIlE, 2-HYDROXY-
-------
APPEHDIX B: STATUS REPORTS BY CAS HUMBER
CAS HUMBER: 87-86-5
SUBMISSIOH .: 8EHQ-0487-06 71
CAS HUMBER: 89-32-7
SUBMISSIOH .: 8EHQ-1287-0711
CAS HUMBER: 89-32-7
SUBMISSIOH .: 8EHQ-1287-0711
CAS HUMBER: 91-20-3
SUBMISSIOH .: 3EHQ-1237-0704
CAS HUMBER: 94-96-2
SUBMISSIOH .: 3EHQ-1283-0773
U1
0 CAS HUMBER: 98-]3-7
N
SUBMISSIOH .: 8EHQ-0333-0726
CAS HUMBER: 98-73-7
SUBMISSIOH .: 8EHQ-0388-0726
CAS HUMBER:
99-42-3
SUBMISSIOH .: 8EHQ-0287-0657 S
CAS HUMBER:
99-66-1
SUBMISSIOH .: SEHQ-0587-0672 S
CAS HUMBER:
101-54-2
SUBMISSIOH .: 8EHQ-088S-0746
CHEMICAL HAME: PHEHOL, PEHTACHLORO-
CHEMICAL NAME: IH,3H-BENZO[I,2-C:4,5-C']DIFURAH-l,3,5,7-TETROHE
CHEMICAL HAME: PYROMELLITIC DIANHYDRIDE
CHEMICAL HAME: NAPHTHALENE
CHEMICAL NAME: 1,3-HEXANEDIOL, 2-ETHYL-
CHEMICAL NAME: BENZOIC ACID, P-TERT-8UTYL-
II
CHEMICAL NAME: 8ENZOIC ACID, 4-(I,I-DIMETHYLETHYL)-
II
CHEMICAL NAME: BENZOIC ACID, 4-HYDROXY-3-NITRO-, METHYL ESTER
CHEMICAL NAME: PENTANOIC ACID, 2-PROPYL-
CHEMICAL NAME: 1,4-BENZENEDIAMINE, N-PHENYL-
-------
APPENDIX B: STATUS REPORTS 8Y CAS NUM8ER
CAS NUMBER: 104-76-7 CHEMICAL NAME: I-HEXANOL. 2-ETHYl-
SUBMISSION I: 8EHQ-0587-0672 S
CAS NUMBER: 106-89-8 CHEMICAL NAME: EPICHlOROHYDRIN
SUBMISSION I: 8EHQ-1287-0709 S
CAS NUMBER: 106-89-8 CHEMICAL NAME: OXIRANE, (CHLOROMETHYU-
SUBMISSION I: 8EHQ-1287-0709 S
CAS NUMBER: 106-97-8 CHEMICAL NAME: 8UTANE
SUBMISSION I: 8EHQ-0487-0671
CAS NUMBER: 107-06-2 CHEMICAL NAME: ETHANE, 1,2-DICHLORO-
SUBMISSION I: 8EHQ-0487-0662
U1 CAS NUMBER: 107-07-3 CHEMICAL NAME: ETHAHOL, 2-CHLORO-
O
w SUBMISSIOH I: 8EHQ-1187-0698
CAS HUMBER: 107-16-4 CHEMICAL HAME: ACETONITRILE, HYDROXY-
SUBMISSIOH I: 8EHQ-0988-0754
CAS HUMBER: 107-20-0 CHEMICAL NAME: ACETALDEHYDE, CHLORO-
SUBMISSION I: 8EHQ-0387-0660
CAS NUMBER: 107-21-1 CHEMICAL NAME: 1,2-ETHANEDIOL
SUBMISSION I: 8EHQ-I088-0761
CAS NUMBER: 107-21-1 CHEMICAL HAME: ETHYl ENE GL yeOL
SUBMISSIOH I: 8EHQ-I088-0761
-------
APPENDIX B:
STATUS REPORTS BY CAS NUMBER
CAS NUMBER: 103-05-4 CHEMICAL NAME: ACETIC ACID ETHENYl ESTER
SUBMISSION I: 8EHQ-0187-0650
CAS NUMBER: 108-05-4 CHEMICAL NAME: VINYl ACETATE
SUBMISSION I: 8EHQ-0187-0650
CAS NUMBER: 103-18-9 CHEMICAL NAME: 2-PROPANAMINE. N-(1-METHYlETHYl)-
SUBMISSION I: 8EHQ-1287-0705
CAS HUMBER: 108-20-3 CHEMICAl NAME: PROPANE. 2.2'-OXYBIS-
SUBMISSION I: 8EHQ-0487-0671
CAS HUMBER: 108-95-2 CHEMICAL NAME: PHENOL
SUBMISSION I: 8EHQ-1088-0759
U1
0 CAS HUMBER: 109-77-3 CHEMICAL NAME: PROPANEDINITRllE
~
SUBMISSION I: 8EHQ-0983-0754
CAS NUMBER: 111-87-5 CHEMICAL NAME: 1-0CTAHOl
SUBMISSION I: 8EHQ-1088-0762
CAS NUMBER: 112-60-7
SUBMISSION I: 8EHQ-0987-0693
CAS NUMBER: 117-81-7
SUBMISSIOH I: 8EHQ-0587-0672 S
CAS NUMBER: 123-86-4 CHEMICAL NAME: ACETIC ACID. BUTYl ESTER
SUBMISSION I: 3EHQ-0337-0659
CHEMICAL NAME: ETHANOL. 2.2'-[OXYBIS(2.1-ETHANEDIYlOXY)]BIS-
CHEMICAL NAME: 1.2-BENZENEDICARBOXYlIC ACID. BIS(2-ETHYlHEXYl) ESTER
-------
APPENDIX B:
STATUS REPORTS BY CAS NUMBER
CAS NUMBER, 123-91-1 CHEMICAL NAME, 1,4-DIOXANE
SUBMISSION .: 8EHQ-I083-0761
CAS NUMBER, 126-99-8 CHEMICAL NAME: 1, 3-BUTADIENE, 2-CHLORO-
SUBMISSION .: 8EHQ-0887-0689 If
CAS NUMBER: 126-99-8 CHEMICAL NAME: CHLOROPRENE
SUBMISSION .: 8EHQ-0837-0689 If
CAS NUMBER: 137-40-6 CHEMICAL NAME: MYCOBAN (SODIUM SALT)
SUBMISSION .: 8EHQ-1287-0699
CAS NUMBER: 137-40-6 CHEMICAL NAME: PROPANOIC ACID, SODIUM SALT
SUBMISSION .: 8EHQ-1287-0699
V1 CAS NUMBER: 142-22-3 CHEMICAL NAME: CR-39 MONOMER
0
V1 SUBMISSION .: 8EHQ-0487-0666 S
CAS NUMBER: 142-22-3 CHEMICAL NAME: 2,5,8,10-TETRAOXATRIDEC-12-ENOIC ACID, 9-0XO-, 2-PROPENYL ES
TER
SUBMISSION .: 8EHQ-0487-0666 S
CAS NUMBER: 149-57-5 CHEMICAL NAME: HEXANOIC ACID, 2-ETHYL-
SUBMISSION .: 8EHQ-0587-0672 S 8EHQ-I088-0764 S
CAS NUMBER: 151-21-3 CHEMICAL NAME: SODIUM DODECYL SULFATE (SDS)
SUBMISSION .: 8EHQ-0987-0694 If
CAS HUMBER: 151-21-3 CHEMICAL NAME: SODIUM LAURYL SULFATE (SLS)
SUBMISSIOH .: 8EHQ-0987-0694 If
-------
APPENDIX B:
CAS NUMBER: 151-21-3
SUBMISSION .: 8EHQ-0987-D694
CAS NUMBER: 552-30-7
SUBMISSION .: 8EHQ-1287-0711
CAS NUMBER: 552-30-7
SUBMISSION .: 8EHQ-1287-0711
CAS NUMBER: 556-67-2
SUBMISSION .: 8EHQ-0288-0718
CAS NUMBER: 565-]4-2
SUBMISSION .: 3EHQ-0188-07 H
(J1
0 CAS NUMBER: 593-88-4
(j\
SUBMISSION .: 8EHQ-0683-0735
CAS NUMBER: 680-31-9
SUBMISSION .: 8EHQ-1088-0759
CAS NUMBER: 630-31-9
SUBMISSION .: 8EHQ-1083-0759
CAS NUMBER: 760-67-8
SUBMISSION .: 8EHQ-0387-0656
CAS NUMBER: 768-52-5
SUBMISSION .: 8EHQ-1287-0702
STATUS REPORTS BY CAS NUMBER
CHEMICAL NAME: SULFURIC ACID MONODODECYl ESTER SODIUM SALT
If
CHEMICAL NAME: 5-ISOBENZOFURANCARBOXYlIC ACID. 1.3-DIHYDRO-l.3-DIOXO-
CHEMICAL NAME: TRIMEllITIC ANHYDRIDE
CHEMICAL NAME: CYClOTETRASIlOXANE. OCTAMETHYl-
If
CHEMICAL NAME: BUTANOIC ACID. 2-BROMO-3-METHYl-
CHEMICAL NAME: ARSINE. TRIMETHYl-
CHEMICAL NAME: HEXAMETHYlPHOSPHORAMIDE
CHEMICAL NAME: PHOSPHORIC TRIAMIDE. HEXAMETHYl-
CHEMICAL NAME: HEXANOYl CHLORIDE. 2-ETHYl-
CHEMICAL NAME: BENZENAMINE. N-(I-METHYlETHYl)-
8EHQ-1287-0703
-------
APPENDIX B:
CAS NUMBER: 872-50-4
SUBMISSION .: 8EHQ-I087-0695
CAS NUMBER: 941-69-5
SUBMISSION .: 8EHQ-0887-0690
CAS NUMBER: 1072-98-6
SUBMISSION .: aEHQ-06a8-0736
CAS NUMBER: 1163-19-5
SUBMISSION .: 8EHQ-0288-0720
CAS NUMBER: 1309-64-4
SUBMISSION .: aEHQ-06a8-0737
(J1 CAS NUMBER: 1322-93-6
0
-J SUBMISSION .: 8EHQ-I088-0755
CAS HUMBER, 1322-93-6
SUBMISSION ., 8EHQ-1088-0755
CAS NUMBER: 1327-33-9
SUBMISSION .: 8EHQ-0288-0720
CAS NUMBER: 1330-78-5
SUBMISSION .: 8EHQ-0788-0744 S
CAS NUMBER: 1332-58-7 CHEMICAL NAME: KAOLIN
SUBMISSION .: 8EHQ-I088-0755
STATUS REPORTS BY CAS HUMBER
CHEMICAL NAME: 2-PYRROlIDINONE, I-METHYl-
CHEMICAL NAME: IH-PYRROlE-2,5-DIONE, I-PHENYl-
CHEMICAL NAME: PYRIDINE, 2-AMINO-5-CHlORO-
CHEMICAL NAME: BENZENE, 1,1'-OXYBIS[2,3,4,5,6-PENTABROMO-
CHEMICAL NAME: ANTIMONY OXIDE CSB203)
CHEMICAL NAME: NAPHTHAlENESUlFONIC ACID, BISCI-METHYlETHYl)-, SODIUM SALT
CHEMICAL NAME: SEllOGEN HR
CHEMICAL NAME: ANTIMONY OXIDE
CHEMICAL NAME, PHOSPHORIC ACID, TRISCMETHYlPHENYl) ESTER
-------
APPENDIX B: STATUS REPORTS BY CAS NUMBER
CAS NUMBER: 1332-58-]
SUBMISSION .: 8EHQ-10aa-0755
CAS NUMBER: 1336-36-3
SUBMISSION .: 8EHQ-1l88-0769
CAS NUMBER: 1336-36-3
SUBMISSION .: 8EHQ-llaa-0769
CAS NUMBER: 1649-08-]
SUBMISSION .: aEHQ-0587-0676
CAS NUMBER: 1649-08-7
SUBMISSION .: 8EHQ-0587-0676
Vl
0 CAS NUMBER: 1746-01-6
co
SUBMISSION .: 8EHQ-0487-06 71
CAS NUMBER: 1746-81-2
SUBMISSION .: 8EHQ-10aa-0755
CAS NUMBER: 1746-81-2
SUBMISSION .: aEHQ-1088-0]55
CAS NUMBER: 1746-lIl-2
SUBMISSION .: 8EHQ-1088-0755
CAS NUMBER: 1779-17-5
SUBMISSION .: lIEHQ-1288-0777
CHEMICAL NAME: SPESWHITE (CLAY)
CHEMICAL NAME: 1,1'-BIPHENYL, CHLORO DERIVS.
It
CHEMICAL HAME: POLYBROMINATED BIPHENYLS (PCB)
II
CHEMICAL NAME: ETHANE, 1,2-DICHLORO-I,l-DIFLUOR07
CHEMICAL NAME: HCFC-132B
CHEMICAL HAME: DIOXIN, 2,3,7,8-TETRACHLORODIBENZO-P-
CHEMICAL NAME: ARESIH
CHEMICAL NAME: LIHUROH, MOHO-
CHEMICAL HAME: UREA, H'-(4-CHLOROPHEHYL)-H-METHOXY-H-METHYL-
CHEMICAL HAME: l,3-ISOBEHZOFURAHDIOHE, 5,5'-(I-METHYLETHYLIDEHE)BIS-
-------
APPENDIX B: STATUS REPORTS BY CAS NUMBER
CAS HUMBER: 2004-03-7 CHEMICAL HAME: PURINE, 6-METHYl-
SUBMISSION .: 8EHQ-0388-0723
CAS HUMBER: 2465-27-2
SUBMISSION .: 8EHQ-0588-0730
CAS HUMBER: 2465-27-2
SUBMISSION .: 8EHQ-0588-0730
CAS NUMBER: 2465-27-2
SUBMISSION .: 8EHQ-0588-0730
CAS NUMBER: 3033-62-3
SUBMISSION .: 8EHQ-0687-0683
CAS NUMBER: 3033-62-3
V1
0 SUBMISSION .: 8EHQ-0687-0683
\.0
CAS NUMBER: 3064-70-8
SUBMISSION .: 8EHQ-0587-0673
CAS NUMBER: 3126-63-4
SUBMISSION I: 8EHQ-0787-0685
CAS NUMBER: 3236-71-3
SUBMISSION I: 8EHQ-1287-0700
CAS NUMBER: 3734-67-6
SUBMISSION I: 8EHQ-0788-0743
CHEMICAL HAME: AURAMIHE HYDROCHLORIDE
CHEMICAL HAME: C. I. BASIC YEllOW 2
CHEMICAL NAME: BENZEHAMINE, 4,4'-CARBOHIMIDOYlBIS[H,N-DIMETHYl-, MONOHYDROC
HlORIDE
CHEMICAL HAME: ETHAHAMIHE, 2,2'-OXYBIS[N,H-DIMETHYl-
CHEMICAL HAME: HIAX CATALYST A-99
CHEMICAL HAME: METHAHE, SUlFOHYlBIS[TRICHlORO-
CHEMICAL NAME: OXIRAHE, 2,2'-[2,2-BIS[(OXIRAHYlMETHOXY)METHYl]-1,3-PROPANED
IYlBIS(OXYMETHYlEHE)]8IS-
CHEMICAL HAME: FLUORENE, 9,9-BIS(4-HYDROXYPHEHYl)-
CHEMICAL NAME: C. I. ACID RED 1
-------
APPENDIX B:
CAS NUMBER:
3734-67-6
SUBMISSION I: 8EHQ-0788-0743
CAS NUMBER: 3734-67-6
SUBMISSION I: 8EHQ-0788-0743
CAS NUMBER: 3846-71-7
SUBMISSION I: 8EHQ-0888-0747
CAS NUMBER: 3846-71-7
SUBMISSION I: 8EHQ-0888-0747
CAS NUMBER: 3864-99-1
SUBMISSION I: 8EHQ-1088-0756
Ul CAS NUMBER: 3864-99-1
f-'
0
SUBMISSION I: 8EHQ-10aa-0756
CAS NUMBER: 4075-31-4
SUBMISSION I: 8EHQ-1287-0699
CAS NUMBER: 4075-81-4
SUBMISSION I: 8EHQ-1287-0699
CAS NUMBER: 4338-98-1
SUBMISSION I: 8EHQ-0287-0654
CAS NUMBER: 5417-82-3
SUBMISSION I: 8EHQ-0487-0663
STATUS REPORTS BY CAS NUMBER
CHEMICAL NAME: 2,7-NAPHTHALENEDISULFONIC ACID, 5-(ACETYLAMIHO)-4-HYDROXY-3-
(PHENYLAZO)-, DISODIUM SALT
CHEMICAL NAME: RED 2G
CHEMICAL NAME: PHENOL, 2-(2H-BENZOTRIAZOL-2-YL)-4,6-BIS(1,1-DIMETHYLETHYL)-
CHEMICAL NAME: TINUVIN 320
CHEMICAL NAME: PHENOL, 2-(5-CHlORO-ZH-BENZOTRIAZOL-2-YL)-4,6-BIS(1,1-DIMETH
YlETHYU-
CHEMICAL NAME: TINUVIN 327
CHEMICAL NAME: MYCOBAN (CALCIUM SALT)
CHEMICAL NAME: PROPANOIC ACID, CALCIUM SALT
CHEMICAL NAME: Z(3H)-BENZOTHIAZOLONE, 3-METHYL-, HYDRAZONE, MONOHYDROCHLORI
DE
CHEMICAL NAME: PROPANEDINITRIlE, (l-ETHOXYETHYLIDENE)-
-------
APPENDIX B: STATUS REPORTS BY CAS NUMBER
CAS NUMBER: 6262-51-7
SUBMISSION .: 3EHQ-0537-0673
CAS HUMBER: 6294-52-6
SUBMISSION .: 3EHQ-0533-0732
CAS HUMBER: 7173-51-5
SUBMISSION .: 3EHQ-Ola3-0712
CAS NUMBER: 7440-33-2
SUBMISSIOH .: 3EHQ-0633-0735
CAS HUMBER: 7440-41-7
SUBMISSIOH .: 3EHQ-10aa-0759
U1 CAS HUMBER: 7440-44-0
i--'
i--' SUBMISSION .: 3EHQ-0437-0663
CAS NUMBER: 7440-47-3
SUBMISSION .: 8EHQ-1033-0759
CAS HUMBER: 7440-66-6
SUBMISSION .: 3EHQ-1083-0759
CAS HUMBER: 7631-36-9
SUBMISSION .: 3EHQ-0437-0663
CAS NUMBER: 7647-01-0
SUBMISSION .: 3EHQ-0337-0n3
CHEMICAL HAME: CYCLOPROPANE, PENTACHLORO-
CHEMICAL HAME: BENZOTHIAZOLE, 2-AMIHO-5,6-DIMETHOXY-
CHEMICAL NAME: 1-DECANAMIHIUM, H-DECYL-H,H-DIMETHYL-, CHLORIDE
II
CHEMICAL NAME: ARSENIC
3EHQ-1033-0759
CHEMICAL NAME: BERYLLIUM
CHEMICAL HAME: CARBOH
CHEMICAL HAME: CHROMIUM
CHEMICAL NAME: ZIHC
CHEMICAL NAME: SILICA
CHEMICAL HAME: HYDROCHLORIC ACID
-------
APPENDIX B: STATUS REPORTS BY CAS NUMBER
CAS NUMBER: 7647-01-0 CHEMICAL NAME: MURIATIC ACID
SUBMISSION I: 8EHQ-0887-0688
CAS NUMBER: 7647-14-5
SUBMISSION I: 8EHQ-0887-0U8
CAS NUMBER: 7647-18-9
SUBMISSION I: 8EHQ-0688-0737
CAS NUMBER: 7664-93-9
SUBMISSION I: 8EHQ-0887-0U8
CAS NUMBER: 7757-82-6
SUBMISSION I: 8EHQ-0887-0U8
lJl
I-' CAS NUMBER: 7783-06-4
N
SUBMISSION I: 8EHQ-0488-0727
CAS NUMBER: 8005-72-9
SUBMISSION I: 8EHQ-OU7-06 77
CAS NUMBER: 8005-72-9
SUBMISSION I: 8EHQ-0687-0677
CAS NUf":BER: 8005-72-9
SUBMISSION I: 8EHQ-0687-0677
CAS NUMBER: 8005-72-9
SUBMISSION I: 8EHQ-0687-0677
CHEMICAL NAME: SODIUM CHLORIDE, (NACL)
CHEMICAL NAMEI ANTIMONY CHLORIDE (SBCLS)
CHEMICAL NAME: SULFURIC ACID
CHEMICAL NAME: SULFURIC ACID DISODIUM SALT
CHEMICAL NAME: HYDROGEN SULFIDE, (HZS)
CHEMICAL NAME: 7-BENZOTHIAZOLESULFONIC ACID, 6-METHYL-2-(4-(4-(6-METHYL-7-S
ULFOBENZOTHIAZOL-2-YL)PHENYLAZO)PHENYL)-
CHEMICAL NAME: C.I. DIRECT YELLOW 28
CHEMICAL NAME: PYRAZOL YELLOW BO ZSOX
CHEMICAL NAME: SOLAR YELLOW RG
-------
APPENDIX B: STATUS REPORTS BY CAS NUMBER
CAS NUMBER: 8006-14-2 CHEMICAL NAME: NATURAL GAS
SUBMISSION .: 8EHQ-0688-0735
CAS NUMBER: 8061-51-6
SUBMISSION .: 8EHQ-1088-0755
CAS NUMBER: 8061-51-6
SUBMISSION .: 8EHQ-1088-0755
CAS NUMBER: 9005-64-5
SUBMISSION .: 8EHQ-0288-0718
CAS NUMBER: 9012-09-3
SUBMISSION .: 8EHQ-1188-0772
CAS NUMBER: 9012-09-3
\J1
~ SUBMISSION .: 8EHQ-1188-0772
VJ
CAS HUMBER: 9016-87-9
SUBMISSION .: 8EHQ-0788-0H1
CAS NUMBER: 10025-91-9
SUBMISSION .: 8EHQ-0688-0737
CAS HUMBER: 10025-91-9
SUBMISSION .: 8EHQ-0688-0737
CAS NUMBER: 11096-82-5
SUBMISSIOH .: 8EHQ-1188-0769
CHEMICAL HAME: lIGHOSUlFOHIC ACID, SODIUM SALT
CHEMICAL HAME: POlYFON H
CHEMICAL HAME: SORBITAH, MONODODECANOATE, POLYCOXY-1,2-ETHAHEDIYl) DERIVS.
II
CHEMICAL NAME: CELLULOSE, TRIACETATE
CHEMICAL NAME: TRIACETATE FI8ERS, CELLULOSE
CHEMICAL NAME: ISOCYANIC ACID, POLYMETHYLENEPOlYPHENYLENE ESTER
CHEMICAL NAME: ANTIMONY CHLORIDE, (S8Cl3)
CHEMICAL HAME: STIBIHE, TRICHlORO-
CHEMICAL NAME: AROCHlOR 1260
If
-------
APPENDIX B: STATUS REPORTS BY CAS NUMBER
CAS NUMBER: 13047-13-7 CHEMICAL NAME: DIMEZONE S
SUBMISSION .: 8EHQ-0287-0653
CAS NUMBER: 13047-13-7 CHEMICAL NAME: IRGAFORM 1266
SUBMISSION .: 8EHQ-0287-0653
CAS NUMBER: 13047-13-7
SUBMISSION .: 8EHQ-0287-0653
CAS NUMBER: 13463-67-7
SUBMISSION .: 8EHQ-0487-0668
CAS NUMBER: 13893-53-3
SUBMISSION .: 8EHQ-0988-0754
lJ1
I-' CAS NUMBER: 14447-15-5
,po
SUBMISSION I: 8EHQ-0688-0739
CAS NUMBER: 14448-67-0
SUBMISSION I: 8EHQ-0287-0654
CAS NUMBER: 177 96-82-6
SUBMISSION I: 8EHQ-0786-06U
CAS NUMBER: 17796-82-6
SUBMISSION I: 8EHQ-0786-06U
CAS NUMBER: 25213-39-2
SUBMISSION I: 8EHQ-0487-0668
CHEMICAL NAME: 3-PYRAZOLIDINONE, 4-(HYDROXYMETHYL)-4-METHYL-1-PHENYL-
CHEMICAL NAME: TITANIUM OXIDE (TI02)
CHEMICAL NAME: BUTANENITRILE, 2-AMINO-2,3-DIMETHYL-
CHEMICAL NAME: ACETIC ACID, CYANO-, PROPYL ESTER
CHEMICAL NAME: 2(3H)-BENZOTHIAZOLONE, 3-METHYL-, HYDROZONE, HYDROCHLORIDE
CHEMICAL NAME: 1H-ISOINDOLE-l,3(2H)-DIONE, 2-(CYCLOHEXYLTHIO)-
CHEMICAL NAME: SANTOGARD PVI
CHEMICAL HAME: 2-PROPEHOIC ACID, 2-METHYL-, BUTYL ESTER, POLYMER WITH ETHEH
YLBENZENE
-------
APPENDIX B: STATUS REPORTS BY CAS NUMBER
CAS NUMBER: 25322-63-3 CHEMICAL NAME: CARBOWAX PEG-3000
SUBMISSION .: aEHQ-0433-0723
CAS NUMBER: 25322-63-3
SUBMISSION .: 3EHQ-0433-0723
CAS NUMBER: 25973-55-1
SUBMISSION .: 8EHQ-0988-0748
CAS NUMBER: 25973-55-1
SUBMISSION .: 8EHQ-0988-0748
CAS NUMBER: 26741-53-7
SUBMISSION .: 3EHQ-1287-0706
U1
f--'
U1 CAS NUMBER: 26741-53-7
SUBMISSION .: aEHQ-1287-0706
CAS NUMBER: 26741-53-7
SUBMISSION .: 3EHQ-1237-0706
CAS HUMBER: 26741-53-7
SUBMISSION .: 8EHQ-1287-0706
CAS NUMBER: 26741-53-7
SUBMISSION .: 8EHQ-1287-0706
CAS NUMBER: 26741-53-7
SUBMISSION .: 3EHQ-1287-0706
CHEMICAL NAME: POlY(OXY-1,2-ETHANEDIYl), .AlPHA.-HYDRO-.OMEGA.-HYDROXY-
CHEMICAL NAME: PHENOL, 2-(2H-BENZOTRIAZOl-2-Yl)-4,6-BIS(1,1-DIMETHYlPROPYl)
CHEMICAL NAME: TINUVIN 323
CHEMICAL NAME: 2,4,3,10-TETRAOXA-3,9-DIPHOSPHASPIRO[S.SJUNDECANE, 3,9-BIS[2
,4-BIS(1,1-DIMETHYlETHYl)PHENOXYJ-
CHEMICAL HAME: UlTRANOX 624
CHEMICAL NAME: ULTRANOX 626
CHEMICAL NAME: UlTRANOX 626A
CHEMICAL NAME: WESTON MDW-6140
CHEMICAL NAME: WESTON XR-14S2
-------
APPEHDIX B: STATUS REPORTS BY CAS HUMBER
CAS HUMBER: 26741-53-7 CHEMICAL HAME: WESTOH XR-1532
SUBMISSIOH .: 3EHQ-1237-0706
CAS NUMBER: 27193-36-3 CHEMICAL HAME: PHEHOL, DODECYL-
SUBMISSIOH .: 3EHQ-0687-0682
CAS NUMBER: 30965-26-5
SUBMISSIOH .: 3EHQ-0233-0720
CAS HUMBER: 36443-63-2
SUBMISSION .: 3EHQ-0388-0725
CAS NUMBER: 36443-68-2
U'1 SUBMISSION .: 3EHQ-0383-0725
t-'
(j\
CAS HUMBER: 43130-12-7
SUBMISSIOH .: 3EHQ-0533-0730
CAS HUMBER: 43130-12-7
SUBMISSIOH .: 8EHQ-0583-0730
CAS NUMBER: 43130-12-7
SUBMISSIOH .: 3EHQ-0533-0730
CAS HUMBER:
52495-71-3
SUBMISSION .: 3EHQ-1237-0709 S
CAS NUMBER:
55233-63-6
SUBMISSIOH .: 3EHQ-1083-0755
CHEMICAL NAME: 1,4-BEHZEHEDICARBOXYLIC ACID, DIMETHYL ESTER, POLYMER WITH 1
,4-BUTAHEDIOL
CHEMICAL NAME: BEHZEHEPROPAHOIC ACID, 3-(1,1-DIMETHYLETHYL)-4-HYDROXY-5-MET
HYL-, 1,2-ETHAHEDIYLBIS(OXY-2,1-ETHAHEDIYL) ESTER
CHEMICAL HAME: IRGAHOX 245
CHEMICAL HAME: AURAMIHE, ETHYL-, HITRATE SALT
CHEMICAL HAME: C. I. BASIC YELLOW 37
CHEMICAL HAME: BENZEHAMIHE, 4,4'-CARBOHIMIDOYLBIS[H,H-DIETHYL-, MOHOHITRATE
CHEMICAL HAME: POLY(OXY-1,2-ETHAHEDIYL), A-HYDRO-W-(OXIRAHYLMETHOXY)-, ETHE
R WITH 2-ETHYL-2-(HYDROXYMETHYL)-1,3-PROPAHEDIOl (3:1)
CHEMICAL HAME: 8EHZEHAMIHE, H-ETHYL-H~(2-METHYL-2-PROPEHYL)-2,6-DINITRO-4-(
TRIFLUOROMETHYL)-
-------
APPENDIX B:
STATUS REPORTS BY CAS NUMBER
CAS NUMBER: 55283-68-6 CHEMICAL NAME: ETHALFlURALIN
SUBMISSION I: 8EHQ-I088-0755
CAS NUMBER: 55283-68-6 CHEMICAL NAME: SONALAN
SUBMISSION I: 8EHQ-I088-0755
CAS NUMBER: 55406-53-6 CHEMICAL NAME: CARBAMIC ACID, BUTYl-, 3-IODO-2-PROPYHYL ESTER
SUBMISSIOH I: 8EHQ-OI33-071Z II
CAS NUMBER: 59607-71-5 CHEMICAL NAME: THIOCYAHIC ACID, 4-METHOXY-2-NITRQPHEHYL ESTER
SUBMISSION I: 8EHQ-0388-07Z1
CAS HUMBER: 61739-36-4 CHEMICAL NAME: HAPHTHENIC ACIDS, CALCIUM SALTS
SUBMISSION I: 3EHQ-0537-0675 If
Ul
I-' CAS NUMBER: 63231-67-4 CHEMICAL NAME: HI-SIl 233
-..J
SUBMISSION I: 3EHQ-I083-0755
CAS NUMBER: 63231-67-4 CHEMICAL NAME: SILICA Gel
SUBMISSION I: 8EHQ-I088-0755
CAS NUMBER: 63943-38-4
SUBMISSION I: 8EHQ-0487-0661 S
CAS NUMBER: 64741-52-2
SUBMISSION I: 8EHQ-0887-0691 S
CAS NUMBER: 64741-53-3 CHEMICAL NAME: DISTILLATES (PETROLEUM), HEAVY NAPHTHEHIC
SUBMISSION I: 8EHQ-0887-0691 S
CHEMICAL NAME: POLY[(DIMETHYLIMIHIO)-1,6-HEXANEDIYL(DIMETHYLIMINIO)METHYLEN
E[I,I'-BIPHEHYL]-4,4'-DIYLMETHYLEHE DICHLORIDE]
CHEMICAL NAME: DISTILLATES (PETROLEUM), LIGHT NAPHTHENIC
-------
APPEHDIX B:
CAS HUMBER: 64741-56-6
SUBMISSIOH I: 8EHQ-0483-0727
CAS HUMBER: 64741-60-2
SUBMISSIOH I: 8EHQ-0483-0727
CAS HUMBER: 64741-62-4
SUBMISSIOH I: 8EHQ-0488-0727
CAS HUMBER: 64741-75-9
SUBMISSIOH I: 8EHQ-1283-0774
CAS HUMBER: 64741-75-9
SUBMISSIOH I: 8EHQ-1283-0774
Ul
~
Ct:> CAS HUMBER: 64741-76-0
SUBMISSIOH I: 8EHQ-1288-0773
CAS HUMBER: 64741-76-0
SUBMISSIOH I: 8EHQ-1283-0771
CAS HUMBER: 64741-88-4
SUBMISSIOH I: 8EHQ-0887-0691 S
CAS HUMBER: 64742-46-7
SUBMISSIOH I: 8EHQ-1283-0775
CAS HUMBER: 64742-46-7
SUBMISSIOH I: aEHQ-128a-0775
STATUS REPORTS BY CAS NUMBER
CHEMICAL NAME: RESIDUES (PETROLEUM), VACUUM
CHEMICAL NAME: DISTILLATES (PETROLEUM), INTERMEDIATE CATALYTIC CRACKED
CHEMICAL NAME: CLARIFIED OILS, (PETROLEUM), CATALYTIC CRACKED
CHEMICAL NAME: RESID HYDROPROCESSING UNIT (RHU) lIGHT VACUUM GAS OILS
CHEMICAL NAME: RESIDUES, (PETROLEUM), HYDROCRACKED
CHEMICAL NAME: DISTILLATES (PETROLEUM), HEAVY HYDROCRACKED
CHEMICAL NAME: RESID HYDROPROCESSING UNIT (RHU) MIDDLE DISTILLATES
CHEMICAL NAME: DISTILLATES (PETROLEUM), SOLVENT-REFINED HEAVY PARAFFINIC
CHEMICAL NAME: AMOCO NT-45 PROCESS OIL
CHEMICAL HAME: DISTILLATES (PETROLEUM), HYDROTREATED MIDDLE
-------
APPEHDIX B:
CAS HUMBER:
64742-52-5
SUBMISSIOH .: 3EHQ-0887-0691 S
CAS HUMBER: 64742-53-6
SUBMISSIOH .: 3EHQ-0887-0691 S
CAS HUMBER: 64742-65-0
SUBMISSIOH .: 8EHQ-0887-0691 S
CAS HUMBER: 64742-86-5
SUBMISSIOH .: 3EHQ-0837-0687
CAS HUMBER: 64742-87-6
SUBMISSIOH .: SEHQ-1237-0710
U1
~ CAS HUMBER: 64742-95-6
\D
SUBMISSIOH .: 3EHQ-0537-0673
CAS HUMBER: 63214-31-3
SUBMISSIOH .: 8EHQ-0233-0719
CAS HUMBER: 63214-31-3
SUBMISSIOH .: 3EHQ-0233-0719
CAS HUMBER: 63334-30-5
SUBMISSIOH .: 3EHQ-0437-0671
CAS HUMBER: 63334-30-5
SUBMISSIOH .: 3EHQ-0437-0671
STATUS REPORTS BY CAS HUMBER
CHEMICAL HAME: DISTILLATES, (PETROLEUM), HYDROTREATED HEAVY HAPHTHEHIC
CHEMICAL HAME: DISTILLATES (PETROLEUM), HYDROTREATED LIGHT HAPHTHEHIC
CHEMICAL HAME: DISTILLATES (PETROLEUM), SOLVEHT-DEWAXED HEAVY PARAFFIHIC
CHEMICAL HAME: GAS OILS, (PETROLEUM), HYDRODESULfURIZED HEAVY VACUUM
3EHQ-1237-0710
CHEMICAL HAME: GAS OILS, (PETROLEUM), HYDRODESULFURIZED LIGHT VACUUM
CHEMICAL HAME: SOLVEHT HAPHTHA (PETROLEUM), LIGHT AROM.
CHEMICAL HAME: CHEMICAL 400, STEP 1
CHEMICAL HAME: ETHAHOL, 2-[ETHYL[3-METHYL-4-(PHEHYLAZO)PHEHYL]AMIHO]-
CHEMICAL HAME: FUELS, DIESEL
CHEMICAL HAME: OIL (PETROLEUM), DIESEL
-------
CAS NUMBER: 68412-01-1
SUBMISSION .: 8EHQ-0687-0679
CAS NUMBER: 68476-30-2
SUBMISSIOH .: 8EHQ-1l87-0697
CAS NUMBER: 68476-30-2
SUBMISSION .: 8EHQ-1l87-0697
CAS HUMBER: 68553-00-4
SUBMISSIOH .: 8EHQ-0488-0727
CAS NUMBER: 87257-05-4
SUBMISSIOH .: 8EHQ-1287-0709 S
Ul
N CAS HUMBER: 94361-06-5
0
SUBMISSION .: 8EHQ-0287-0658
CAS NUMBER: 94361-06-5
SUBMISSIOH .: 8EHQ-0287-0658
CAS HUMBER: 107534-96-3 CHEMICAl NAME: TERBUCONAZOlE
SUBMISSIOH .: 8EHQ-0688-0738
APPENDIX B:
STATUS REPORTS BY CAS NUMBER
CHEMICAL NAME: D-GlUCITOl. REACTION PRODUCTS WITH EPICHlOROHYDRIH
CHEMICAL NAME: FUEL OIL. HO. 2
CHEMICAL NAME: OIL (~ETROlEUM). FURNACE
CHEMICAL NAME: FUEL OIL. NO.6
CHEMICAL NAME: OXIRANE. 2.2'-(3.7.7.11-TETRAMETHYl-2.5.9.12-TETRAOXATRIDECA
NE-l.13-DIYl)BIS-
CHEMICAL NAME: SAH 619F
CHEMICAL NAME: IH-l.2.4-TRIAZOlE-I-ETHANOl. .AlPHA.-(4-CHlOROPHEHYl)-.AlPHA
.-(I-CYClOPROPYlETHYl)-. (RM.RM)-(.+-.)-
Based on a preliminary evaluation, EPA believed that the submitted information did not ",.rr.nt reporting under
~ect ion 8 (e) of TSCA. In most cases, the submi tter was requested to provide the basis for contendin that the
Information offered, reaS?nable ~u~port for the conclusion that the subject chemical substance(s) or ~ixture(s
presents a substantial risk of ~nJury to health or the environment as defined in EPA's TSCA Section 8(e) Poli )
statement (see Appendix A of thiS volume). cy
-------
CAS NUMBER:
107-20-0
SUBMISSION I: 8EHQ-0387-0660
CAS NUMBER:
CONFIDENT
SUBMISSION I: 8EHQ-1188-0770 S
CAS HUMBER, 123-86-4
SUBMISSION I: 8EHQ-0387-0659
CAS NUMBER: 14447-15-5
SUBMISSION I: 8EHQ-0688-0739
CAS HUMBER: 108-05-4
SUBMISSIOH I: 8EHQ-0187-0650
(Jl
N
~ CAS HUMBER: UNKNOWH
SUBMISSION .: 8EHQ-0987-0692
CAS HUMBER: 67-64-1
SUBMISSION .: 8EHQ-I088-0759
CAS NUMBER: 107-16-4
SUBMISSIOH .: 8EHQ-0988-0754
CAS HUMBER:
COHFIDEHT
SUBMISSION I: 8EHQ-1287-0708 S
CAS HUMBER:
3734-67-6
SUBMISSION .: 8EHQ-0788-0743
APPENDIX C:
STATUS REPORTS BY CHEMICAL HAME
CHEMICAL HAME: ACETALDEHYDE, CHLORO-
CHEMICAL HAME: ACETAL, HETEROCYCLIC
CHEMICAL NAME: ACETIC ACID. BUTYL ESTER
CHEMICAL HAME: ACETIC ACID, CYAHO-. PROPYL ESTER
CHEMICAL HAME: ACETIC ACID ETHEHYl ESTER
CHEMICAL NAME: ACETIC ACID. OXO-, METHYL ESTER OR ETHYL ESTER, HOMOPOLYMER,
REACTIOH PRODUCTS WITH ETHOXYETHEHE AHD REACTIOH PRODUCTS W
ITH METHOXYETHEHE, SODIUM SALTS
CHEMICAL NAME: ACETOHE
CHEMICAL HAME: ACETOHITRIlE. HYDROXY-
CHEMICAL HAME: ACETOPHEHONE OXIME
CHEMICAL HAME: C. I. ACID RED 1
-------
APPENDIX C: STATUS REPORTS BY CHEMICAL NAME
CAS NUMBER: CONFIDENT CHEMICAL NAME: ACRYLIC ACID DERIVATIVES
SUBMISSION I: 8EHQ-1288-0776
CAS NUMBER: CONFIDENT CHEMICAL NAME: ALKYL HETEROCYCLIC NITROGEN COMPOUND
SUBMISSION I: 8EHQ-1088-0760 S
CAS NUMBER: CONFIDENT CHEMICAL NAME: ALKYL PHENOL, MODIFIED
SUBMISSION I: 8EHQ-0787-0686 S
CAS NUMBER: CONFIDENT CHEMICAL NAME: AMIDE, HETEROCYCLIC ARYL
SUBMISSION I: 8EHQ-0988-0750 S
CAS NUMBER: NONE CHEMICAl NAME: AMINE MIXTURE
SUBMISSION I: 8EHQ-0287-0652 S
lJ1
N CAS NUMBER: CONFIDENT CHEMICAL NAME: AMMONIUM CARBOXYLATE, SUBSTITUTED
N
SUBMISSION I: 8EHQ-0587-0674 S
CAS NUMBER: 64742-46-7 CHEMICAL NAME: AMOCO NT-45 PROCESS OIL
SUBMISSION I: 8EHQ-1288-0775
CAS NUMBER: 10025-91-9 CHEMICAL HAME: ANTIMONY CHLORIDE, (SBCU)
SUBMISSION I: 8EHQ-0688-0n7
CAS NUMBER: 7647-18-9 CHEMICAL NAME: ANTIMONY CHLORIDE (SBCL5)
SUBMISSION I: 8EHQ-0688-0737
CAS NUMBER: 1327-33-9 CHEMICAL NAME: ANTIMONY OXIDE
SUBMISSION I: 8EHQ-0288-0720
-------
(J1
N
W
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS HUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS HUMBER:
CAS HUMBER:
1309-64-4
SUBMISSION .: 3EHQ-0633-0737
HONE
SUBMISSION .: 3EHQ-0237-0652 S
1146-31-2
SUBMISSION .: 3EHQ-1033-0755
11096-32-5
SUBMISSION .: 3EHQ-1133-0769
1440-33-2
SUBMISSION .: 3EHQ-0633-0735
593-33-4
SUBMISSIOH .: 3EHQ-063a-0735
CONFIDENT
SUBMISSION .: 3EHQ-1138-076S S
43130-12-7
SUBMISSION .: 8EHQ-0538-0730
2465-27-2
SUBMISSION .: 3EHQ-0533-0730
2465-27-2
SUBMISSIOH .: 3EHQ-05aa-0730
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: AHTIMONY OXIDE (SB203)
CHEMICAL NAME: ARCEL RESIN ANTISTAT
CHEMICAL HAME: ARESIN
CHEMICAL NAME: AROCHLOR 1260
It
CHEMICAL NAME: ARSENIC
3EHQ-1D33-0759
CHEMICAL NAME: ARSINE, TRIMETHYL-
CHEMICAL NAME: ARYL OXIME
CHEMICAL NAME: AURAMINE, ETHYL-, NITRATE SALT
CHEMICAL NAME: AURAMIHE HYDROCHLORIDE
CHEMICAL NAME: C. I. BASIC YELLOW 2
-------
CAS NUMBER: 43130-12-7
SUBMISSION .: 8EHQ-0588-0730
CAS NUMBER: 55283-68-6
SUBMISSION .: 8EHQ-1088-0755
CAS NUMBER: 768-52-5
SUBMISSION .: 8EHQ-1287-0702
CAS NUMBER: 43130-12-7
SUBMISSION .: 8EHQ-0588-0730
CAS NUMBER: 2465-27-2
U1 SUBMISSION .: 8EHQ-0588-0730
N
t!=>-
CAS NUMBER: 101-54-2
SUBMISSION .: 8EHQ-0888-0746
CAS NUMBER: 117-81-7
SUBMISSION .: 8EHQ-0587-0672 S
CAS NUMBER: UNKNOWN
SUBMISSION .: 8EHQ-1083-0759
CAS NUMBER: 30965-26-5
SUBMISSION .: 8EHQ-0288-0720
CAS NUMBER: 36443-68-2
SUBMISSION .: 8EHQ-0388-0725
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: C. I. BASIC YEllOW 37
CHEMICAL NAME: BENZENAMINE, N-ETHYl-N-CZ-METHYl-Z-PROPENYl)-Z,6-DINITRO-4-C
TRIFlUOROMETHYl)-
CHEMICAL NAME: BENZEHAMINE, H-C1-METHYlETHYl)-
8EHQ-1Z87-0703
CHEMICAL NAME: BENZENAMINE, 4,4'-CARBONIMIDOYlBI5[N,N-DIETHYl-, MONONITRATE
CHEMICAL HAME: BENZEHAMINE, 4,4'-CARBONIMIDOYlBIS[H,N-DIMETHYl-, MONOHYDROC
HlORIDE
CHEMICAL NAME: 1,4-BENZEHEDIAMINE, N-PHEHYl-
CHEMICAL NAME: 1,Z-BEHZEHEDICARBOXYlIC ACID, BISCZ-ETHYlHEXYl) ESTER
CHEMICAL HAME: 1,Z-BEHZEHEDICARBOXYlIC ACID DERIY.
CHEMICAL HAME: 1,4-BEHZEHEDICARBOXYlIC ACID, DIMETHYL ESTER, POl,~ER WITH 1
,4-BUTAHEDIOl
CHEMICAL HAME: BEHZEHEPROPAHOIC ACID, 3-C1,1-DIMETHYlETHYl)-4-HYDROXY-5-MET
HYl-, 1,2-ETHAHEDIYlBISCOXY-Z,1-ETHAHEDIYl) ESTER
-------
CAS NUMBER: 99-42-3 CHEMICAL
SUBMISSION .: 8EHQ-0287-0657 S
Ul
N
Ul CAS NUMBER: 98-73-7
SUBMISSION .: 8EHQ-D388-0726
CAS NUMBER: 8005-72-9
SUBMISSION .: 8EHQ-0687-0677
CAS NUMBER: 6294-52-6
SUBMISSION .: 8EHQ-D588-0732
CAS NUMBER: 4338-98-1
SUBMISSION .: 8EHQ-0287-0654
CAS NUMBER: 14448-67-0
SUBMISSION .: 8EHQ-0287-0654
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-0288-0720
CAS NUMBER: CONFIDENT
SUBMISSION .: 8EHQ-D588-D731 S
CAS NUMBER: 1163-}9-5
SUBMISSION .: 8EHQ-0288-0720
CAS NUMBER: 98-73-7
SUBMISSION .: 8EHQ-0388-0726
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: BENZENE, 1,1'-OXYBIS-, BROMINATED DERIV.
CHEMICAL NAME: BENZENE, 1,1'-OXYBIS-, SUBSTITUTED
CHEMICAL NAME: BENZENE, 1,1'-OXYBIS[Z,3,4,5,6-PENTABROMO-
CHEMICAL NAME: BENZOIC ACID, P-TERT-BUTYL-
II
NAME: BENZOIC ACID, 4-HYDROXY-]-NITRO-, METHYL ESTER
CHEMICAL NAME: BENZOIC ACID, 4-(1,1-DIMETHYLETHYL)-
II
CHEMICAL NAME: 7-BENZOTHIAZOLESULFONIC ACID, 6-METHYL-Z-(4-(4-(6-METHYL-7-S
UlFOBENZOTHIAZOl-Z-Yl)PHENYlAZO)PHENYl)-
CHEMICAL NAME: BENZOTHIAZOLE, Z-AMINO-5,6-DIMETHOXY-
CHEMICAL NAME: 2(3H)-BENZOTHIAZOLONE, 3-METHYL-, HYDRAZONE, MONOHYDROCHLORI
DE
CHEMICAL NAME: 2(]H)-BENZOTHIAZOlONE, ]-METHYl-, HYDROZONE, HYDROCHLORIDE
-------
CAS NUMBER: 39-32-7
SUBMISSION .: 3EHQ-1237-0711
CAS NUMBER: 7440-41-7
SUBMISSION .: 3EHQ-1033-0759
CAS NUMBER: 1336-36-3
SUBMISSION .: 3EHQ-1138-0769
CAS NUMBER: CONFIDENT
SUBMISSION .: 3EHQ-1238-0776
CAS NUMBER:
CONFIDENT
SUBMISSION .: 8EHQ-0487-0665 S
U1
N CAS NUMBER: 126-99-3
'"
SUBMISSION .: 3EHQ-0387-0689
CAS NUMBER: 78-]9-5
SUBMISSION .: 8EHQ-0837-0639
CAS HUMBER: 106-9]-8
SUBMISSION .: 3EHQ-04a7-0671
CAS NUMBER: 13893-53-3
SUBMISSION .: 3EHQ-0988-0754
CAS HUMBER: 565-74-2
SUBMISSION .: 8EHQ-0188-0714
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: 1H.3H-BENZO[1.2-C:4.5-C']DIFURAN-1.3.5.7-TETRONE
CHEMICAL NAME: BERYLLIUM
CHEMICAL NAME: 1.1'-BIPHENYL. CHLORO DERIVS.
II
CHEMICAL NAME: BORDON CHEMICAL COMPOUND 9MKU10103R
CHEMICAL NAME: BSC-125 SURFACTANT
II
CHEMICAL NAME: 1.3-BUTADIENE. 2-CHLORO-
II
CHEMICAL NAME: 1.3-BUTADIENE. 2-METHYL-
II
>
CHEMICAL NAME: BUTANE
CHEMICAL NAME: BUTANENITRILE. 2-AMINO-2.3-DIMETHYL-
CHEMICAL NAME: BUTANOIC ACID, 2-BROMO-3-METHYL-
-------
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
<.Jl
tV
-..)
CAS NUMBER:
CAS NUMBER:
78-93-3
SUBMISSION .: 8EHQ-I088-0759
58-08-2
SUBMISSION .: 8EHQ-0587-0672 S
55406-53-6
SUBMISSION .: 8EHQ-0188-0712
CONFIDENT
SUBMISSION I: 8EHQ-0788-0745 S
7440-44-0
SUBMISSION .: 8EHQ-0487-0668
75-15-0
SUBMISSION I: 8EHQ-1088-0759
CONFIDENT
SUBMISSION .: 8EHQ-0487-0667 S
CAS NUMBER: 25322-68-3
SUBMISSION I: 8EHQ-0438-0728
CAS NUMBER: NONE
SUBMISSION I: 8EHQ-1287-0699
CAS NUMBER: 9012-09-3
SUBMISSION .: 8EHQ-1188-0772
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: 2-BUTANONE
CHEMICAL NAME: CAFFEINE
CHEMICAL NAME: CARBAMIC ACID, BUTYl-, 3-IODO-2-PROPYNYl ESTER
If
CHEMICAL NAME: CARBOMONOCYClIC AMINOBUTYROlACTONE
CHEMICAL NAME: CARBON
CHEMICAL NAME: CARBON DISULFIDE
CHEMICAL NAME: CARBONOCHlORIDOTHIOIC ACID, ARYL ESTER
If
CHEMICAL NAME: CARBOWAX PEG-8000
CHEMICAL NAME: CATALYSTS
CHEMICAL NAME: CEllULOSE, TRIACETATE
-------
CAS NUMBER: 68214-31-3
SUBMISSION .: 8EHQ-0288-0719
CAS NUMBER: 67-66-3
SUBMISSION .: 8EHQ-I088-0759
CAS NUMBER: 126-99-8
SUBMISSIOH .: 8EHQ-0887-0689
CAS NUMBER: 7440-47-3
SUBMISSION .: 8EHQ-I088-0759
CAS NUMBER: 64741-62-4
SUBMISSIOH .: 8EHQ-0488-0727
U1
N
Q;)
CAS NUMBER:
CONFIDEHT
SUBMISSION .: 8EHQ-0187-0649 S
CAS NUMBER:
NONE
SUBMISSIOH .: 8EHQ-I088-0761
CAS NUMBER:
142-22-3
SUBMISSIOH .: 8EHQ-0487-0666 S
CAS NUMBER:
NOHE
SUBMISSIOH .: 8EHQ-0788-0742
CAS NUMBER:
CONFIDEHT
SUBMISSIOH .: 8EHQ-I088-0758 S
APPEHDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL HAME: CHEMICAL 400, STEP 1
CHEMICAL NAME: CHLOROFORM
CHEMICAL NAME: CHlOROPREHE
If
CHEMICAL NAME: CHROMIUM
CHEMICAL HAME: CLARIFIED OILS, (PETROLEUM), CATALYTIC CRACKED
CHEMICAL NAME: CONFIDEHTIAL
CHEMICAL HAME: COOlAHTS, AUTOMOTIVE
CHEMICAL NAME: CR-39 MONOMER
CHEMICAL NAME: CUTTING FLUID
If
CHEMICAL HAME: CYClOHEXENOHE, SUBSTITUTED
-------
CAS NUMBER:
6262-51-7
SUBMISSION .: 3EHQ-0537-0673
CAS NUMBER:
556-67-2
SUBMISSION .: 3EHQ-0233-0713
CAS NUMBER:
7173-51-5
SUBMISSION I: 3EHQ-0183-0712
CAS HUMBER:
HOHE
SUBMISSIOH I: 3EHQ-1033-0761
CAS HUMBER:
COHFIDEHT
SUBMISSIOH .: 3EHQ-0137-0649 S
\Jl
N CAS HUMBER: NONE
\!:J
SUBMISSION I: 3EHQ-0233-0720
CAS NUMBER: 13047-13-7
SUBMISSION I: 3EHQ-0237-0653
CAS NUMBER: 123-91-1
SUBMISSION I: aEHQ-1038-0761
CAS NUMBER: NONE
SUBMISSION I: 3EHQ-0487-0671
CAS HUMBER: NONE
SUBMISSION .: 3EHQ-0437-0671
APPENDIX C:
STATUS REPORTS 8Y CHEMICAL NAME
CHEMICAL HAME: CYCLOPROPANE, PENTACHLORO-
CHEMICAL NAME: CYCLOTETRASILOXANE, OCTAMETHYL-
II
CHE"ICAL NA"E: I-DECAHA"IHIU", N-DECYL-H,H-DI"ETHYL-, CHLORIDE
II
CHE"ICAL HA"E: DE-ICIHG FLUIDS, AIRCRAFT
CHE"ICAL HA"E: DIA"IHE, ALKOXYLATED ARO"ATIC
CHE"ICAL HA"E: DIBEHZOFURAHS, BRO"INATED
CHE"ICAL HA"E: DI"EZOHE S
CHE"ICAL HA"E: 1,4-DIOXANE
CHEMICAL HAME: DIOXIH, HEPTACHLORODI8EHZO-P-
CHEMICAL HA"E: DIOXIN, HEXACHLORODI8ENZO-P-
-------
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-0487-0671
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-0487-0671
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-0288-0720
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-0487-0671
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-0487-0671
Ul CAS NUMBER: 1746-01-6
w
0 SUBMISSION .: 8EHQ-0487-0671
CAS NUMBER:
CONFIDENT
SUBMISSION I: 8EHQ-0588-0731 S
CAS NUMBER: 8005-72-9
SUBMISSION I: 8EHQ-0687-0677
CAS NUMBER: 64741-76-0
SUBMISSION I: 8EHQ-1288-0773
CAS NUMBER: 64741-53-3
SUBMISSION I: 8EHQ-0887-0691 S
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: DIOXIN. OCTACHLORODIBENlO-P-
CHEMICAL NAME: DIOXIN. PENTACHLORODIBENlO-P-
CHEMICAL NAME: DIOXINS. BROMINATED
CHEMICAL NAME: DIOXINS. CHLORINATED
CHEMICAL NAME: DIOXIN. TETRACHLORODIBENZO-P-
CHEMICAL NAME: DIOXIN. 2.3.7.8-TETRACHLORODIBENZO-P-
CHEMICAL NAME: DIPHENYL ETHER. SUBSTITUTED
CHEMICAL NAME: C.I. DIRECT YELLOW 28
CHEMICAL NAME: DISTILLATES (PETROLEUM). HEAVY HYDROCRACKED
CHEMICAL NAME: DISTILLATES (PETROLEUM). HEAVY NAPHTHENIC
-------
CAS NUMBER:
64742-52-5
SUBMISSION I: 8EHQ-0887-0691 S
CAS NUMBER: 64742-53-6
SUBMISSION I: 8EHQ-0887-0691 S
CAS NUMBER: 64742-46-7
SUBMISSION I: 8EHQ-1288-0775
CAS NUMBER: 64741-60-2
SUBMISSION I: 8EHQ-0488-0727
CAS NUMBER: 64741-52-2
SUBMISSION I: 8EHQ-0887-0691 S
-------
CAS NUMBER: 3033-62-3
SUBMISSION .: 8EHQ-0687-0683
CAS NUMBER: 75-00-3
SUBMISSION .: 8EHQ-0188-0713
CAS NUMBER: 107-21-1
SUBMISSION .: 8EHQ-I0U-0761
CAS NUMBER: 107-06-2
SUBMISSION .: 8EHQ-0487-0662
CAS NUMBER: 1649-08-7
SUBMISSION .: 8EHQ-0587-0676
Ul
W CAS NUMBER: NONE
N
SUBMISSION I: 8EHQ-1287-0701
CAS NUMBER: 107-07-3
SUBMISSION I: 8EHQ-1187-0698
CAS NUMBER: 68214-81-3
SUBMISSION I: 8EHQ-02U-0719
CAS NUMBER: 112-60-7
SUBMISSION I: 8EHQ-0987-0693
CAS NUMBER:
CONFIDENT
SUBMISSION I: 8EHQ-1188-0771 5
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: ETHANAMINE. 2,2'-OXYBIS[H,N-DIMETHYl-
CHEMICAL NAME: ETHANE, CHlORO-
CHEMICAL NAME: 1,2-ETHANEDIOl
CHEMICAL NAME: ETHANE. 1.2-DICHlORO-
CHEMICAL NAME: ETHANE, 1,2-DICHlORO-l,I-DIFlUORO-
CHEMICAL NAME: ETHAHOl (STRONG ACID PRODUCTIOH PROCESS)
If
CHEMICAL HAME: ETHAHOl. 2-CHlORO-
CHEMICAL HAME: ETHAHOl. 2-[ETHYl[3-METHYl-4-(PHEHYlAZO)PHEHYl]AMIHO]-
CHEMICAL HAME: ETHAHOl. 2.2'-[OXYBIS(2,1-ETHAHEDIYlOXY)]BIS-
CHEMICAL NAME: ETHER. ALKYL ARYL
-------
CAS NUMBER:
CONFIDENT
SUBMISSION I: 8EHQ-0487-0664 S
CAS NUMBER:
CONFIDENT
SUBMISSION I: 8EHQ-09SS-0751 S
CAS NUMBER:
107-21-1
SUBMISSION I: SEHQ-10SS-0761
CAS NUMBER:
CONFIDENT
SUBMISSION I: SEHQ-09SS-0752 S
CAS NUMBER: 3236-71-3
SUBMISSION I: SEHQ-12S7-0700
lJ1
W
w CAS NUMBER: NONE
SUBMISSION I: SEHQ-06SS-073S
CAS NUMBER: NONE
SUBMISSION I: SEHQ-06SS-073S
CAS NUMBER: NONE
SUBMISSION I: SEHQ-02SS-0722
CAS NUMBER: 68476-30-2
SUBMISSION I: SEHQ-llS7-0697
CAS NUMBER: UNKNOWN
SUBMISSION I: SEHQ-llS7-0697
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: ETHER (CYCLIC). HAlOAlKYl SUBSTITUTED
CHEMICAL NAME: ETHER. DIARYl
CHEMICAL NAME: ETHYlEHE GLYCOL
CHEMICAL NAME: FIBER. INORGANIC
CHEMICAL NAME: FLUORENE. 9.9-BIS(4-HYDROXYPHENYl)-
CHEMICAL NAME: FOlICUR TECHNICAL
CHEMICAL NAME: FOlICUR 1.2 EC
CHEMICAL NAME: FREKOTE 700
CHEMICAL NAME: FUEL OIL. NO.2
CHEMICAL NAME: FUEL OIL. NO.2. SUB FRACTIONS
-------
CAS NUMBER: 68553-00-4
SUBMISSION I: 8EHQ-0488-0121
CAS NUMBER: 68334-30-5
SUBMISSION I: 8EHQ-0481-0611
CAS NUMBER: 64142-86-5
SUBMISSION I: 8EHQ-0881-0681
CAS NUMBER: 64142-81-6
SUBMISSION I: 8EHQ-1281-0110
CAS NUMBER: 68412-01-1
SUBMISSION I: 8EHQ-0681-0619
U1 CAS NUMBER: CONFIDENT CHEMICAL NAME: HALOALKYL HETEROCYCLE
w
"'" SUBMISSION I: 8EHQ-1188-0161 S
CAS NUMBER:
NONE
SUBMISSION I: 8EHQ-0581-0613
CAS NUMBER:
1649-08-1
SUBMISSION I: 8EHQ-0581-0616
CAS NUMBER:
CONFIDENT
SUBMISSION I: 8EHQ-1188-0166 S
CAS NUMBER:
680-31-9
SUBMISSION I: 8EHQ-I088-0159
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: FUEL OIL. NO.6
CHEMICAL NAME: FUELS, DIESEL
CHEMICAL NAME: GAS OILS, (PETROLEUM>. HYDRODESULFURIZED HEAVY VACUUM
8EHQ-1281-0110
CHEMICAL NAME: GAS OILS. (PETROLEUM>. HYDRODESULFURIZED LIGHT VACUUM
CHEMICAL NAME: D-GLUCITOL. REACTION PRODUCTS WITH EPICHLOROHYDRIN
CHEMICAL NAME: N-1336 HAN
CHEMICAL NAME: HCFC-132B
CHEMICAL NAME: HETEROARYL ALKYL ETHER
CHEMICAL NAME: HEXAMETHYLPHOSPHORAMIDE
-------
CAS NUMBER:
94-96-2
SUBMISSION I: 8EHQ-1288-0778
APPENDIX C:
STATUS REPORTS BY CHEMICAL HAME
CHEMICAL NAME: 1,3-HEXAHEDIOL, 2-ETHYL-
CAS HUMBER: 149-57-5 CHEMICAL NAME: HEXAHOIC ACID, 2-ETHYL-
SUBMISSIOH I: 8EHQ-0587-0672 S 8EHQ-I088-0764 S
CAS HUMBER: 104-76-7 CHEMICAL HAME: I-HEXAHOL, 2-ETHYL-
SUBMISSIOH I: 8EHQ-0587-0672 S
CAS NUMBER: 760-67-8
SUBMISSION I: SEHQ-0387-0656
CAS NUMBER: 63231-67-4
SUBMISSION I: SEHQ-I088-0755
LTI
W
LTI CAS NUMBER: 7647-01-0
SUBMISSION I: 8EHQ-OS87-0688
CAS NUMBER: 7783-06-4
SUBMISSION I: 8EHQ-0488-0727
CAS NUMBER: UNKHOWH
SUBMISSIOH I: 8EHQ-0487-0669
CAS HUMBER: UHKNOWH
SUBMISSION I: 8EHQ-0487-0669
CAS NUMBER: NONE
SUBMISSION I: 8EHQ-0488-0728
CHEMICAL NAME: HEXAHOYL CHLORIDE, 2-ETHYL-
CHEMICAL HAME: HI-SIL 233
CHEMICAL NAME: HYDROCHLORIC ACID
CHEMICAL HAME: HYDROGEN SULFIDE, (H2S)
CHEMICAL NAME: 2-IMIDAZOLIDINOHE, 1,3-DIBROMO-4.4,S,5-TETRAMETHYL-
M
CHEMICAL NAME: 2-IMIDAZOlIDIHONE, 1,3-DICHlORO-4,4.5,5-TETRAMETHYl-
M
CHEMICAL NAME: IMPOSIT
-------
CAS NUMBER:
CONFIDENT
SUBMISSION I: 3EHQ-0988-0753 S
CAS NUMBER: CONFIDENT
SUBMISSION I: 8EHQ-1188-0763 S
CAS NUMBER: 13047-13-7
SUBMISSION I: 8EHQ-0287-0653
CAS NUMBER: 36443-63-2
SUBMISSION I: 8EHQ-0388-0725
CAS NUMBER: 552-30-7
SUBMISSION I: 8EHQ-1237-0711
CAS NUMBER: 1779-17-5
lJ1 SUBMISSION I: 8EHQ-1288-0777
w
G'I
CAS NUMBER: 9016-87-9
SUBMISSION I: 3EHQ-0788-0741
CAS NUMBER: 177 96-82-6
SUBMISSION I: 3EHQ-0736-0631
CAS NUMBER: 78-79-5
SUBMISSION I: 3EHQ-0887-0689
CAS NUMBER:
67-63-0
SUBMISSION I: 8EHQ-1088-0760 S
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: INDOlENINIUM SALT
CHEMICAL NAME: INORGANIC POTASSIUM HALIDE COMPLEX
CHEMICAL NAME: IRGAFORM 1266
CHEMICAL NAME: IRGANOX 245
CHEMICAL NAME: 5-ISOBENZOFURANCARBOXYlIC ACID, 1,3-DIHYDRO-1,3-DIOXO-
CHEMICAL NAME: 1,3-ISOBENZOFURANDIONE, 5,5'-(1-METHYlETHYlIDENE)BIS-
CHEMICAL NAME: ISOCYANIC ACID, POLYMETHYLENEPOlYPHENYLENE ESTER
CHEMICAL NAME: 1H-ISOINDOLE-1,3(2H)-DIONE, 2-(CYClOHEXYlTHIO)-
CHEMICAL NAME: ISOPRENE
*
CHEMICAL NAME: ISOPROPANOL
-------
CAS NUMBER: NONE
SUBMISSION .: 3EHQ-1287-0701
CAS NUMBER: 1332-58-7
SUBMISSION .: 3EHQ-1038-0755
CAS NUMBER: NONE
SUBMISSION .: 3EHQ-0438-0728
C4S NUMBER: NONE
SUBMISSION .: 8EHQ-D1a8-01l2
CAS NUMBER: 3061-51-6
SUBMISSIOH .: 8EHQ-1088-11755
Ul
W
-..J CAS NUMBER: 1746-81-2
SUBMISSION I: 3EHQ-1088-0755
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-0688-0733
CAS NUMBER: 75-09-2
SUBMISSION .: 8EHQ-1l88-0772
CAS NUMBER: 3064-70-8
SUBMISSION .: 8EHQ-0587-0673
C45 NUMBER: 67-66-3
SUBMISSION .: 8EHQ-1088-0759
APPENDIX C:
STATUS REPORTS BY CHEMICAL N4ME
CHEMICAL NAME: ISOPROPANOL (STRONG ACID PRODUCTION PROCESS)
"
CHEMICAL NAME: KAOLIN
CHEMICAL NAME: LEDERMIX
CHEMICAL NAME: LH-25 PRESERVATIVE
"
CHEMICAL NAME: LIGNOSULFONIC ACID. SODIUM SALT
CHEMICAL NAME: LINURON. MONO-
CHEMICAL NAME: LYHX 1.2
CHEMICAL NAME: METHANE. DICHlORC-
CHEMICAL HAME: METHANE. SUlFOHYlBIS[TRICHLORO-
CHEMICAL NAME: METHANE. TRICHLORO-
-------
CAS NUMBER: 75-69-4
SUBMISSION .: 8EHQ-I083-0759
CAS NUMBER: 75-09-2
SUBMISSION .: 8EHQ-1l88-0772
CAS NUMBER: 78-93-3
SUBMISSION .: 8EHQ-I088-0759
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-1287-0699
CAS NUMBER: 7647-01-0
SUBMISSION .: 8EHQ-0887-0688
U1
W CAS NUMBER: 4075-81-4
(X)
SUBMISSION .: 8EHQ-1287-0699
CAS NUMBER: 137-40-6
SUBMISSION .: 8EHQ-1287-0699
CAS NUMBER: 91-20-3
SUBMISSION .: 8EHQ-1287-0704
CAS NUMBER: UNKNOWN
SUBMISSION .: 8EHQ-0687-0680
CAS NUMBER: 3734-67-6
SUBMISSION .: 8EHQ-0788-0743
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: METHANE, TRICHLOROFLUORO-
CHEMICAL NAME: METHYLENE CHLORIDE
CHEMICAL NAME: METHYL ETHYL KETONE (MEK)
CHEMICAL NAME: MISC. CHEMICALS
8EHQ-1287-0701
"
8EHQ-0288-0722
CHEMICAL NAME: MURIATIC ACID
CHEMICAL NAME: MYCOBAN (CALCIUM SALT)
CHEMICAL NAME: MYCOBAN (SODIUM SALT)
CHEMICAL NAME: NAPHTHALENE
CHEMICAL NAME: NAPHTHALENE, DIIODO-
CHEMICAL NAME: 2,7-NAPHTHALENEDISULFONIC ACID, S-(ACETYLAMINO)-4-HYDROXY-3-
(PHENYLAZO)-, DISODIUM SALT
-------
CAS NUMBER: UNKNOWN
SUBMISSIOH I: 8EHQ-0687-0680
CAS HUMBER: 1322-91-6
SUBMISSIOH I: 8EHQ-1088-0755
CAS HUMBER: UHKHOWH
SUBMISSIOH I: 8EHQ-0687-0680
CAS HUMBER: UHKNOWN
SUBMISSIOH I: 8EHQ-0687-0680
CAS HUMBER: 61789-36-4
SUBMISSION I: 8EHQ-0587-0675
U1
W
\1J CAS HUMBER: 8006-14-2
SUBMISSIOH I: 8EHQ-0688-0735
CAS NUMBER: 3033-62-3
SUBMISSIOH I: 8EHQ-0687-0683
CAS NUMBER:
CONFIDEHT
SUBMISSION I: 8EHQ-0487-0670 S
CAS NUMBER:
111-87-5
SUBMISSION I: 8EHQ-1088-0762
CAS HUMBER:
HONE
SUBMISSION I: 8EHQ-0788-0744 S
APPENDIX C:
STATUS REPORTS BY CHEMICAL HAME
CHEMICAL HAME: HAPHTHAlEHES, DI-, TRI-, AHD TETRAIODO-, MIXED
CHEMICAL NAME: NAPHTHAlENESUlFONIC ACID, BIS(l-METHYlETHYl)-, SODIUM SALT
CHEMICAL NAME: NAPHTHAlEHE, TETRAIODO-
CHEMICAL HAME: HAPHTHAlEHE, TRIIODO-
CHEMICAL HAME: HAPHTHENIC ACIDS. CALCIUM SALTS
)II
CHEMICAL NAME: HATURAl GAS
CHEMICAL HAME: HIAX CATALYST A-99
CHEMICAL HAME: NITROBENZEHE, SUBSTITUTED
CHEMICAL HAME: 1-0CTAHOl
CHEMICAL HAME: OIL, JET ENGINE
-------
I.J.
..,.
o
CAS HUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
CAS NUMBER:
683:54-30-5
SUBMISSION .: 8EHQ-0487-0671
68476-30-2
SUBMISSION .: 8EHQ-1187-0697
UNKNOWN
SUBMISSION I: 8EHQ-1187-0697
UNKNOWN
SUBMISSION I: 8EHQ-0587-0675
CONFIDENT
SUBMISSION I: 8EHQ-0587-0674 S
106-89-&
SUBMISSION I: 8EHQ-1287-0709 S
CONFIDENT
SUBMISSION I: 8EHQ-0487-0665 S
3126-63-4
SUBMISSION .: 8EHQ-0787-0685
87257-05-4
SUBMISSION .: 8EHQ-1287-0709 S
NONE
SUBMISSION I: 8EHQ-058S-0733
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL HAME: OIL (PETROLEUM), DIESEL
CHEMICAL NAME: OIL (PETROLEUM), FURNACE
CHEMICAL NAME: OIL (PETROLEUM), FURNACE, SUB FRACTIONS
CHEMICAL NAME: OIL (PETROLEUM), MINERAL CARRIER
II
CHEMICAL NAME: OLEFIN, SULFURIZED
CHEMICAL NAME: OXIRAHE, (CHlOROMETHYl)-
CHEMICAL NAME: OXIRANE, METHYl-, POLYMER WITH OXIRANE, BLOCKED
II!
CHEMICAL NAME: OXIRANE, 2,2'-[2,2-BIS[(OXIRANYlMETHOXY)METHYl]-1,3-PROPAHED
IYLBIS(OXYMETHYlEHE)]8IS-
CHEMICAL NAME: OXIRANE, 2,2'-(3,7,7,11-TETRAMETHYl-2,5,9,12-TETRAOXATRIDECA
NE-l,13-DIYl)BIS-
CHEMICAL NAME: PAllADIUM PLATING COMPOUND
-------
CAS HUMBER:
HONE
SUBMISSION .: 8EHQ-0588-0733
CAS NUMBER:
99-66-1
SUBMISSION .: 8EHQ-0587-0672 S
CAS NUMBER: 108-95-2
SUBMISSION .: 8EHQ-I088-0759
CAS HUMBER: HONE
SUBMISSION .: 8EHQ-0388-0724 S
CAS NUMBER: CONFIDENT
SUBMISSION .: 8EHQ-0388-0724 S
U1
"'"
I-' CAS HUMBER: 27193-86-8
SUBMISSION .: 8EHQ-0687-0682
CAS HUMBER: 87-86-5
SUBMISSION I: 8EHQ-0487-0671
CAS NUMBER: 3846-71-7
SUBMISSION I: 8EHQ-0888-0747
CAS HUMBER: 25973-55-1
SUBMISSION .: UHQ-0988-0748
CAS NUMBER: 3864-99-1
SUBMISSION .: 8EHQ-1088-0756
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: PD MAKEUP
CHEMICAL NAME: PENTANGIC ACID, 2-PROPYL-
CHEMICAL NAME: PHENOL
CHEMICAL NAME: PHENOL DERIVATIVES. STERICALLY HINDERED, MIXTURE
CHEMICAL NAME: PHENOL DERIVATIVE, STERICAllY HINDERED
CHEMICAL NAME: PHENOL, DODECYl-
CHEMICAL NAME: PHENOL. PENTACHlORO-
CHEMICAL NAME: PHENOL. 2-(2H-BENZOTRIAZOl-2-Yl)-4,6-BIS(l,l-DIMETHYlETHYl)-
CHEMICAL NAME: PHENOL, 2-(2H-BENZOTRIAZOL-2-Yl)-4,6-BISC1,1-DIMETHYLPROPYL)
CHEMICAL HAME: PHENOL. 2-CS-CHlORO-2H-BENZOTRIAZOl-2-Yl)-4,6-BISCl,1-DIMETH
YlETHYL)-
-------
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CAS NUMBER:
1330-n~-5
CHEMICAL NAME: PHOSPHORIC ACID, TRIS(METHYLPHENYL) ESTER
SUBMISSION .: 8EHQ-0788-0744 S
CAS NUMBER:
78-30-8
CHEMICAL NAME: PHOSPHORIC ACID, TRIS(Z-METHYLPHENYL) ESTER
SUBMISSION .: 8EHQ-0788-0744 S
CAS NUMBER:
680-31-9
CHEMICAL NAME: PHOSPHORIC TRIAMIDE, HEXAMETHYL-
SUBMISSION .: 8EHQ-I088-0759
CAS NUMBER:
NONE
CHEMICAL NAME: PHOTOCOPYING PRODUCTS/PROCESS
SUBMISSION .: 8EHQ-0487-0668
CAS NUMBER: CONFIDENT CHEMICAL NAME: PHTHALIMIDE (III), SUBSTITUTED
SUBMISSION I: 8EHQ-I088-0758 S
U1
~ CAS NUMBER: CONFIDENT CHEMICAL NAME: PHTHALIMIDE (II), SUBSTITUTED
N
SUBMISSION I: 8EHQ-I088-0758 S
CAS NUMBER: CONFIDENT CHEMICAL NAME: PHTHALIMIDE (I>, SUBSTITUTED
SUBMISSIOH I: 8EHQ-I088-0758 S
CAS HUMBER: 1336-36-3 CHEMICAL NAME: POLYBROMIHATED BIPHEHYLS (PCB)
SUBMISSION I: 8EHQ-1188-0769 M
CAS NUMBER:
63943-38-4
CHEMICAL NAME: POLY[(DIMETHYLIMIHIO)-1,6-HEXANEDIYL(DIMETHYLIMINIO)METHYLEH
E[I,I'-BIPHENYL]-4,4'-DIYLMETHYLENE DICHLORIDE]
SUBMISSION I: 8EHQ-0487-0661 S
CAS NUMBER:
CONFIDENT
CHEMICAL NAME: POLYESTER, MODIFIED ALIPHATIC ALICYCLIC
SUBMISSION .: 8EHQ-0688-0734 S
-------
CAS NUMBER: 8061-51-6
SUBMISSION I: 8EHQ-1088-0755
CAS NUMBER: UNKNOWN
SUBMISSION I: 8EHQ-02U-0715
CAS NUMBER: 52495-71-3
SUBMISSION I: 8EHQ-1287-0709 S
CAS NUMBER: 25322-68-3
SUBMISSION I: 8EHQ-0488-0728
CAS NUMBER: 108-18-9
(.Jl SUBMISSION I: 8EHQ-1287-0705
"'"
w
CAS NUMBER: 109-77-3
SUBMISSION I: 8EHQ-0988-0754
CAS NUMBER: 5417-82-3
SUBMISSION I: 8EHQ-0487-0663
CAS NUMBER: 78-97-7
SUBMISSION I: 8EHQ-0988-0754
CAS NUMBER: 108-20-3
SUBMISSION I: 8EHQ-0487-0671
CAS NUMBER: 4075-81-4
SUBMISSION I: 8EHQ-1287-0699
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: POLYFON H
CHEMICAL NAME: POLYGLYCIDYL ETHYL, 2,2,6,6-TETRAMETHYLOL CYCLOHEXANOL
CHEMICAL NAME: POLY(OXY-1,2-ETHAHEDIYL), A-HYDRO-W-(OXIRAHYLMETHOXY)-, ETHE
R WITH 2-ETHYL-2-(HYDROXYMETHYL)-1,3-PROPANEDIOL (3:1)
CHEMICAL HAME: POLY(OXY-l,2-ETHAHEDIYL), .ALPHA.-HYDRO-.OMEGA.-HYDROXY-
CHEMICAL HAME: 2-PROPANAMINE, H-(l-METHYLETHYL)-
CHEMICAL NAME: PROPANEDINITRILE
CHEMICAL NAME: PROPANEDIHITRILE, (l-ETHOXYETHYLIDENE)-
CHEMICAL NAME: PROPAHEHITRILE, 2-HYDROXY-
CHEMICAL NAME: PROPANE, 2,2'-OXYBIS-
CHEMICAL NAME: PROPANOIC ACID, CALCIUM SALT
-------
CAS NUMBER:
137-40-6
SUBMISSION I: 3EHQ-1287-0699
CAS NUMBER:
67-63-0
SUBMISSION I: 8EHQ-I033-0760 S
CAS NUMBER: UNKNOWN
SUBMISSION I: 3EHQ-1033-0757
CAS NUMBER: 67-64-1
SUBMISSION .: 3EHQ-I033-0759
CAS NUMBER: 73-95-5
SUBMISSION .: 8EHQ-0337-0660
L11
~
~ CAS NUMBER: CONFIDENT
SUBMISSION I: 3EHQ-1233-0776
CAS NUMBER: 25213-39-2
SUBMISSION .: 8EHQ-0437-0663
CAS NUMBER: 53-03-2
SUBMISSION .: 3EHQ-0537-0672 S
CAS NUMBER: 2004-03-7
SUBMISSION .: 8EHQ-0383-0723
CAS NUMBER: 13047-13-7
SUBMISSION .: 8EHQ-0287-0653
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: PROPANOIC ACID, SODIUM SALT
CHEMICAL NAME: 2-PROPANOL
CHEMICAL NAME: 2-PROPANOL, 1-[BIS(2-HYDROXYETHYL)AMINO]-3-(4-ISONONYLPHENOX
Y)-
CHEMICAL NAME: 2-PROPANONE
CHEMICAL NAME: 2-PROPANONE, l-CHLORO-
CHEMICAL NAME: 2-PROPENOIC ACID DERIVATIVES
CHEMICAL NAME: 2-PROPENOIC ACID, 2-METHYL-, BUTYL ESTER, POLYMER WITH ETHEH
YLBENZENE
CHEMICAL NAME: IH-PURINE-2,6-DIONE, 3,7-DIHYDRO-l,3,7-TRIMETHYL-
CHEMICAL NAME: PURINE, 6-METHYL-
CHEMICAL NAME: 3-PYRAZOLIDINONE, 4-(HYDROXYMETHYL)-4-METHYL-I-PHENYL-
-------
CAS HUMBER:
CONFIDENT
SUBMISSION .: 8EHQ-0287-0655 S
CAS HUMBER:
8005-72-9
SUBMISSION .: 8EHQ-0687-0677
CAS NUMBER:
CONFIDENT
SUBMISSION .: 8EHQ-0933-0749 S
CAS HUMBER:
CONFIDEHT
SUBMISSIOH .: 3EHQ-1237-0707 S
CAS NUMBER: 1072-98-6
SUBMISSIOH .: 3EHQ-0683-0736
U1 CAS HUMBER: 39-32-7
*'"
U1 SUBMISSION .: 8EHQ-1237-0711
CAS NUMBER: 941-69-5
SUBMISSIOH .: 8EHQ-0837-0690
CAS NUMBER: IH2-50-4
SUBMISSION .: aEHQ-1037-0695
CAS HUMBER: 3734-67-6
SUBMISSIOH .: aEHQ-0733-0743
CAS NUMBER: 64741-75-9
SUBMISSIOH .: aEHQ-1283-0774
APPENDIX C:
STATUS REPORTS BY CHEMICAL HAME
CHEMICAL NAME: 2-PYRAZOlIN-5-0NE. I-PHEHYl-AlKYlAMIHO-
CHEMICAL NAME: PYRAZOl YEllOW 8G 250~
CHEMICAL NAME: PYRIDINE. ALKYL
CHEMICAL HAME: PYRIDIHECAR80XYlATE
3EHQ-0233-0716 S
3EHQ-0283-0717 S
CHEMICAL HAME: PYRIDINE. 2-AMINO-5-CHlORO-
CHEMICAL NAME: PYROMEllITIC DIANHYDRIDE
CHEMICAL HAME: 1H-PYRROlE-2.5-DIONE, I-PHEHYl-
CHEMICAL NAME: 2-PYRROlIDINONE. I-METHYl-
CHEMICAL NAME: RED 2G
CHEMICAL NAME: RESID HYDROPROCESSING UHIT (RHU) lIGHT VACUUM GAS OILS
-------
CAS NUMBER: 64741-76-0
SUBMISSION I: 8EHQ-1288-0773
CAS NUMBER: 64741-75-9
SUBMISSION I: 8EHQ-1288-0774
CAS HUMBER: 64741-56-6
SUBMISSION I: 8EHQ-0488-0727
CAS NUMBER: 17796-82-6
SUBMISSION I: 8EHQ-0786-0681
CAS NUMBER: 94361-06-5
SUBMISSION I: 8EHQ-0287-0658
U1
tI=> CAS HUMBER: HOHE
(j'I
SUBMISSIOH I: 8EHQ-0188-0712
CAS NUMBER: HONE
SUBMISSION I: 8EHQ-0288-0722
CAS HUMBER: 1322-93-6
SUBMISSION I: 8EHQ-I088-0755
CAS HUMBER: CONFIDENT CHEMICAL NAME: SILANE
SUBMISSION I: 8EHQ-0688-0734 S
CAS NUMBER: 7631-86-9 CHEMICAL NAME: SILICA
SUBMISSION I: 8EHQ-0487-0668
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: RESID HYDROPROCESSING UNIT (RHU) MIDDLE DISTILLATES
CHEMICAL NAME: RESIDUES. (PETROLEUM). HYDROCRACKED
CHEMICAL NAME: RESIDUES (PETROLEUM). VACUUM
CHEMICAL NAME: SANTOGARD PVI
CHEMICAL NAME: SAN 619F
CHEMICAL NAME: SAPSTAIH COHTROL CHEMICAL NP-l
II
CHEMICAL NAME: SCOTCHWELD AF-163-2 OST
CHEMICAL NAME: SELLOGEN HR
-------
CAS NUMBER: 63231-67-4
SUBMISSION .: 8EHQ-1088-0755
CAS HUMBER: 7647-14-5
SUBMISSIOH .: 8EHQ-0887-0688
CAS NUMBER: 151-21-3
SUBMISSIOH .: 8EHQ-0987-0694
CAS HUMBER: 151-21-3
SUBMISSION .: 8EHQ-0987-06H
CAS HUMBER: 8005-72-9
SUBMISSION .: 8EHQ-0687-0677
Ul
,;:..
~ CAS HUMBER: 64742-95-6
SUBMISSIOH I: 8EHQ-0587-0673
CAS NUMBER: 55283-68-6
SUBMISSIOH .: 8EHQ-1088-0755
CAS NUMBER: 9005-64-5
SUBMISSIOH .: 8EHQ-0288-0718
CAS HUMBER: 1332-58-7
SUBMISSION I: 8EHQ-I088-0755
CAS HUMBER: 10025-91-9 CHEMICAL NAME: STIBIHE, TRICHLORO-
SUBMISSION .: 8EHQ-0688-0737
APPENDIX C:
STATUS REPORTS BY CHEMICAL HAME
CHEMICAL NAME: SILICA GEL
CHEMICAL HAME: SODIUM CHLORIDE, (HACL)
CHEMICAL HAME: SODIUM DODECYL SULFATE (SDS)
)(
CHEMICAL HAME: SODIUM LAURYL SULFATE (SLS)
If
CHEMICAL NAME: SOLAR YELLOW RG
CHEMICAL NAME: SOLVENT HAPHTHA (PETROLEUM), LIGHT AROM.
CHEMICAL NAME: SONALAH
CHEMICAL NAME: SORBITAH, MOHODODECAHOATE. POLY(OXY-l.2-ETHAHEDIYL) DERIVS.
If
CHEMICAL HAME: SPESWHITE (CLAY)
-------
CAS HUMBER:
CONFIDENT
SUBMISSION .: 8EHQ-0488-0729 S
CAS NUMBER: 7664-93-9
SUBMISSION .: 8EHQ-0887-0688
CAS NUMBER: 7757-82-6
SUBMISSION .: 8EHQ-0887-0688
CAS NUMBER: 151-21-3
SUBMISSION .: 8EHQ-0987-0694
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-I087-0696
U1
.p.
CO CAS NUMBER: 107534-96-3
SUBMISSION .: 8EHQ-0688-0738
CAS NUMBER:
142-22-3
SUBMISSION .: 8EHQ-0487-0666 S
CAS NUMBER:
26741-53-7
SUBMISSION .: 8EHQ~1287-0706
CAS NUMBER:
CONFIDENT
SUBMISSION .: 8EHQ-I088-0763 S
CAS NUMBER:
CONFIDENT
SUBMISSION .: 8EHQ-0688-0740 S
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: SULFLURAMID, ETHYL
CHEMICAL NAME: SULFURIC ACID
CHEMICAL HAME: SULFURIC ACID DISODIUM SALT
CHEMICAL HAME: SULFURIC ACID MOHODODECYL ESTER SODIUM SALT
II
CHEMICAL HAME: SURFACTAHTS (HOH-IOHIC), ALKOXYLATED
CHEMICAL HAME: TERBUCOHAZOLE
CHEMICAL HAME: 2,5,8,10-TETRAOXATRIDEC-12-EHOIC ACID, 9-0XO-, 2-PROPEHYL ES
TER
CHEMICAL HAME: 2,4,8,lO-TETRAOXA-J,9-DIPHOSPHASPIRO[5.5]UHDECAHE, 3,9-BIS[2
, 4-BIS( 1, I-DIMETI< {lETHYUPHEHOXY]-
CHEMICAL HAME: THIADIAZOLE SULFOHAMIDE, ALKYLAMIHOCARBOHYL SUBSTITUTED
CHEMICAL HAME: THIAZIHOHYDRAZIHE, SUBSTITUTED
-------
CAS NUMBER: 59607-71-5
SUBMISSION ,: aEHQ-0388-0721
CAS NUMBER: 3846-71-7
SUBMISSION ,: 8EHQ-0888-0747
CAS NUMBER: 3864-99-1
SUBMISSION .: 8EHQ-I088-0756
CAS NUMBER: 25973-55-1
SUBMISSION .: 8EHQ-0988-0748
CAS NUMBER: 13463-67-7
SUBMISSION .: 8EHQ-0487-0668
(.J1
..,. CAS NUMBER: CONFIDENT
\.0
SUBMISSION .: 8EHQ-I088-0764 S
CAS NUMBER: CONFIDENT
SUBMISSION .: 8EHQ-I088-0764 S
CAS NUMBER: 9012-09-3
SUBMISSION .: 8EHQ-1188-0772
CAS NUMBER: 107534-96-3
SUBMISSION .: 8EHQ-0688-0738
CAS HUMBER: 94361-06-5
SUBMISSION ,: 8EHQ-0287-0658
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: THIOCYANIC ACID. 4-METHOXY-2-NITROPHENYl ESTER
CHEMICAL NAME: TINUVIN 320
CHEMICAL NAME: TINUVIN 327
CHEMICAL NAME: TINUVIH 328
CHEMICAL NAME: TITANIUM OXIDE (TI02)
CHEMICAL NAME: TOlYlCYClOAlKEHYl SUBSTITUTED ALKYL ESTER
CHEMICAL NAME: TOlYlCYClOAlKEHYl SUBSTITUTED PHOSPHOROTHIOATE ESTER
CHEMICAL NAME: TRIACETATE FIBERS. CEllULOSE
CHEMICAL NAME: IH-l.2.4-TRIAZOlE-1-ETHAHOl. .AlPHA.-[2-(4-CHlOROPHEHYl)ETHY
l]-.AlPHA.-(1.1-DIMETHYlETHYl)-{.+-.)-
CHEMICAL NAME: IH-l.2.4-TRIAZOlE-1-ETHAHOl. .AlPHA.-(4-CHlOROPHENYl)-.AlPHA
.-(l-CYClOPROPYlETHYl)-, (RM.RM)-(.+-.)-
-------
CAS NUMBER: 552-30-7
SUBMISSION .: 8EHQ-1287-0711
CAS NUMBER: 26741-53-7
SUBMISSION .: 8EHQ-1287-0706
CAS NUMBER: 26741-53-7
SUBMISSION .: 8EHQ-1287-0706
CAS NUMBER: 26741-53-7
SUBMISSION .: 8EHQ-1287-0706
CAS NUMBER: NONE
SUBMISSION .: 8EHQ-0187-0651
lJl
lJl CAS NUMBER: 1746-81-2
0
SUBMISSION .: 8EHQ-I088-0755
CAS NUMBER: 108-05-4
SUBMISSION .: 8EHQ-0187-0650
CAS NUMBER: 26741-53-7
SUBMISSION .: 8EHQ-1287-0706
CAS NUMBER: 26741-53-7
SUBMISSION .: 8EHQ-1287-0706
CAS NUMBER: 26741-53-7
SUBMISSION .: 8EHQ-1287-0706
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CHEMICAL NAME: TRIMELLITIC ANHYDRIDE
CHEMICAL NAME: ULTRANOX 624
CHEMICAL NAME: ULTRANOX 626
CHEMICAL HAME: ULTRANOX 626A
CHEMICAL NAME: UNKNOWN CHEMICALCS)
If
CHEMICAL NAME: UREA, H'-C4-CHLOROPHENYL)-N-METHOXY-N-METHYL-
CHEMICAL NAME: VINYL ACETATE
CHEMICAL NAME: WESTOH MDW-6140
CHEMICAL HAME: WESTON XR-1452
CHEMICAL NAME: WESTON XR-1532
-------
~
~
APPENDIX C:
STATUS REPORTS BY CHEMICAL NAME
CAS NUMBER:
NONE
CHEMICAL NAME: XEROX 9000-TYPE XEROGRAPHIC TONER
SUBMISSION ,: 8EHQ-0487-0668
CAS NUMBER:
CONFIDENT
CHEMICAL NAME: XYLYLCYCLOALKENYL SUBSTITUTED ALKYL ESTER
SUBMISSION .: 8EHQ-I088-0764 S
*
Based on a preliminary evaluation, EP~ believed that the submitted information did not warrant reporting under
Section 8(e) of TSCA. In most cases, the submitter was requested to provide the b..i. for contending that the
information offered reasonable support for the conclu8ion that the 8ubject chemical sub8tance(s) or mlxture(s)
presents a substantial risk of injury to health or the environment as defined in EP~'s TSC~ Section 8(e) policy
statement (see Appendix A of this volume).
-------
APPENDIX (D): STATUS REPORTS BY INFORMATION TYPE
ACUTE TOXICITY (ANIMAl)
SUBMISSION .: 8EHQ-OZ87-065Z S 8EHQ-OZ87-0653 8EHQ-0287-065'\
8EHQ-OZ87-0655 S 8EHQ-0387-0656 8EHQ-OZ87-06S7 S
8EHQ-0387-0659 8EHQ-0387-0660 8EHQ-O'i87-0661 S
8EHQ-0487-0663 8EHQ-O'i87-066S S If 8EHQ-O'i87-0666 S
8EHQ-0487-0667 S Ii 8EHQ-0487-0669 If 8EHQ-0487-0670 S
8EHQ-OS87-0673 8EHQ-0587-0678 8EHQ-0687-068G
8EHQ-0787-0686 S aEHQ-I087-0696 aEHQ-1287-0700
8EHQ-IZ87-0706 8EHQ-1287-0707 S aEHQ-0188-07H
aEHQ-0388-0721 8EHQ-03M-07Z3 aEHQ-0538-0732
aEHQ-06M-07 H 8EHQ-0688-07'iO S aEHQ-0788-0H2 If
8EHQ-0788-0744 S 8EHQ-0988-0753 S 8EHQ-0988-0754
8EHQ-I088-0760 S 8EHQ-IOM-0762 8EHQ-1188-0768 S
U1 8EHQ-1288-0n8
U1
N
ACUTE TOXICITY (HUMAN)
SUBMISSION .: 8EHQ-0487-0666 S 8EHQ-0487-0671 8EHQ-1287-0700
8EHQ-0688-0736 8EHQ-1088-0755
ALLERGENICITY (ANIMAL)
SUBMISSION .: 8EHQ-OZ87-0653 8EHQ-0287-0657 S 8EHQ-0487-0661 S
8EHQ-0687-0680 8EHQ-0787-0686 S 8EHQ-08n-OUO
8EHQ-1287-0700 8EHQ-12IH-0711 8EHQ-IIlU-0712 Ii
8EHQ-0388-0721 8EHQ-OSU-0733 8EHQ-06M-0139
8EHQ-0688-0740 S 8EHQ-1188-0768 S 8EMQ-12M-On7
8EHQ-1288-0n8
-------
ALLERGENICITY (HUMAN)
SUBMISSION .: 8EHQ-0987-0694
CELL TRANSFORMATION (IN VITRO)
SUBMISSION .: 8EHQ-0687-0679
CHEMICAL/PHYSICAL PROPERTIES
SUBMISSION .: 8EHQ-0287-0653
8EHQ-0387-0656
8EHQ-0487-0661 5
Ul
Ul
W
8EHQ-0487-0667 5
8EHQ-0587-0678
8EHQ-0687-0682
8EHQ-1287-0706
8EHQ-0388-0721
8EHQ-0688-0739
8EHQ-I088-0755
8EHQ-1188-0768 S
CHRONIC TOXICITY (AHIMAl)
SUBMISSIOH .: 8EHQ-0187-0650
8EHQ-0786-0681
8EHQ-0887-0691 S
8EHQ-1287-0704
8EHQ-0188-0713
8EHQ-0788-0741
APPENDIX (D): STATUS REPORTS BY INFORMATION TYPE
II
8EHQ-0488-0728
II
8EHQ-0287-0654 8EHQ-0287-0655 S
8EHQ-0287-0657 S 8EHQ-0387-0659
8EHQ-0487-0663 8EHQ-0487-0666 S
8EHQ-0487-0668 8EHQ-0587-0673
8EHQ-0687-0679 8EHQ-0687-0680
8EHQ-0787-0686 S 8EHQ-0887-0691 S
8EHQ-1287-0711 8EHQ-0288-0720
&EHQ-0488-0727 8EHQ-0588-0732
8EHQ-0688-0740 S 8EHQ-0788-0741
8EHQ-I088-0757 &EHQ-IOaa-0762
8EHQ-1288~0778
8EHQ-0487-0668 8EHQ-OS87-067S If
8EHQ-0787-0684 S aEHQ-0887-0687
8EHQ-0987-0692 8EHQ-1187-06 97
8EHQ-1287-0708 S 8EHQ-1287-0710
8EHQ-0388-0725 8EHQ-0588-0730
8EHQ-0788-0745 S 8EHQ-0988-0752 S
-------
APPENDIX (D): STATUS REPORTS BY INFORMATION TYPE
U1
U1
..,.
CHRONIC TOXICITY (ANIMAL)
SUBMISSION .: 8EHQ-I088-0760 S
8EHQ-1288-0775
CHRONIC TOXICITY (HUMAN)
SUBMISSION .: aEHQ-0187-0651 II
8EHQ-1l87-0698
8EHQ-1l88-0772
CLASTOGENICITY (ANIMAl)
SUBMISSION .: 8EHQ-0887-0689 II
8EHQ-I088-0758 S
CLASTOGENICITY (IN VITRO)
SUBMISSION .: 8EHQ-0687-0679
8EHQ-0987-0693
8EHQ-0787-0685
8EHQ-0288-0715
8EHQ-0787-0686 S
8EHQ-I088-0758 S
8EHQ-1288-0n 3
8EHQ-1288-0774
8EHQ-0887-0688
8EHQ-1287-0699
8EHQ-0987-0694
8EHQ-1287-0701
8EHQ-0987-0692
8EHQ-1288-0776
8EHQ-0987-0693
DNA DAMAGE/REPAIR
SUBMISSION .: 8EHQ-0187-0649 S
3EHQ-0687-0679
8EHQ-0288-0715
8EHQ-0787-0685
8EHQ-0688-0737
8EHQ-0987-0692
ECOTOXICITY/AQUATIC TOXICITY
SUBMISSION .: 8EHQ-0287-0653
8EHQ-0487-0666 S
8EHQ-0288-0718
EMERGENCY INCIDENT OF ENV. CONTAMINATION
SUBMISSION I: 8EHQ-1138-0769
II
II
II
If
-------
APPENDIX (D): STATUS REPORTS BY INFORMATION TYPE
ENV. OCCURRENCE/RELEASE/FATE
SUBMISSION I: 8EHQ-0287-0651 8EHQ-0487-0662 8EHQ-0487-0671
aEHQ-0688-0715 8EHQ-1088-0759 8EHQ-IOaa-0761
8EHQ-1l88-0769 It
EPIDEMIOLOGY/CLINICAL
SUBMISSION I: 8EHQ-0187-0651 It 8EHQ-0487-0671 8EHQ-0887-0688
8EHQ-0987-0694 It 8EHQ-1l87-0698 8EHQ-1287-0699
8EHQ-1287-0701 It 8EHQ-0288-0722 aEHQ-0688-0736
8EHQ-l0aa-0755 8EHQ-1l88-0772
(Jl GROUNDWATER CONTAMINATION
(Jl
(Jl
SUBMISSION I: 8EHQ-0487-0662 &:m-l(BH)75g
HUMAN EXPOSURE (ACCIDENTAL)
SUBMISSION I: 8EHQ-0487-0671 8EHQ-0688-0716
HUMAN EXPOSURE (MONITORING)
SUBMISSION I: 8EHQ-0487-0662 8EHQ-0487-0671 8EHQ-0587-0672 S
8EHQ-0687-0682 8EHQ-0288-0722 8EHQ-068a-0735
8EHQ-0988-0752 S aEHQ-108a-0761
HUMAN EXPOSURE (PRODUCT CONTAMINATION)
SUBMISSION I: 8EHQ-02a8-0720 8EHQ-0688-073S 8EHQ-1088-0761
-------
IMMUNOTOXICITY (ANIMAL)
SUBMISSION I: 3EHQ-0533-0732
METABOLISM/PHARMACOKINETICS (ANIMAL)
SUBMISSION I: 3EHQ-0437-0666 S
MUTAGENICITY (IN VITRO)
SUBMISSIOH I: 3EHQ-0137-0649 S
3EHQ-0637-0677
3EHQ-0737-0636 S
3EHQ-1237-0706
3EHQ-0233-0719
lJ1
lJ1
cr-.
3EHQ-I033-0753 S
NEUROTOXICITY (ANIMAL)
SUBMISSION I: 3EHQ-0237-0655 S
8EHQ-0133-0714
3EHQ-0633-0740 S
3EHQ-1283-0776
ONCOGENICITY (ANIMAL)
SUBMISSION I: 8EHQ-0187-0650
3EHQ-0787-0634 S
3EHQ-0987-0692
8EHQ-1287-0703 S
8EHQ-0383-0725
APPENDIX (D): STATUS REPORTS BY INFORMATION TYPE
8EHQ-0537-0672 S
3EHQ-0287-0653
3EHQ-0687-0679
8EHQ-0287-0654
8EHQ-0787-068!?
3EHQ-0987-0692
8EHQ-1287-0709 S
3EHQ-0987-0693
8EHQ-0288-0715
8EHQ-0638-0737
3EHQ-I088-0760 S
3EHQ-0788-0743
8EHQ-0587-0678
3EHQ-0588-0733
3EHQ-1287-0706
8EHQ-0688-0739
8EHQ-0788-0744 S
8EHQ-I088-0757
8EHQ-0587-0675
8EHQ-0887-0687
M
8EHQ-0786-0681
8EHQ-0887-0691 S
8EHQ-1l87-0697
3EHQ-1237-0710
8EHQ-1287-0704
8EHQ-0188-0713
3EHQ-0588-0730
8EHQ-0788-0741
-------
ONCOGENICITY (ANIMAL)
SUBMISSION .: 8EHQ-0788-0745 S
8EHQ-1288-0773
ONCOGENICITY (HUMAN)
SUBMISSION .: 8EHQ-0187-0651
8EHQ-1287-0699
PRODUCT COMPOSITION/CHEMICAL IDENTITY
SUBMISSION .: 8EHQ-0187-0649 S
8EHQ-0387-0656
V1
V1
-...j
IIEHQ-04117-0665 S II
8EHQ-04117-0669 II
IIEHQ-0587-0674 S
8EHQ-0787-0686 S
IIEHQ-1287-07011 S
8EHQ-021111-0716 S
8EHQ-03811-0724 S
8EHQ-0488-0728
IIEHQ-0588-0733
8EHQ-0688-0740 S
IIEHQ-09811-0749 S
IIEHQ-0988-0752 S
IIEHQ-IOIIII-07511 S
8EHQ-I0811-0763 S
8EHQ-III1I1-0766 5
APPENDIX (D): STATUS REPORTS BY INFORMATION TYPE
8EHQ-I088-0760 S
8EHQ-1288-0774
8EHQ-I088-0763 S
8EHQ-1288-0775
II
8EHQ-0887-0688
8EHQ-1287-0701
8EHQ-1187-0698
8EHQ-1188-0772
II
8EHQ-0287-0652 S 8EHQ-0287-0655 5
8EHQ-0487-0661 S IIEHQ-04117-0664 S
8EHQ-0487-0667 S II 8EHQ-0487-0668
8EHQ-0487-0670 S 8EHQ-0487-0671
8EHQ-0687-0680 8EHQ-0787-0684 S
8EHQ-1187-0697 8EHQ-1287-0707 S
8EHQ-1287-0709 S 8EHQ-0188-0714
8EHQ-028S-0717 S 8EHQ-0288-0720
8EHQ-0388-0725 8EHQ-0488-0727
8EHQ-0488-0729 S 8EHQ-0588-0731 S
8EHQ-0688-0734 S 8EHQ-0688-0735
8EHQ-0788-0744 5 8EHQ-0788-0745 S
8EHQ-0988-0750 S 8EHQ-0988-0751 5
8EHQ-0988-0753 S 8EHQ-I088-0155
8EHQ-I088-0760 S 8EHQ-I088-0761
8EHQ-I088-0764 S 8EHQ-1188-0765 S
8EHQ-1188-0767 5 8EHQ-1188-0768 5
-------
APPENDIX CD>: STATUS REPORTS BY INFORMATION TYPE
PRODUCT COMPOSITION/CHEMICAL IDENTITY
SUBMISSION I: 8EHQ-1188-0770 S 8EHQ-1188-0771 S 8EHQ-1288-0776
PRODUCTION/USE/PROCESS
SUBMISSION I: 8EHQ-0187-0649 S 8EHQ-0287-0653 8EHQ-0287-0654
8EHQ-0287-0655 S 8EHQ-0287-0657 S 8EHQ-0287-0658
8EHQ-0387-0659 8EHQ-0487-0661 S 8EHQ-0487-0663
8EHQ-0487-0664 S 8EHQ-0487-0665 S If 8EHQ-0487-0667 S If
8EHQ-0487-0669 If 8EHQ-0487-0670 S 8EHQ-0487-0671
8EHQ-0587-0672 S 8EHQ-0587-0673 8EHQ-0587-0674 S
8EHQ-0587-0675 If 8EHQ-0587-0676 8EHQ-0687-0677
8EHQ-0587-06 78 8EHQ-0687-0679 8EHQ-0687-0680
8EHQ-0687-0682 8EHQ-0687-0683 8EHQ-0787-0684 S
lr1 8EHQ-0787-0685 8EHQ-0787-0686 S 8EHQ-0887-0687
lr1
co 8EHQ-0887-0688 8EHQ-0887-0689 If 8EHQ-0887-0690
8EHQ-0887-0691 S 8EHQ-0987-0692 8EHQ-0987-0694 If
8EHQ-I087-0695 8EHQ-1187-0698 8EHQ-1287-0699
8EHQ-1287-0700 8EHQ-1287-0701 If 8EHQ-1287-0704
8EHQ-1287-0706 8EHQ-1287-0709 S 8EHQ-1287-0710
8EHQ-0188-0714 8EHQ-0288-0715 8EHQ-0288-0716 S
8EHQ-0288-0717 S 8EHQ-0288-0719 8EHQ-0288-0720
8EHQ-0388-0721 8EHQ-0288-0722 8EHQ-0388-0723
8EHQ-0388-0724 S 8EHQ-0388-0725 8EHQ-0488-0729 S
8EHQ-0588-0730 8EHQ-0588-0731 S 8EHQ-0588-0732
8EHQ-0588-0733 8EHQ-0688-0734 S 8EHQ-0688-0735
8EHQ-0688-0738 8EHQ-0688-0739 8EHQ-0688-0740 S
-------
PRODUCTION/USE/PROCESS
SUBMISSION .: 8EHQ-0788-0742
8EHQ-0888-0746
8EHQ-0988-0749 S
8EHQ-0988-0752 S
8EHQ-I088-0755
8EHQ-I088-0758 S
8EHQ-I088-0763 S
8EHQ-1188-0767 S
8EHQ-1188-0771 S
8EHQ-1288-0778
U1
U1
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REPORTING RATIONALE
SUBMISSION I: 8EHQ-0587-0672 S
8EHQ-1188-0772
REPRODUCTIVE TOXICITY/TERATO. (ANIMAL)
SUBMISSION I: 8EHQ-0287-0653
8EHQ-0487-0666 S
8EHQ-0687-0682
8EHQ-0288-0716 S
8EHQ-0388-0726
8EHQ-0588-0731 S
8EHQ-0988-0748
8EHQ-0988-0751 S
8EHQ-I088-0764 S
APPENDIX (D): STATUS REPORTS BY INFORMATION TYPE
If
8EHQ-0788-0744 S 8EHQ-0788-0745 S
8EHQ-0888-0H7 8EHQ-0988-0748
8EHQ-0988-0750 5 8EHQ-0988-0751 S
8EHQ-0988-0753 S 8EHQ-0988-0754
8EHQ-I088-0756 8EHQ-I088-0757
8EHQ-I088-0759 8EHQ-I088-0760 5
8EHQ-1188-0765 S 8EHQ-1188-0766 S
8EHQ-1188-0768 5 8EHQ-1188-0770 5
8EHQ-1288-0775 8EHQ-1288-0776
8EHQ-1287-0706
8EHQ-0488-0729 5
If
8EHQ-0287-0658 8EHQ-0487-0664 S
8EHQ-0587-0672 S 8EHQ-0587-0676
8EHQ-I087-0695 8EHQ-1287-0706
8EHQ-0288-0717 5 8EHQ-0388-0721
8EHQ-0488-0727 8EHQ-0488-0729 S
8EHQ-0688-0738 8EHQ-0888-0Jlt6
8EHQ-0988-0749 S 8EHQ-0988-0750 S
8EHQ-I088-0758 S 8EHQ-I088-0760 S
8EHQ-1188-0765 S 8EHQ-1188-0766 S
-------
APPEHDIX (D): STATUS REPORTS BY IHFORMATIOH TYPE
REPRODUCTIVE TOXICITY/TERATO. (AHIMAL)
SUBMISSIOH I: 8EHQ-1188-0767 S
8EHQ-1188-0770 S
8EHQ-1188-0771 S
8EHQ-1288-0778
REPRODUCTIVE TOXICITY/TERATO. (HUMAH)
SUBMISSIOH I: 8EHQ-0288-0722
SUBACUTE TOXICITY (AHIMAL)
SUBMISSIOH I: 8EHQ-0287-06S3
8EHQ-0687-0680
8EHQ-1287-0700
8EHQ-0487-0664 S
aEHQ-0687-0683
8EHQ-OS87-0674.S
8EHQ-0787-0686 5
8EHQ-1287-0705
aEHQ-O 18&-0 714
8EHQ-0688-0734 5
8EHQ-1287-0703
8EHQ-0388-0724 S
8EHQ-1088-07S7
8EHQ-048&-0727
8EHQ-1288-0777
tJl
CT\
o
SUBCHROHIC TOXICITY (AHIMAl)
SUBMISSIOH I: 8EHQ-0487-0668
aEHQ-1287-0706
8EHQ-0888-0747
8EHQ-OS87-0676
8EHQ-0488-0729 5
8EHQ-1287-0702
8EHQ-0788-0744 5
8EHQ-1088-0760 5
8EHQ-098&-0748
8EHQ-1088-0763 5
8EHQ-108&-07S6
TSCA 8(C) ALLEGATIOH
SUBMISSIOH I: 8EHQ-0887-0690
~.{1jg4
.
.
Based on a preliminary evaluation, EPA believed that the submitted information did not warrant reporting under
Sect ion R (e) of TSCA. In most cases, the submitter was requested to provide the basis tor contending that the
information offered reasonable support for the conclusion that the subject chemical substance(s) or mixture(s)
presents a substantial risk of injury to health or the environment as defined in EPA's TSCA Section B(e) policy
statement (see Appendix A of this volume).
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
3EHQ-0137-0649 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CAS NUMBER: CONFIDENT
CHEMICAL NAME: CONFIDENTIAL
CHEMICAL NAME: DIAMINE, ALKOXYLATED AROMATIC
3EHQ-0187-0650
SUBMITTER: SOCIETY OF THE PLASTICS INDUSTRY, INC.
CAS HUMBER : 108-05-~
CAS NUMBER : 103-05-~
CHEMICAL NAME: ACETIC ACID ETHENYL ESTER
CHEMICAL NAME: VINYL ACETATE
.U1
0"1
~
3EHQ-0137-0651 II SUBMITTER: XEROX CORPORATION
CAS NUMBER : NONE CHEMICAL NAME: UNKNOWN CHEMICAL
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION HUMBER
8EHQ-0287-0657 S
SUBMITTER: EASTMAN KODAK COMPANY
CAS NUMBER: 99-42-3
CHEMICAL HAME: BENZOIC ACID, 4-HYDROXY-3-NITRO-, METHYL ESTER
8EHQ-0287-0658
SUBMITTER: SANDOZ CROP PROTECTION CORPORATION
CAS NUMBER: 94361-06-5
CAS HUMBER: 94361-06-5
CHEMICAL HAME: SAN 619F
CHEMICAL NAME: IH-l,2,4-TRIAZOLE-I-ETHANOL, .ALPHA.-(4-CHLOROPHENYL)-.ALPHA
.-(I-CYCLOPROPYLETHYL)-, (RM,RM)-(.+-.)-
8EHQ-D387-D659
SUBMITTER: 3M COMPANY
CAS HUMBER: 123-86-4
CHEMICAL NAME: ACETIC ACID, BUTYL ESTER
8EHQ-0387-0660
SUBMITTER: WACKER CHEMICALS (USA), INC.
CAS NUMBER: 78-95-5
CAS NUMBER: 107-20-0
CHEMICAL NAME: 2-PROPANONE, l-CHlORO-
CHEMICAL NAME: ACETALDEHYDE, CHlORO-
U1
(j\
N
8EHQ-0487-0661 S
SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER: 63943-38-4
CHEMICAL NAME: POLY[(DIMETHYlIMIHIO)-1,6-HEXANEDIYl(DIMETHYLIMINIO)METHYlEN
E[I,I'-BIPHEHYL]-4,4'-DIYLMETHYLENE DICHLORIDE]
8EHQ-0487-0662
SUBMITTER: VISTA CHEMICAL COMPANY
CAS HUMBER: 107-06-2
CHEMICAL NAME: ETHANE, 1,2-DICHLORO-
8EHQ-0487-0663
SUBMITTER: EASTMAN KODAK COMPANY
CAS NUMBER: 5417-82-3
CHEMICAL NAME: PROPANEDIHITRILE, (l-ETHOXYETHYlIDENE)-
8EHQ-0487-0664 S SUBMITT ER: E. 1. DUPONT DE NEMOURS & COMPAHY, INC.
CAS HUMBER : CONFIDENT CHEMICAL NAME: ETHER (CYCLIC), HAlOALKYl SUBS T nUTED
8EHQ-0487-0665 S II SUBMITTER: COHFIDENTIAL
CAS NUMBER : COHFIDEHT CHEMICAL HAME: BSC-125 SURFACTAHT
CAS NUMBER: COHFIDEHT CHEMICAL HAME: OXIRAHE, METHYL-, POLYMER WITH OXIRANE. BLOCKED
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-0487-0666 S
SUBMITTER: COHFIDENTIAl
CAS NUMBER: 142-22-3
CAS NUMBER: 142-22-3
CHEMICAL NAME: CR-39 MONOMER
CHEMICAL NAME: 2,5,8,10-TETRAOXATRIDEC-12-ENOIC ACID, 9-0XO-, 2-PROPENYl ES
TER
8EHQ-0487-0667 S
)If
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CHEMICAL HAME: CARBOHOCHlORIDOTHIOIC ACID, ARYL ESTER
8EHQ-0487-0668
CAS NUMBER: NONE
SUBMITTER: XEROX CORPORATION
CHEMICAL NAME: PHOTOCOPYING PRODUCTS/PROCESS
CAS NUMBER: NONE
CAS NUMBER: 7440-44-0
CHEMICAL HAME: XEROX 9000-TYPE XEROGRAPHIC TONER
CHEMICAL NAME: CARBON
U1
0'>
(..oJ
CAS NUMBER: 7631-86-9
CAS HUMBER: 13463-67-7
CHEMICAL HAME: SILICA
CHEMICAL HAME: TITANIUM OXIDE, (TI02)
CAS HUMBER: 25213-39-2
CHEMICAL NAME: 2-PROPENOIC ACID, 2-METHYl-, BUTYL ESTER, POLYMER WITH ETHEN
YLBENZENE
8EHQ-0487-0669
)If
SUBMITTER: PPG IHDUSTRIES, INC.
CAS HUMBER: UNKNDWN
CAS HUMBER: UNKNOWN
CHEMICAL NAME: 2-IMIDAZOLIDINONE, 1,3-DIBROMO-4,4,5,5-TETRAMETHYL-
CHEMICAL NAME: 2-IMIDAZOLIDIHONE, 1,3-DICHLORO-4,4,5,5-TETRAMETHYL-
8EHQ-0487-0670 S
SUBMITTER: CONFIDENTIAL
CAS HUMBER: CONFIOENT
CHEMICAL NAME: HITROBEHZENE. SUBSTITUTED
8EHQ-0487-0671 SUBMITTER: KOPPERS COMPANY, INC.
CAS NUMBER : NONE CHEMICAL NAME: DIOXIN, HEPTACHLORODIBENZO-P-
CAS HUMBER : HONE CHEMI CAL NAME: DIOXIN, HEXACHLORODIBENZO-P-
CAS HUMBER : NOHE CHEMICAL HAME: DIOXIN, OCTACHLORODIBENZO-P-
CAS HUMBER : HOHE CHEMICAL HAME: DIOXIN, PENTACHLORODIBEHZO-P-
CAS HUMBER : HONE CHEMICAL NAME: DIOXIHS, CHLORIHATED
-------
APPEHDIX E: STATUS REPORTS BY SUBMISSIOH HUMBER
8EHQ-0437-0671
CAS HUMBER: NONE
SUBMITTER: KOPPERS COMPANY, INC.
CHEMICAL NAME: DIOXIN, TETRACHLORODIBENZO-P-
CAS NUMBER: 37-36-5
CHEMICAL NAME: PHENOL, PENTACHLORO-
CAS NUMBER : 106-97-8 CHEMICAL NAME: BUTANE
CAS NUMBER : 103-20-3 CHEMICAL NAME: PRUPANE, 2,2'-OXYBIS-
CAS NUMBER : 1746-01-6 CHEMICAL NAME: DIOXIN, 2,3,7,3-TETRACHLORODIBENZO-P-
CAS NUMBER : 633H-30-5 CHEMI CAL NAME: FUEL S, DIESEL
CAS NUMBER : 68334-30-5 CHEMICAL NAME: OIL (PETROLEUM), DIESEL
3EHQ-0537-0672 S
SUBMITTER: SHELL OIL COMPANY
CAS NUMBER: 58-03-2
CHEMICAL NAME: CAFFEINE
Ul
0-.
,j:>.
CAS NUMBER : 53-08-2 CHEMICAL NAME: IH-PURINE-2,6-DIONE, 3,7-DIHYDRO-l,3,7-TRIMETHYL-
CAS NUMBER : 99-66-1 CHEMICAL NAME: PENTAHOIC ACID, 2-PROPYL -
CAS NUMBER : 104-76-7 CHEMI CAL HAME: 1-HEXAHOL, 2-ETHYL-
CAS HUMBER : 117-31-7 CHEMICAL NAME: 1,2-BENZEHEDICARBOXYLIC ACID, BIS(2-ETHYLHEXYL) ESTER
CAS NUMBER : 149-57-5 CHEMICAL NAME: HEXAHOIC ACID, 2-ETHYL-
3EHQ-0537-0673
CAS NUMBER: NONE
SUBMITTER: STAUFFER CHEMICAL COMPAHY
CHEMICAL NAME: N-1386 HAH
CAS HUMBER: 3064-70-3
CAS NUMBER: 64742-95-6
CHEMICAL HAME: METHAHE, SULFONYLBIS[TRICHLORO-
CHEMICAL NAME: SOLVEHT HAPHTHA, (PETROLEUM), LIGHT AROM.
3EHQ-0587-0674 S
SUBMITTER: COHFIDENTIAL
CAS NUMBER: CONFIDENT
CAS NUMBER: CONFIDENT
CHEMICAL NAME: AMMONIUM CARBOXYLATE, SUBSTITUTED
CHEMICAL NAME: OLEFIN, SULFURIZED
8EHQ-0587-0675
II
SUBMITTER: CHEMICAL MANUFACTURERS ASSOCIATIOH
CAS NUMBER: UNKNOWN
CAS NUMBER: 61789-36-4
CHEMICAL NAME: OIL (PETROLEUM), MINERAL CARRIER
CHEMICAL NAME: NAPHTHENIC ACIDS, CALCIUM SALTS
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION HUMBER
8EHQ-0587-0675
If
SUBMITTER: CHEMICAL MANUFACTURERS ASSOCIATION
8EHQ-0587-0676
SUBMITTER: E. I. DUPONT DE NEMOURS & COMPANY, INC.
CAS NUMBER: 1649-08-]
CAS NUMBER: 1649-08-]
CHEMICAL NAME: ETHANE, 1,2-DICHlORO-1,1-DIFlUORO-
CHEMICAL NAME: HCFC-132B
8EHQ-068]-0677
SUBMITTER: LEVER BROTHERS COMPANY
CAS NUMBER : 8005-]2-9 CHEMICAl NAME: ]-BENZOTHIAZOlESUlFONIC ACID, 6-METHYl-2-(4-(4-(6-METHYl-]-S
UlFOBENZOTHIAZOl-2-Yl)PHENYlAZO)PHENYl)-
CAS NUMBER : 8005-]2-9 CHEMICAL NAME: C. I. DIRECT YEllOW 28
CAS NUMBER : 8005-]2-9 CHEMICAL NAME: PYRAZOL YELLOW BG 250r.
CAS NUMBER : 8005-72-9 CHEMICAL NAME: SOLAR YellOW RG
Ul
0'>
Ul
8EHQ-0587-0678
SUBMITTER: EASTMAN KODAK COMPANY
CAS NUMBER: 6262-51-]
CHEMICAL NAME: CYCLOPROPANE, PENTACHLORO-
8EHQ-0687-0679
SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER: 68412-01-1
CHEMICAL NAME: D-GLUCITOl, REACTION PRODUCTS WITH EPICHLOROHYDRIN
8EHQ-0687-0680
SUBMITTER: EASTMAN KODAK COMPAHY
CAS NUMBER: UNKNOWN
CAS NUMBER: UNKNOWN
CHEMICAL NAME: NAPHTHAlENE. DIIODO-
CHEMICAL NAME: NAPHTHALENES, DI-, TRI-, AND TETRAIODO-, MIXED
CHEMICAL NAME: NAPHTHALENE, TETRAIODO-
CHEMICAL NAME: NAPHTHALENE, TRIIODO-
CAS NUMBER: UNKNOWN
CAS HUMBER: UNKNOWN
8EHQ-0786-0681
SUBMITTER: MONSANTO COMPANY
CAS NUMBER: 17796-82-6
CAS NUMBER: 17796-82-6
CHEMICAL NAME: IH-ISOINDOlE-l,3(2H)-DIONE, 2-(CYClOHEXYLTHIO)-
CHEMICAL NAME: SANTOGARD PVI
8EHQ-068]-0682
SUBMITTER: MONSANTO COMPANY
CAS NUMBER: 27193-86-8
CHEMICAL NAME: PHENOL, DODECYl-
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NuMBER
8EHQ-0687-06112
SUBMITTER: MONSANTO COMPANY
8EHQ-0687-0683
SUBMITTER: UNION CARBIDE CORPORATION
CAS ~UMBER : 3033-62-3
CAS NUMBER: 3033-62-3
CHEMICAL NAME: ETHANAMIHE. 2.2'-OXYBIS[H.H-DIMETHYl-
CHEMICAL HAME: HIAX CATALYST A-99
8EHQ-0787-0684 S
CAS HUMBER: HOHE
SUBMITTER: DOW CORNIHG CORPORATIOH
CHEMICAL HAME: DOW CORHIHG S-5370 RTV
8EHQ-0787-0685
SUBMITTER: CIBA-GEIGY CORPORATIOH
CAS HUMBER: 3126-63-4
CHEMICAL HAME: OXIRANE. 2.2'-[2.2-BIS[(OXIRAHYlMETHOXY)METHYl]-1,3-PROPAHED
IYlBIS(OXYMETHYlEHE)]BIS-
8EHQ-0787-0686 S SUBMITTER: COHFIDEHTIAl
U1 CAS HUMBER : COHFI DEHT CHEMICAl HAME: ALKYl PHEHOl. MODIFIED
(j'1
(j'1
8EHQ-0887-0687 SUBMITTER: TEXACO INC.
CAS HUMBER: 64742-86-5
CHEMICAL HAME: GAS OILS. (PETROLEUM), HYDRODESUlFURIZED HEAVY VACUUM
8EHQ-0887-0688
SUBMITTER: AMERICAH CYAHAMID COMPAHY
CAS HUMBER : 7647-01-0 CHEMICAL HAME: HYDROCHLORIC ACID
CAS HUMBER : 7647-01-0 CHEMICAL HAME: MURIATIC ACID
CAS HUMBER : 7647-14-5 CHEMICAL HAME: SODIUM CHLORIDE. (HACU
CAS NUMBER : 7664-'3-9 CHEMICAL HAME: SULFURIC ACID
CAS NUMBER : 7757-82-6 CHEMICAL HAME: SULFURIC ACID DISODIUM SALT
8EHQ-0887-0689 II SUBMITTER: NATIONAL TOXICOLOGY PROGRAM
CAS HUMBER : 78-79-5 CHEMICAL HAME: 1.3-BUTADIEHE. 2-METHYl-
CAS HUMBER : 78-79-5 CHEMICAl HAME: ISOPREHE
CAS NUMBER : 126-99-8 CHEMICAL HAME: 1.3-BUTADIEHE, 2-CHlORO-
CAS NUMBER : 126-99-8 CHEMICAL NAME: CHlOROPRENE
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-0887-0689
IE
SUBMITTER: NATIONAL TOXICOLOGY PROGRAM
8EHQ-0887-0690
SUBMITTER: ATLANTIC RICHFIELD COMPANY
CAS NUMBER: 941-69-5
CHEMICAL NAME: 1H-PYRROLE-2,5-DIONE. 1-PHENYl-
8EHQ-0887-0691 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: 64741-52-2 CHEMICAL NAME: DISTILLATES, (PETROLEUM), LIGHT NAPHTHENIC
CAS HUMBER : 64741-53-3 CHEMICAL NAME: DISTILLATES, (PETROLEUM), HEAVY NAPHTHEHIC
CAS HUMBER : 64741-88-4 CHEMICAL HAME: DISTILLATES, (PETROLEUM), SOLVENT-REFINED HEAVY PARAFFINIC
CAS NUMBER : 64742-52-5 CHEMICAL HAME: DISTILLATES, (PETROLEUM), HYDROTREATED HEAVY NAPHTHEHIC
CAS HUMBER : 64742-53-6 CHEMICAL NAME: DISTIllATES, (PETROLEUM), HYDROTREATED LIGHT HAPHTHENIC
CAS HUMBER : 64742-65-0 CHEMICAL NAME: DISTILLATES, (PETROLEUM), SOLVEHT-DEWAXED HEAVY PARAFFINIC
Ul
0'>
-.J
8EHQ-0987-0692
SUBMITTER: MONSANTO COMPAHY
CAS NUMBER: UNKNOWN
CHEMICAL NAME: ACETIC ACID, OXO-, METHYL ESTER OR ETHYL ESTER, HOMOPOLYMER,
REACTION PRODUCTS WITH ETHOXYETHENE AND REACTION PRODUCTS W
ITH METHOXYETHENE, SODIUM SALTS
8EHQ-0987-0693
SUBMITTER: UNION CARBIDE CORPORATION
CAS HUMBER: 112-60-7
CHEMICAL NAME: ETHANOL, 2,2'-[OXYBIS(2,1-ETHANEDIYLOXY)]BIS-
8EHQ-0987-0694 II SUBMITTER: WESTVACO CORPORATION
CAS HUMBER : 151-21-] CHEMICAL NAME: SODIUM DODECYL SULFATE (SDS)
CAS HUMBER : 151-21-3 CHEMICAL NAME: SODIUM LAURYL SULFATE (SLS)
CAS NUMBER : 151-21-3 CHEMICAL NAME: SULFURIC ACID MOHODODECYL ESTER SODIUM SAlT
8EHQ-1087-0695
SUBMITTER: CIBA-GEIGY CORPORATIOH
CAS NUMBER: 872-50-4
CHEMICAL NAME: 2-PYRROlIDINONE, 1-METHYL-
8EHQ-10a7-0696
CAS HUMBER: HOHE
SUBMITTER: UNION CARBIDE CORPORATION
CHEMICAL NAME: SURFACTAHTS (HOH-IOHIC), ALKOXYLATED
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-I087-0696
SUBMITTER: UNION CARBIDE CORPORATION
8EHQ-1l87-0697
SUBMITTER: AMOCO CORPORATION
CAS NUMBER: UNKNOWN
CAS HUMBER: UNKNOWN
CHEMICAL NAME: FUEL OIL, HO. 2, SUB FRACTIONS
CHEMICAL NAME: OIL (PETROLEUM), FURNACE, SUBFRACTIOHS
CAS NUMBER: 68476-30-2
CAS NUMBER: 68476-30-2
CHEMICAL NAME: FUEL OIL, HO. 2
CHEMICAL NAME: OIL (PETROLEUM), FURNACE
8EHQ-1l87-0698
SUBMITTER: UNION CARBIDE CORPORATION
CAS NUMBER : 107-07-3 CHEMICAL NAME: ETHANOL, 2-CHLORO-
8EHQ-1287-0699 SUBMITTER: E. I. DUPONT DE NEMOURS & COMPANY, INC.
CAS NUMBER : NONE CHEMICAL NAME: CATALYSTS
CAS NUMBER : HONE CHEMICAL NAME: MISC. CHEMICALS
lJ1 CAS HUMBER : IH-40-6 CHEMICAL NAME: MYCOBAN (SODIUM SAl 1)
0'1
co CAS HUMBER : 137-40-6 CHEMICAl HAME: PROPANOIC ACID, SODIUM SALT
CAS HUMBER : 4075-81-4 CHEMICAL NAME: MYCOBAH (CALCIUM SALT)
CAS HUMBER : 4075-81-4 CHEMICAl HAME: PROPANOIC ACID, CAlCIUM SAlT
8EHQ-1287-0700
SUBMITTER: SHELL OIL COMPANY
CAS HUMBER: 3236-71-3
CHEMICAL NAME: FLUORENE, 9,9-BIS(4-HYDROXYPHENYL)-
8EHQ-1287-0701
II
SUBMITTER: UHIOH CARBIDE CORPORATION
CHEMICAL HAME: ETHANOL (STRONG ACID PRODUCTIOH PROCESS)
CAS HUMBER: NONE
CAS HUMBER: HOHE
CAS HUMBER: HOHE
CHEMICAL NAME: ISOPROPAHOL (STROHG ACID PRODUCTION PROCESS)
. CHEMICAL NAME: MISC. CHEMICALS
8EHQ-1287-0702
SUBMITTER: MOHSANTO COMPANY
CAS HUMBER: 768-52-5
CHEMICAL HAME: BENZEHAMINE, N-(I-METHYLETHYL)-
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-12IH-0703
SUBMITTER: MONSANTO COMPANY
CAS NUMBER: 768-52-5
CHEMICAL NAME: BENZENAMINE, N-(I-METHYLETHYL)-
8EHQ-1287-0704
SUBMITTER: TEXACO INC.
CAS NUMBER: 91-20-3
CHEMICAL NAME: NAPHTHALENE
8EHQ-1287-0705
SUBMITTER: MONSANTO COMPANY
CAS NUMBER: 108-UI-9
CHEMICAL NAME: 2-PROPANAMINE, N-(I-METHYLETHYL)-
8EHQ-1287-0706
SUBMITTER: BORG-WARNER CHEMICALS, INC.
CAS NUMBER : 26741-53-7 CHEMICAL NAME: 2,4,8,10-TETRAOXA-3,9-DIPHOSPHASPIRO[5.5]UNDECANE, 3,9-BIS[2
,4-BIS(I,I-DIMETHYLETHYL)PHENOXY]-
CAS NUMBER : 26741-53-7 CHEMICAL NAME: ULTRANOX 624
iJl CAS NUMBER : 26741-53-7 CHEMICAL NAME: ULTRANOX 626
0' CAS NUMBER 26741-53-7
'-D : CHEMICAL NAME: ULTRANOX 626A
CAS NUMBER : 26741-53-7 CHEMICAL NAME: WESTON MDW-6140
CAS NUMBER : 26741-53-7 CHEMICAL NAME: WESTON XR-1452
CAS NUMBER : 26741-53-7 CHEMICAL NAME: WESTON XR-1532
8EHQ-1287-0707 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CHEMICAL NAME: PYRIDINECARBOXYLATE
8EHQ-1287-0708 S
SUBMITTER: CONFIDENTIAL
CAS HUMBER: CONFIDENT
CHEMICAL NAME: ACETOPHENONE OXIME
8EHQ-1287-0709 S
SUBMITTER: HENKEL CORPORATION
CAS NUMBER: 106-89-8
CAS NUMBER: 106-89-8
CHEMICAL NAME: EPICHLOROHYDRIN
CHEMICAL NAME: OXIRANE, (CHLOROMETHYL)-
CAS NUMBER: 87257-05-4
CHEMICAL NAME: POLY(OXY-l,2-ETHANEDIYL), A-HYDRO-W-(OXIRANYLMETHOXY)-, ETHE
R WITH 2-ETHYL-2-(HYDROXYMETHYL)-1,3-PROPANEDIOL (3:1)
CHEMICAL NAME: OXIRANE, 2,2'-(3,7,7,11-TETRAMETHYL-2,5,9,12-TETRAOXATRIDECA
Nt-l,l~-UlTL)bl~-
CAS NUMBER: 52495-71-3
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-1287-0709 S
SUBMITTER: HENKEL CORPORATION
8EHQ-1287-0710
SUBMITTER: TEXACO INC.
CAS NUMBER: 64742-86-5
CAS NUMBER: 64742-87-6
CHEMICAL NAME: GAS OILS, (PETROLEUM), HYDRODESULFURIZED HEAVY VACUUM
CHEMICAL NAME: GAS OILS, (PETROLEUM), HYDRODESULFURIZED LIGHT VACUUM
8EHQ-1287-0711
SUBMITTER: AMOCO CORPORATION
CAS NUMBER: 89-32-7
CAS NUMBER: 89-32-7
CHEMICAL NAME: IH,3H-BENZO[I,2-C:4,5-C']DIFURAN-l,3,5,7-TETRONE
CHEMICAL NAME: PYROMELLITIC DIANHYDRIDE
CAS NUMBER: 552-30-7
CAS NUMBER: 552-30-7
CHEMICAL NAME: 5-ISOBENZOFURANCARBOXYLIC ACID, 1,3-DIHYDRO-l,3-DIOXO-
CHEMICAL NAME: TRIMELLITIC ANHYDRIDE
8EHQ-0188-0712
M
SUBMITTER: KOPPERS COMPANY, INC.
CHEMICAL NAME: LH-25 PRESERVATIVE
U1
-J
o
CAS NUMBER: NONE
CAS NUMBER: NONE
CHEMICAL NAME: SAPSTAIN CONTROL CHEMICAL NP-l
CHEMICAL NAME: I-DECANAMINIUM, N-DECYL-N,N-DIMETHYL-, CHLORIDE
CAS NUMBER: 7173-51-5
CAS NUMBER: 55406-53-6
CHEMICAL NAME: CARBAMIC ACID, BUTYL-, 3-IODO-2-PROPYNYL ESTER
8EHQ-0188-0713
SUBMITTER: DOW CHEMICAL COMPANY
CAS NUMBER: 75-00-3
CHEMICAL NAME: ETHANE, CHLORO-
8EHQ-0188-0714
SUBMITTER: EASTMAN KODAK COMPANY
CAS NUMBER : 565-7~-2
CHEMICAL NAME: BUTANOIC ACID, 2-BROMO-3-METHYL-
8EHQ-0288-0715
SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER: UNKNOWN
CHEMICAL NAME: POLYGLYCIDYL ETHYL, 2,2,6,6-TETRAMETHYLOL CYCLOHEXANOL
3EHQ-0288-0716 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CHEMICAL NAME: PYRIDINECARBOXYLATE
3EHQ-0288-0717 S
SUBMITTER: CONFIDENTIAL
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-------
APPEHDIX E: STATUS REPORTS BY SUBMISSIOH HUMBER
8EHQ-0288-0717 S
SUBMITTER: COHFIDEHTIAL
8EHQ-0288-0718
II
SUBMITTER: DOW CORHIHG CORPORATIOH
CAS HUMBER: 556-67-2
CAS HUMBER: 9005-64-5
CHEMICAL HAME: CYCLOTETRASILOXAHE, OCTAMETHYL-
CHEMICAL HAME: SORBITAH, MOHODODECAHOATE, POLY(OXY-1,2-ETHAHEDIYL) DERIYS.
8EHQ-0288-0719
SUBMITTER: OLIH CORPORATIOH
CAS HUMBER: 68214-81-3
CAS HUMBER: 68214-81-3
CHEMICAL HAME: CHEMICAL 400, STEP 1
CHEMICAL HAME: ETHANOL, 2-[ETHYL[3-METHYL-4-(PHENYLAZO)PHENYLJAMINO]-
8EHQ-0288-0720
CAS HUMBER: NOHE
SUBMITTER: GEHERAl ELECTRIC COMPAHY
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CAS NUMBER: HOHE
CAS HUMBER: HONE
CHEMICAl HAME: BEHZEHE, l,l'-OXYBIS-, BROMIHATED DERIY.
CHEMICAl HAME: DI8EHZOFURAHS, BROMIHA TED
CHEMICAl HAME: DIOXIHS, BROMIHATED
CHEMICAl HAME: BEHZEHE, 1,l'-OXYBIS[2,3,4,5,6-PEHTABROMO-
CHEMICAl HAME: AHTIMOHY OXIDE
CAS HUMBER: 1163-19-5
CAS HUMBER: 1327-33-9
CAS HUMBER: 30965-26-5
CHEMICAL HAME: 1,4-BEHZEHEDICARBOXYLIC ACID, DIMETHYL ESTER, POLYMER WITH 1
,4-BUTAHEDIOL
8EHQ-0388-0721
SUBMITTER: EASTMAH KODAK COMPAHY
CAS HUMBER: 59607-71-5
CHEMICAL HAME: THIOCYAHIC ACID, 4-METHOXY-2-HITROPHENYL ESTER
8EHQ-0288-0722 SUBMITTER: BOEIHG COMPANY
CAS HUMBER : HOHE CHEMICAl HAME: FREKOTE 700
CAS HUMBER : NONE CHEMICAl NAME: MISC. CHEMICALS
CAS HUMBER : HONE CHEMICAL NAME: SCOTCHWElD AF-163-2 OST
8EHQ-0388-07Z3
SUBMITTER: MOHSAHTO COMPAHY
CAS HUMBER: 2004-03-7
CHEMICAL HAME: PURIHE, 6-METHYL-
8EHQ-0388-0724 5
SUBMITTER: CIBA-GEIGY CORPORATION
~A~ NUM~~K : ~UN~lU~"1
~H~Ml~Al "AM~: ~H~"Ul U~K1VAllV~, ~1~Kl~AllT Hl"U~K~U
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-0388-0724 S
SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER: CONFIDENT
CAS NUMBER: NONE
CHEMICAL NAME: PHENOL DERIVATIVE, STERICALLY HINDERED
CHEMICAL NAME: PHENOL DERIVATIVES, STERICALLY HINDERED, MIXTURE
8EHQ-0388-0725
SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER: 36443-68-2
CHEMICAL NAME: BENZENEPROPANOIC ACID, 3-(1,1-DIMETHYLETHYL)-4-HYDROXY-5-MET
HYL-, 1,2-ETHANEDIYLBIS(OXY-2,1-ETHANEDIYL) ESTER
CHEMICAL NAME: IRGANOX 245
CAS NUMBER: 36443-68-2
8EHQ-0388-0726
If
SUBMITTER: HOECHST CELANESE CORPORATION
CAS NUMBER: 98-73-7
CAS NUMBER: 98-73-7
CHEMICAL NAME: BENZOIC ACID, P-TERT-BUTYL-
CHEMICAL NAME: BENZOIC ACID, 4-(1,1-DIMETHYLETHYL)-
8EHQ-0488-0727
SUBMITTER: AMOCO CORPORATION
Ul
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CAS NUMBER : 7783-06-4 CHEMICAL NAME: HYDROGEN SULFIDE, (H2S)
CAS NUMBER : 64741-56-6 CHEMI CAl NAME: RESIDUES, (PETROLEUM), VACUUM
CAS NUMBER : 64741-60-2 CHEMICAl NAME: DISTILLATES, (PETROLEUM), INTERMEDIATE CAUL YTIC CRACKED
CAS NUMBER : 64741-62-4 CHEMICAL NAME: CLARIFIED OILS, (PETROLEUM), CATALYTIC CRACKED
CAS NUMBER : 68553-00-4 CHEMICAL NAME: FUEL OIL, NO. 6
8EHQ-0488-0728
CAS NUMBER: NONE
SUBMITTER: UNION CARBIDE CORPORATION
CHEMICAL NAME: IMPOSIT
CAS NUMBER: NONE
CAS NUMBER: 25322-68-3
CHEMICAL NAME: LEDERMIX
CHEMICAL NAME: CARBOWAX PEG-BOOO
CAS NUMBER: 25322-6B-3
CHEMICAL NAME: POLY(OXY-1,2-ETHANEDIYL), .ALPHA.-HYDRO-.OMEGA.-HYDROXY-
8EHQ-0488-0729 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CHEMICAL NAME: SULFLURAMID, ETHYL
8EHQ-0588-0no
SUBMITTER: BASF CORPORATION
~A~ NUM~tK : ~~b~-~/-~
~HtMl~Al NAMt: AUKAMINt HYUKU~HlUKIUt
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION HUMBER
8EHQ-0588-07JO
SUBMITTER: BASF CORPORATION
CAS NUMBER : 2465-27-2 CHEMICAL NAME: C. 1. BASIC YElLOW 2
CAS NUMBER : 2465-27-2 CHEMICAL NAME: BENZENAMIHE, 4,4'-CARBOHIMIDOYLBIS[N,N-DIMETHYL-, MONOHYDROC
HLORIDE
CAS NUMBER : 43IJO-12-7 CHEMICAL NAME: AURAMIHE, ETHYl-, NITRATE SALT
CAS NUMBER : 43IJO-12-7 CHEMICAL NAME: C. 1. BASIC YElLOW 37
CAS NUMBER : 43IJO-12-7 CHEMICAL NAME: BENZENAMIHE, 4,4'-CARBOHIMIDOYLBIS[N,H-DIETHYL-, MONONITRATE
8EHQ-0588-07Jl S
SUBMITTER: DOW CHEMICAL COMPAHY
CAS NUMBER: CONFIDEHT
CAS NUMBER: CONFIDENT
CHEMICAL NAME: BENZEHE, 1,1'-OXYBIS-, SUBSTITUTED
CHEMICAL NAME: DIPHENYL ETHER, SUBSTITUTED
8EHQ-0588-0732
SUBMITTER: EASTMAH KODAK COMPAHY
U1
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CAS NUMBER: 6294-52-6
CHEMICAL NAME: BEHZOTHIAZOLE, 2-AMINO-5,6-DIMETHOXY-
8EHQ-0588-07B
CAS HUMBER: NONE
SUBMITTER: AMERICAN TELEPHONE AND TELEGRAPH COMPANY CAT&T)
CHEMICAL NAME: PALLADIUM PLATIHG COMPOUND
CAS HUMBER: HONE
CHEMICAL HAME: PD MAKEUP
8EHQ-0688-0734 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDEHT
CAS HUMBER: CONFIDENT
CHEMICAL NAME: POLYESTER, MODIFIED ALIPHATIC ALICYCLIC
CHEMICAL HAME: SILANE
8EHQ-0688-0735
SUBMITTER: PENNZOIL COMPANY
CAS NUMBER: 593-88-4
CAS HUMBER: 7440-38-2
CHEMICAL HAME: ARSINE, TRIMETHYL-
CHEMICAL NAME: ARSENIC
CAS NUMBER: 8006-14-2
CHEMICAL NAME: NATURAL GAS
8EHQ-0688-0736
SUBMITTER: REILLY TAR & CHEMICAL CORPORATION
CAS NUMBER: 1072-98-6
CHEMICAL NAME: PYRIDINE, 2-AMINO-5-CHLORO-
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-0688-0736
SUBMITTER: REILLY TAR & CHEMICAL CORPORATION
8EHQ-0688-0737
SUBMITTER: ANITMONY OXIDE INDUSTRY ASSOCIATION
CAS NUMBER : 1309-64-4 CHEMICAL NAME: ANTIMONY OXIDE, (SB203)
CAS NUMBER : 7647-18-9 CHEMICAL NAME: ANTIMONY CHLORIDE, (SBCL5)
CAS NUMBER : 10025-91-9 CHEMICAL NAME: ANTIMONY CHLORIDE, (SBCU)
CAS NUMBER : 10025-91-9 CHEMICAL NAME: STIBINE, TRICHLORO-
8EHQ-0688-0738
CAS NUMBER: NONE
SUBMITTER: MOBAY CORPORATION
U1
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CAS NUMBER: 107534-96-3
CAS NUMBER: 107534-96-3
CHEMICAL NAME: FOLI CUR TECHNICAL
CHEMICAL NAME: FOLICUR 1.2 EC
CHEMICAL NAME: LYNX 1. 2
CHEMICAL NAME: TERBUCONAZOLE
CAS NUMBER: NONE
CAS NUMBER: NONE
CHEMICAL NAME: IH-l,2,4-TRIAZOLE-I-ETHANOL, .ALPHA.-[2-(4-CHLOROPHENYL)ETHY
L]-.ALPHA.-(I,I-DIMETHYLETHYL)-(.+-.)-
8EHQ-0688-0739
SU8MITTER: EASTMAN KODAK COMPANY
CAS NUMBER: 14447-15-5
CHEMICAL NAME: ACETIC ACID, CYANO-, PROPYL ESTER
8EHQ-0688-0740 S
SUBMITTER: EASTMAN KODAK COMPANY
CAS NUMBER: CONFIDENT
CHEMICAL NAME: THIAZINOHYDRAZINE, SU8STITUTED
8EHQ-0788-0741
SUBMITTER: INTERNATIONAL ISOCYANATE INSTITUTE, INC.
CAS NUMBER: 9016-87-9
CHEMICAL NAME: ISOCYANIC ACID, POLYMETHYLENEPOLYPHENYLENE ESTER
8EHQ-0788-0742
If
SUBMITTER: ATLANTIC RICHFIELD COMPANY
CHEMICAL NAME: CUTTING FLUID
CAS NUMBER: NONE
8EHQ-0788-0743
SUBMITTER: PROCTER & GAMBLE COMPANY
CAS NUMBER: 3734-67-6
CAS NUMBER: 3734-67-6
CHEMICAL NAME: C. I. ACID RED 1
CHEMICAL NAME: 2,7-NAPHTHALENEDISULFONIC ACID, 5-(ACETYlAMINO)-4-HYDROXY-3-
l~H~NTLAŁUJ-, U1SUUlun SALI
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-0788-0743
SUBMITTER: PROCTER & GAMBLE COMPANY
CAS NUMBER: 3734-67-6
CHEMICAL NAME: RED 2G
8EHQ-0788-0744 S
CAS NUMBER: NONE
SUBMITTER: MOBIL RESEARCH AND DEVELOPMENT CORPORATION
CHEMICAL NAME: OIL. JET ENGINE
CAS NUMBER: 78-30-8
CAS NUMBER: 1330-78-5
CHEMICAL NAME: PHOSPHORIC ACID. TRISC2-METHYlPHENYl) ESTER
CHEMICAL NAME: PHOSPHORIC ACID. TRISCMETHYlPHENYl) ESTER
8EHQ-0788-0745 S
SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER: CONFIDENT
CHEMICAL NAME: CARBOMONOCYClIC AMINOBUTYROlACTONE
8EHQ-0888-0746
SUBMITTER: MONSANTO COMPANY
CAS NUMBER: 101-54-2
CHEMICAL NAME: 1.4-BENZENEDIAMINE, N-PHENYl-
U1
-.J
U1
8EHQ-0888-0747
SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER: 3846-71-7
CAS NUMBER: 3846-71-7
CHEMICAL NAME: PHENOL. 2-(2H-BENZOTRIAZOl-2-Yl)-4,6-BISC1,1-DIMETHYLETHYL)-
CHEMICAL NAME: TINUVIN 320
8EHQ-0988-0748
SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER: 25973-55-1
CHEMICAL NAME: PHENOL, 2-(2H-BENZOTRIAZOl-2-Yl)-4,6-BISC1,1-DIMETHYlPROPYl)
CAS NUMBER: 25973-55-1
CHEMICAL NAME: TINUVIN 328
8EHQ-0988-0749 S SUBMITTER: CONFIDEHTIAl
CAS NUMBER : COHFIDENT CHEMICAL HAME: PYRIDIHE. ALKYl
8EHQ-0988-0750 S SUBMITTER: COHFIDENTIAl
CAS HUMBER: COHFIDENT CHEMICAL HAME: AMIDE. HETEROCYCLIC ARYL
8EHQ-0988-0751 S SUBMITTER: CONFIDEHTIAl
CAS HUMBER : COHFIDENT CHEMICAL NAME: ETHER. DIARYl
-------
APPEHDIX E: STATUS REPORTS BY SUBMISSIOH HUMBER
8EHQ-0988-0751 S
SUBMITTER: COHFIDEHTIAl
8EHQ-0988-0752 S
SUBMITTER: 3M COMPANY
CAS NUMBER: CONFIDENT
CHEMICAL NAME: FIBER, INORGANIC
8EHQ-0988-0753 S
SUBMITTER: HOECHST CELANESE CORPORATION
CAS NUMBER: CONFIDENT
CHEMICAL NAME: INDOlENINIUM SALT
8EHQ-0988-0754
SUBMITTER: AMERICAH CYAHAMID COMPAHY
CAS HUMBER: 78-97-7
CAS NUMBER: 107-16-4
CHEMICAL NAME: PROPANENITRIlE, 2-HYDROXY-
CHEMICAL NAME: ACETONITRILE, HYDROXY-
CAS HUMBER: 109-77-3
CAS HUMBER: 13893-53-3
CHEMICAL NAME: PROPANEDINITRIlE
CHEMICAL NAME: BUTANEHITRIlE, 2-AMINO-2,3-DIMETHYl-
U1
-..j
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8EHQ-I088-0755
SUBMITTER: Ell LIllY AND COMPANY
CAS NUMBER : 1322-93-6 CHEMICAL HAME: NAPHTHAlENESUlFONIC ACID, BIS(I-METHYlETHYl)-, SODIUM SAlT
CAS NUMBER : 1322-93-6 CHEMICAL NAME: SEllOGEN HR
CAS NUMBER : 1332-58-7 CHEMICAL NAME: KAOLIN
CAS NUMBER : 1332-58-7 CHEMICAL NAME: SPESWHITE (CLAY>
CAS NUMBER : 1746-81-2 CHEMICAL NAME: ARESIH
CAS NUMBER : 1746-81-2 CHEMICAL NAME: LINURON, MONO-
CAS HUMBER : 1746-81-2 CHEMICAL NAME: UREA, N'-(4-CHlOROPHENYl)-H-METHOXY-N-METHYl-
CAS NUMBER : 8061-51-6 CHEMICAl NAME: LIGNOSUlFONIC ACID, SODIUM SALT
CAS HUMBER : 8061 51-6 CHEMICAL NAME: POlYFON H
CAS NUMBER : 55283-68-6 CHEMI CAl NAME: BENZENAMINE, N-ETHYl-H-(2-METHYl-2-PROPEHYl)-2,6-DINITRO-4-(
TRIFlUOROMETHYl)-
CAS HUMBER : 55283-68-6 CHEMICAL HAME: ETHAlFlURALIH
CAS HUMBER : 55283-68-6 CHEMICAL HAME: SOHAl AH
CAS HUMBER : 63231-67-4 CHEMICAL NAME: HI-SIl 233
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
3EHQ-I083-0755
SUBMITTER: ELI LILLY AND COMPANY
CAS NUMBER: 63231-67-4
CHEMICAL NAME: SILICA GEL
8EHQ-l0aa-0756
SUBMITTER: CIBA-GEIGY CORPORATIOH
CAS HUMBER: 3864-99-1
CAS NUMBER: 3864-99-1
CHEMICAL HAME: PHEHOL, Z-(S-CHLORO-ZH-BEHZOTRIAZOL-Z-YL)-4,6-BIS(I,I-DIMETH
YlETHYl)-
CHEMICAL HAME: TIHUVIH 327
3EHQ-I083-0757
SUBMITTER: CIBA-GEIGY CORPORATIOH
CAS NUMBER: UNKHOWN
CHEMICAL HAME: Z-PROPAHOl, 1-[BIS(Z-HYDROXYETHYL)AMIHO]-3-(4-ISOHOHYLPHEHOX
Y)-
3EHQ-I088-0758 S
SUBMITTER: VALEHT U.S.A. CORPORATIOH
~
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CAS NUMBER: CONFIDEHT
CAS NUMBER: CONFIDEHT
CHEMICAL HAME: CYCLOHEXEHOHE, SUBSTITUTED
CHEMICAL HAME: PHTHALIMIDE (III), SUBSTITUTED
CAS NUMBER: COHFIDEHT
CAS NUMBER: CONFIDEHT
CHEMICAL HAME: PHTHALIMIDE (II), SUBSTITUTED
CHEMICAL HAME: PHTHALIMIDE (I), SUBSTITUTED
8EHQ-I088-0759
SUBMITTER: E. I. DUPOHT DE HEMOURS & COMPAHY, IHC.
CAS HUMBER: UNKHOWH
CAS HUMBER: 67-64-1
CHEMICAL NAME: 1.2-BEHZEHEDICARBOXYLIC ACID DERIV.
CHEMICAL HAME: ACETOHE
CAS HUMBER: 67-64-1
CAS HUMBER : 67-66~3
CHEMICAL HAME: 2-PROPAHOHE
CHEMICAL HAME: CHLOROFORM
CAS HUMBER: 67-66-3
CAS HUMBER: 75-15-0
CHEMICAL NAME: METHAHE. TRICHlORO-
CHEMICAL HAME: CARBOH DISULFIDE
CAS HUMBER: 75-69-4
CAS HUMBER: 78-93-3
CHEMICAL HAME: METHAHE, TRICHLOROFlUORO-
CHEMICAL HAME: 2-BUTAHOHE
CAS HUMBER: 78-93-3
CAS HUMBER: 108-95-2
CHEMICAL HAME: METHYLETHYLKETOHE (MEK)
CHEMICAL HAME: PHENOL
CAS HUMBER: 680-31-9
CHEMICAL HAME: HEXAMETHYLPHOSPHORAMIDE
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
3EHQ-I033-0759
SUBMITTER: E. I. DUPONT DE NEMOURS I COMPANY, INC.
CAS NUMBER : 630-31-9 CHEMICAL NAME: PHOSPHORIC TRIAMIDE, HEXAMETHYL-
CAS NUMBER : 7440-33-2 CHEMICAL NAME: ARSENIC
CAS NUMBER : 7440-41-7 CHEMICAL NAME: BERYLLIUM
CAS NUMBER : 7440-47-3 CHEMICAL NAME: CHROMIUM
CAS NUMBER : 7440-66-6 CHEMICAL HAME: ZINC
3EHQ-I0aa-0760 5
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CAS NUMBER: 67-63-0
CHEMICAL NAME: ALKYL HETEROCYCLIC NITROGEN COMPOUND
CHEMICAL NAME: ISOPROPANOL
CAS NUMBER: 67-63-0
CHEMICAL NAME: 2-PROPANOL
Ul 3EHQ-lOa3-0761 SUBMITTER: GELMAN SCIENCES INC.
-..j NAME:
():) CAS NUMBER : NONE CHEMICAL COOLANTS, AUTOMOTIVE
CAS NUMBER : NONE CHEMICAL NAME: DE-ICING FLUIDS, AIRCRAFT
CAS NUMBER : 107-21-1 CHEMICAL NAME: 1,2-ETHANEDIOL
CAS NUMBER : 107-21-1 CHEMICAL NAME: ETHYL ENE GL YCOL
CAS HUMBER : 123-91-1 CHEMICAL HAME: 1,4-DIOXANE
3EHQ-1033-0762
SUBMITTER: AMOCO CORPORATIOH
CAS HUMBER: 111-37-5
CHEMICAL HAME: 1-0CTAHOL
3EHQ-l0a3-0763 S
SUBMITTER: UNIOH CARBIDE CORPORATIOH
CAS HUMBER: COHFIDEHT
CHEMICAL NAME: THIADIAZOLE SULFOHAMIDE, ALKYLAMIHOCARBOHYL SUBSTITUTED
aEHQ-10aa-0764 S SUBMITTER: UHIOH CARBIDE CORPORATIOH
CAS HUMBER: COHFIDEHT CHEMICAL HAME: TOLYLCYCLOALKEHYL SUBSTITUTED ALKYL ESTER
CAS HUMBER : COHFIDEHT CHEMICAL HAME: TOLYLCYCLOALKEHYL SUBSTITUTED PHOSPHOROTHIOATE ESTER
CAS HUMBER: COHFIDENT CHEMICAL NAME: XYLYLCYCLOALKEHYL SUBSTITUTED ALKYL ESTER
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-I088-0764 S SUBMITTER: UNION CARBIDE CORPORATION
CAS NUMBER : 149-57-5 CHEMICAL NAME: HEXANOIC ACID, 2- ETHYl-
8EHQ-1188-0165 S SUBMITT ER: CONFIDENTIAl
CAS NUMBER : CONFIDENT CHEMICAL ,o\ME: ARYl OXIME
8EHQ-1188-0766 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CHEMICAL NAME: HETEROARYL ALKYL ETHER
8EHQ-1188-0761 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CHEMICAL NAME: HALOALKYL HETEROCYCLE
8EHQ-1188-0768 S
SUBMITTER: EASTMAN KODAK COMPANY
CAS NUMBER : CONFIDENT CHEMICAL NAME: INORGANIC POTASSIUM HALIDE COMPLEX
Ul
~
I.D 8EHQ-1188-0769 II SUBMITTER: CIBA-GEIGY CORPORATION
CAS NUMBER : 1336-36-3 CHEMICAl NAME: 1,1' -BIPHENYL, CHLORO DERIVS.
CAS NUMBER : 1336-36-3 CHEMICAL NAME: POLYBROMINATED BIPHENYlS (PCB)
CAS NUMBER : 11096-82-5 CHEMICAL NAME: AROCHLOR 1260
8EHQ-1188-0770 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CHEMICAL NAME: ACETAL, HETEROCYCLIC
8EHQ-1188-0171 S
SUBMITTER: CONFIDENTIAL
CAS NUMBER: CONFIDENT
CHEMICAL NAME: ETHER, ALKYL ARYL
8EHQ-1188-0772
SUBMITTER: HOECHST CELANESE CORPORATION
CAS NUMBER: 75-09-2
CAS HUMBER: 75-09-2
CHEMICAL NAME: METHANE, DICHLORO-
CHEMICAL NAME: METHYLEHE CHLORIDE
CAS NUMBER: 9012-09-3
CAS NUMBER: 9012-09-3
CHEMICAL NAME: CELLULOSE, TRIACETATE
CHEMICAL NAME: TRIACETATE FIBERS, CELLULOSE
-------
APPENDIX E: STATUS REPORTS BY SUBMISSION NUMBER
8EHQ-1188-0772
SUBMITTER: HOECHST CELAHESE CORPORATIOH
8EHQ-1288-0773
SUBMITTER: AMOCO OIL COMPANY
CAS NUMBER: 64741-76-0
CAS NUMBER: 64741-76-0
CHEMICAL NAME: DISTILLATES (PETROLEUM), HEAVY HYDROCRACKED
CHEMICAL HAME: RESID HYDROPROCESSING UNIT (RHU) MIDDLE DISTILLATES
8EHQ-1288-0774
SUBMITTER: AMOCO OIL COMPANY
CAS NUMBER: 64741-75-9
CAS NUMBER: 64741-75-9
CHEMICAL NAME: RESID HYDROPROCESSING UNIT (RHU) LIGHT VACUU~ GA~ OILS
CHEMICAL NAME: RESIDUES, (PETROLEUM), HYDROCRACKED
8EHQ-1288-0775
SUBMITTER: AMOCO OIL COMPANY
CAS NUMBER: 64742-46-7
CAS NUMBER: 64742-46-7
CHEMICAL NAME: AMOCO NT-45 PROCESS OIL
CHEMICAL NAME: DISTILLATES, (PETROLEUM), HYDROTREATED MIDDLE
~
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8EHQ-1288-0776
SUBMITTER: AMERICAN TELEPHONE AND TELEGRAPH COMPANY
CAS NUMBER: CONFIDENT
CAS NUMBER: CONFIDENT
CHEMICAL NAME: ACRYLIC ACID DERIVATIVES
CHEMICAL NAME: BORDON CHEMICAL COMPOUND 9MKU10108R
CAS NUMBER: CONFIDENT
CHEMICAL NAME: 2-PROPENOIC ACID DERIVATIVES
8EHQ-1288-0777
SUBMITTER: AMOCO CHEMICAL COMPANY
CAS NUMBER: 1779-17-5
CHEMICAL NAME: 1,3-ISOBENZOFURANDIONE, 5,5'-(I-METHYLETHYLIDENE)BIS-
8EHQ-1288-0778
SUBMITTER: EASTMAH KODAK COMPANY
CAS NUMBER: 94-96-2
CHEMICAL NAME: 1,3-HEXANEDIOL, 2-ETHYL-
.
Baged on a preliminary evaluation, EPA believe~ that the 9ubmitted information did not warrant reporting under
~ectlon ~(e) of TSCA. In m09t cage9, the 9ubmltter was requested to provide the basi9 for contending that the
Information offered rea90nable 9upport for the conclusion that the 9ubject chemical 9ubstance(9) i t (
Pre t b t t' I 'k f ' , h or m xure s)
gen 9 a 9U 9 an la rl9 0 InJury to ealth or the environment as defined in EPA'9 TSCA S t' 8() ,
9tatement (see Appendix A of thi9 volume). ec Ion e policy
-------
50272 . Ift1
REPORT DOCUMENTATION II. REPORT NO.
PAGE EPA
4. TItle .nd Subtitle
560/2-89-001
I~
I. Recipient'. Accenlon No.
"Preliminary Evaluations of Initial TSCA
Section 8(e) Substantial Risk Notices"
January 1987 - December 1988
7. Author(s) Office of Toxic Substances/OPTS
U.S. Environmental Protection Agency (EPA)
9. Performlnc O....nlz.tlon N..... .nd Addrwu
5. Report Date
March 1989
6.
L "'rformlnc O....nlution Rapt. No.
10. Prolect/Tuk/Work Unit No.
Office of Pesticides and Toxic Substances
U.S. Environmental Protection Agency
401 "M" Street, S.W.
Washington, D.C. 20460
(TS- 788)
11. Cont..ct(C) or Gr.nt(G) No.
(C)
(G)
1~ Sponsorinc O....nlz.tlon N.m. .nd Add....s
Office of Pesticides and Toxic Substances
U.S. Environmental Protection Agency
401 "M" Street, S.W.
WashinQton D.C. 20460
II. TYIM of Report & .....od Cownod
(TS-788)
01/01/87 to 12/31/88
14.
15. Supplement.ry Note.
16. Abst..ct (Umlt: 200 wordS)
'!his volLnne contains, in ascending submission number order, "status reports"
(i.e., preliminary evaluations) prepared by the staff of the Office of Toxic
Substances in EPA's Office of Pesticides and Toxic Substances for initial
submissions received by EPA from chemical manufacturers, bnporters, processors
and distributors from January 1, 1987 to December 31, 1988 under Section 8(e).
the "substantial risk" infonna.tion reporting provision of the Toxic Substances
COntrol Act ('!'SCA). '!he status reports contained in this compendium reflect
only the initial phase of the Agency's evaluation process for the submitted
infonna.tion.
'!his '!'SCA Section 8 (e) status report volume has been published by EPA for two
reasons. First, a volume of Section 8 (e) status reports with appropriate
indices will make the submitted infonna.tion more accessible. Second, this
volume may, by providing specific examples of submitted infonna.tion and EPA's
preliminary evaluation of that infonna.tion, help those persons who are subject
to Section 8 (e) understand better the types of infonna.tion that should be
submitted to EPA under this mandatory reporting provision of '!'SCA.
17. Document Anelyal. eo DncrItItors
Toxic Substances
TSCA
Section 8(e)
Substantial Risk
b. Identifiers/Open-Ended Terms
Control Act
c. COSATI field/Group
11. Avellebility Stetemen~
II. Security Cle.. (ThIs Report)
21. No. of Pac..
581
Unlimited Distribution
20. Security Class (ThIs .....)
zz. Price
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