A f—f^jk United States
VVtRr\ Environmental Protection
Agency
Summary Report for the
Screening-Level Review of
Toxicity Information
Contained in the Integrated
Risk Information System
(IRIS) Database - Phase II
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NCEA-S-1393
September 2002
Summary Report for the Screening-level Review of
Toxicity Information Contained in the
Integrated Risk Information System (IRIS) Database
Phase II
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Screening-Level Review of the IRIS Database Phase II September 2002
DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental Protection
Agency policy and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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Screening-Level Review of the IRIS Database Phase II September 2002
CONTENTS
1.0 INTRODUCTION AND PURPOSE 1
2.0 METHODS 3
2.1 Task 1: Selecting 200 IRIS Chemicals 3
2.2 Task 2: Identifying Existing Authoritative Scientific Literature Compilations 3
2.3 Task 3: Conducting Literature Searches 7
2.4 Task 4: Sorting Literature Search Results 9
2.5 Task 5: Evaluating Health Effects Information 11
3.0 RESULTS AND CONCLUSIONS 13
APPENDICES
Appendix A: List of 200 Chemicals
Appendix B: Sample Lotus Notes Report
Appendix C: Electronic Files
Appendix D: Reference Sorting Criteria
Appendix E: Decision Trees
Appendix F: Chemical Summaries
Appendix G: Summary of Findings
LIST OF TABLES
Table 1: Literature Compilations and Toxicity Information Considered in
the Phase II Screening-Level Review 4
Table 2: Literature Search Terms 8
Table 3: Laboratory Species and Toxicological Terms 11
Table 4: Results of Screening-Level Review of IRIS 14
in
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Screening-Level Review of the IRIS Database Phase II September 2002
AUTHORS
The National Center for Environmental Assessment, Office of Research and
Development, was responsible for the preparation of this report. This document was prepared by
Eastern Research Group, Inc. (ERG), Lexington, MA, under Contract No. 68-C-99-237, Task
Order No. 62. Susan Rieth served as the Work Assignment Manager.
IV
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Screening-Level Review of the IRIS Database Phase II September 2002
1.0 INTRODUCTION AND PURPOSE
The Integrated Risk Information System (IRIS) is a U.S. Environmental Protection Agency
(EPA) database containing EPA consensus positions on potential adverse health effects that may
result from chronic (or lifetime) exposure to chemical substances found in the environment. This
database is maintained by EPA's National Center for Environmental Assessment (NCEA). The
consensus positions for individual chemicals are documented in the form of IRIS summaries,1
which contain qualitative and quantitative health information, including reference doses (RfDs)
for non-cancer health effects resulting from oral exposure, reference concentrations (RfCs) for
non-cancer health effects resulting from inhalation exposure, cancer weight-of-evidence (WOE)
designations, and cancer slope factors (CSFs) and inhalation unit risks (ILJRs) for the
carcinogenic effects of chemicals via ingestion and inhalation, respectively.
IRIS was originally developed in the mid-1980s to ensure consistency among health assessments
completed and utilized by various EPA regions and program offices. Since IRIS was created,
summaries for over 500 chemicals have been added to IRIS. For a number of chemicals
summarized in IRIS, additional health effects research has since been published in the literature,
but is not reflected in the current IRIS summaries. Consideration of these more recent research
findings could potentially result in revised toxicity values (i.e., RfDs, RfCs, CSFs, or lURs) or
cancer WOE designations for some chemicals.
In order to address questions about how well IRIS toxicity values reflect the current scientific
literature, EPA initiated a screening-level review of the available literature for chemicals in the
IRIS database. The purpose of the review was to reach preliminary determinations regarding the
likelihood that a toxicological reassessment based on an evaluation of new health effects
literature could potentially result in significant changes in the existing toxicity values or WOE
designations. In addition, the results of the screening-level review will provide information for
the annual IRIS Program priority-setting process for identifying chemicals for reassessment.
A screening-level methodology was adopted because an in-depth evaluation of recent health
effects literature is a time- and resource-intensive process that represents the majority of the
effort required in assessing a chemical. The screening-level methodology was designed to
preliminarily identify and characterize new health effects literature for chemicals listed in the
IRIS database. This methodology is not intended to provide a comprehensive or critical
evaluation of this literature.
The size of the IRIS database precluded screening-level reviews of all of the chemicals included
in this database at one time. Under the Phase I screening-level review, completed in November
2001, screening-level reviews were conducted for 100 chemicals randomly selected from the
1 IRIS summaries prepared since 1996 include supporting Toxicological Review
documents.
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Screening-Level Review of the IRIS Database Phase II September 2002
IRIS database of more than 500 chemicals. Under Phase II, screening-level reviews were
conducted for 200 chemicals randomly selected from the more than 400 remaining chemicals in
the IRIS database. This report summarizes the results of the Phase II screening-level review. The
remaining chemicals from the IRIS database will undergo screening-level reviews in the future.
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Screening-Level Review of the IRIS Database Phase II September 2002
2.0 METHODS
The screening-level review of the toxicity values contained in the IRIS summaries was
conducted in five steps: 1) randomly selecting the 200 chemicals for review, 2) identifying
recent toxicology literature compilations prepared by EPA and other authoritative organizations,
3) conducting literature searches to identify relevant health effects literature published since the
IRIS summaries were completed, 4) sorting the literature (based primarily on a review of titles
and abstracts) identified during the literature searches, and 5) evaluating the new health effects
information and determining if this information could potentially produce a significant change in
the current IRIS toxicity values.
2.1 Task 1: Selecting 200 IRIS Chemicals
EPA prepared a list of all chemicals currently in the IRIS database, excluding chemicals being
reassessed under the IRIS program or those chemicals evaluated under the Phase I screening-
level review. The list of remaining chemicals was imported into Microsoft Excel to randomly
select 200 chemicals for the Phase II screening-level reviews. Using the RANDQ function, each
chemical was assigned a random number greater than or equal to 0 and less than 1. The list of
these chemicals was then reorganized using the Sort tool and the chemicals were arranged in
ascending order by the randomly assigned number. The first 200 chemicals identified in this
random sort were selected for the Phase II literature-screening reviews and are listed in
Appendix A.
2.2 Task 2: Identifying Existing Authoritative Scientific Literature Compilations
A chemical-specific strategy for identifying toxicity literature was developed for each chemical.
These strategies were based on the date that the current toxicity values or WOE designation were
posted on IRIS and the availability of toxicity literature compilations produced by authoritative
scientific organizations. This section describes the process used to gather and evaluate this
information, as well as the protocol applied to develop chemical-specific literature search
strategies.
For each chemical, information regarding the toxicity value or WOE designation, the principal
study or studies on which a value was based, and the consensus date was extracted from the IRIS
database, as listed in Table 1. For many chemicals, one or more toxicity values or the WOE
designation was unavailable, either because EPA has not yet undertaken an assessment of the
given value or because EPA conducted an assessment and concluded that insufficient
information was available to derive a toxicity value. The reason why a toxicity value or WOE
designation was unavailable was also extracted from the IRIS database.
EPA programs such as the Office of Pesticide Programs (OPP) and other authoritative scientific
organizations such as the International Agency for Research on Cancer (IARC) and the Agency
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Screenme-Level Review of the IRIS Database Phase II
September 2002
for Toxic Substances and Disease Registry (ATSDR) periodically review and summarize the
toxicology literature for chemicals that are included in the IRIS database. Literature
compilations, like these, for individual chemicals were identified by searching Web-based
databases or EPA files, as listed in Table 1. Key toxiciry information extracted from each of
these documents is also listed in Table 1.
Table 1: Literature Compilations and Toxiciry Information Considered in
the Phase II Screening-Level Review
Source
IRIS
IRIS Submission
Desk
ATSDR
Toxicological
Profiles2
Health Canada3
IARC Monographs
WHO/IPCS
NTP Cancer
Bioassay
NTP Report on
Carcinogens
OPPRED
documents
Information Extracted
Toxiciry values and
WOE designation
Principal study
descriptions
Consensus date
Publication date
Relevant information
Publication date
Minimal risk levels
Principal study
descriptions
Publication date
Toxicity values and
cancer classification
Principal study
descriptions
Publication date
IARC classification
Publication date
Publication date
Results
Publication date
Cancer classification
Publication date
Toxicity values
Principal study
descriptions
Location of Source1
http./Avww.epa gov/iris/subst/mdex.html
Available through EPA
TERA's on-line ITER database
http.//iter.ctcnet net/publicurl/pub_search_hst cfm
http //www atsdr cdc gov/toxpro2 html
TERA's on-line ITER database
http://iter ctcnet net/pubhcurl/pub_search_list.cfm
http://193.51.164 1 1/monoeval/grlist.html
http./Avww who mt/dsa/cat98/zehc htm
http //ntp-server niehs nih gov/mam_pages/
NTP_ALL_STDY_PG html
http.//ntp-server.niehs nih gov/NewHomeRoc/AboutRoC.
html
http://www epa gov/REDs/
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Screening-Level Review of the IRIS Database Phase II September 2002
Table 1: Literature Compilations and Toxicity Information Considered in
the Phase II Screening-Level Review
Source
Information Extracted
Location of Source1
NCEA Provisional
Assessments4
Date of assessment
Toxicity values and
cancer classification
Principal study
descriptions
Available through EPA
Notes:
1 Several of the Web site addresses changed between Phase I and Phase II; however, the content
contained on these Web sites remained the same. The Web sites listed were accessed during the Phase II
screening-level reviews and are only as accurate as the date of the latest revision of this document.
2 ATSDR Supplemental Documents were considered during the Phase I screening-level review.
These documents, however, did not add to the information contained in the ATSDR Toxicological
Profiles. As such, the ATSDR Supplemental Documents were not included as a source of toxicity
information in the Phase II screening-level review.
1 Health Canada toxicity values were compiled from several sources including: Environmental
Carcinogenesis and Ecotoxicology Review, Part C of Journal of Environmental Science and Health; and
the Health Canada priority substances list assessment reports.
4 Provisional toxicity values are developed by NCEA for the Superfund Health Risk Assessment
Technical Support Center and the Hazardous Waste Identification Rule. These toxicity values undergo
internal and external peer review, but do not undergo EPA consensus review and do not appear in the
IRIS database.
ATSDR Agency for Toxic Substances and IRIS Integrated Risk Information System
Disease Registry NCEA National Center for Environmental
EPA U.S. Environmental Protection Assessment
Agency NTP National Toxicology Program
I ARC International Agency for Research OPP Office of Pesticide Programs
on Cancer RED Reregistration Eligibility Decision
IPCS International Programme on WHO World Health Organization
Chemical Safety
A Lotus Notes database was developed to organize the information for each chemical extracted
from both the IRIS database and literature compilations. Procedures were incorporated to ensure
the accuracy of the information entered into the Lotus Notes database. For example, data entry
fields in the Lotus Notes database were formatted to accept only specific formats (e.g., text or
number). For fields with a limited number of possible entries (e.g., cancer classification), entry
options were limited. Some fields also included limits on the number of characters that could be
entered. In addition, hard copies of the IRIS summaries and literature compilations were
obtained and a manual quality assurance/quality control review was conducted for information
entered in the Lotus Notes database.
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Screening-Level Review of the IRIS Database Phase II September 2002
The Lotus Notes database was formatted to present toxicity information available for each
chemical in a standard report. These reports not only presented toxicity values from various
sources, but also indicated where toxicity values or literature compilations were unavailable.
Appendix B contains a sample of the standard report generated for one of the chemicals included
in the Lotus Notes database. Appendix C contains copies of the electronic files, including the
Lotus Notes database, created for the screening-level review.
Information contained in the Lotus Notes database was then used to develop a literature search
strategy for each individual chemical. The literature search strategy was based on the consensus
date for the toxicity values or WOE designations in the existing IRIS summaries and the
availability of literature compilations from authoritative scientific organizations. The literature
search strategies fell into one of the following general categories:
1. No literature compilations from authoritative scientific sources were published after the
consensus date for the IRIS toxicity values and/or WOE designation. A determination
was made to conduct a literature search beginning with the year before the consensus
date to the present.
Example: The consensus date was June 4, 1990. No literature compilations were
identified. A determination was made to conduct a literature search from 1989 to the
present.
2. A literature compilation from an authoritative scientific source was published after the
consensus date for the IRIS toxicity values and/or WOE designation. A determination
was made to conduct a literature search beginning with the year before that compilation
was published to the present.
Example: The consensus date was June 4,1990. ATSDR published a lexicological
profile in 1997, which included a toxicity value (Minimal Risk Level) based on data
considered in the existing IRIS summary. A determination was made to conduct a
literature search from 1996 to the present.
3. A literature compilation from an authoritative scientific source was published after the
consensus date for the IRIS toxicity values and/or WOE designation. The literature
compilation contained a toxicity value based on study information made available after
the IRIS consensus date, suggesting that significant new health effects literature exists
that may result in a revised IRIS toxicity value. A literature search was considered
unnecessary to establish that potentially significant new health effects information exists.
Example: The consensus date was June 4, 1990. ATSDR published a toxicity value in
1997 that was different from the value presented in the existing IRIS summary and was
based on a 1995 study. The 1995 study was identified as health effects information that
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Screening-Level Review of the IRIS Database Phase II September 2002
could potentially produce a change in the IRIS summary. An additional literature search
was considered unnecessary.
For each chemical, literature search strategies were developed for each of the toxicity values
assessed in the IRIS summary, including the RfD, RfC, and cancer endpoints (CSF, IUR, and
WOE designation). These literature search strategies were documented in the Lotus Notes
database for each chemical, as shown in the sample report provided in Appendix B.
When no assessment of the health effects literature for a toxicity value or WOE designation has
been conducted for an individual chemical, a screening-level review to determine whether the
value reflected the current health effects literature could not be performed. Nonetheless, if
information that might support the derivation of a toxicity value was identified when screening
the selected literature compilations, this information was noted in the Lotus Notes database.
2.3 Task 3: Conducting Literature Searches
Based on the literature search strategies developed in Task 2, chemical-specific literature
searches were conducted to identify toxicologic and epidemiologic studies relevant to the
development of IRIS toxicity values or WOE designations. For the purposes of this screening-
level review, the following Web-based databases2 were searched:
• TOXLINE Special (http://toxnet.nlm.nih.gov/): This database contains bibliographic
information covering the biochemical, pharmacological, physiological, and toxicological
effects of drugs and other chemicals. References from an assortment of specialized
journals and other sources are included.
MEDL1NE (available through PUBMED at
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi): This databases contains bibliographic
citations and author abstracts from more than 4,000 biomedical journals.
• CANCERL1T (http://www. cancer.gov/search/cancerjiterature/) • This database contains
bibliographic citations and abstracts about chemical carcinogenicity from biomedical
journals, proceedings, books, reports, and doctoral theses.
CCRIS (http://toxnet.nlm.nih.gov/): This database summarizes data regarding
carcinogenicity, mutagenicity, tumor promotion, and tumor inhibition test results. The
reported data are derived from studies cited in primary journals, current awareness tools,
NCI reports, and other special sources.
2 Several of the Web sites addressees changed between Phase I and Phase II; however, the content
contained on these Web sites remained the same. The Web sites listed were accessed during the Phase II
screening-level reviews and are only as accurate as the date of the latest revision of this document.
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TSCA TS (http://esc.syrres. com/efdb/TSCA TS. htm): The Toxic Substance Control Act
Test Submission (TSCATS) database was developed as a central location of information
regarding unpublished technical reports submitted by industry to EPA under the Toxic
Substances Control Act (TSCA). The database categorizes studies on over 8,000
chemicals by health effects, environmental effects, and environmental fate.
• EPA Office of Pesticide Programs (OPP) (http://www.epa.gov/pesticides/search.htm):
OPP maintains a search page that allows users to search the Consumer Fact Sheets,
Chemical Fact Sheets (technical information), OPP Publications (by title or publication
number), Pesticide Registration (PR) Notices, Reregistration Eligibility Decisions
(REDs), or the entire Web site for information regarding pesticides.
Additional information about each of the databases searched is provided on the listed Web sites.
For chemicals with IRIS summaries containing toxicity values and WOE designations, the first
five databases were searched. For chemicals with IRIS summaries containing only a RfD and/or
a RfC, only TOXLINE, MEDLINE, and TSCATS were searched because CANCERLIT and
CCRIS contain information specific to cancer endpoints only. For pesticides, the OPP Web site
was also searched.
A consistent set of search terms was applied in searching TOXLINE, MEDLINE, and
CANCERLIT. Searches were initially performed using the chemical abstracts registry service
(CAS) number and synonyms. If less than 50 references were found, the search was refined to
identify studies containing the CAS number, synonyms, and any of the toxicology terms listed in
Table 2. Results from the refined search were saved. All the terms listed in Table 2 were used
when refining searches of TOXLINE and MEDLINE; however, only those search terms related
to cancer endpoints were used to refine searches of CANCERLIT.
Table 2: Literature Search Terms
toxic
adverse effect
cancer *
carcinog *
tumor*
oncogen *
neoplasm *
mutag *
mutat *
genotox *
fetotox
embryotox
teratolog
teratogen
reproduct, toxic
development, toxic
neurotox
immunotox
pharmacokinetic
metabolism
epidemiol
human stud
terms that apply to cancer endpoints and used to search CANCERLIT
CCRIS summarizes cancer-related study results by chemical name or CAS number. As such,
searching by CAS number alone identified all relevant entries. If the CAS number was listed in
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CCRIS, the search results were saved. If the CAS number was not listed in CCRIS, then no
cancer-related data were available.
TSCATS also provides study results by chemical name or CAS number, but also allows the user
to specify the category of study types sought. For each chemical, TSCATS was searched by CAS
number first to identify the chemical and then by "health effects" to identify only those studies
related to chemical toxicity.
In addition to REDs, which were included in the Lotus Notes database where available, the OPP
Web site may contain other documents relevant to the toxicity of individual pesticides. Thus, a
search of the OPP Web site (by CAS number) was conducted for pesticides included in the Phase
II screening-level review. Additional information, if available, was most often identified in the
OPP "Index of Cleared Science Reviews."
The literature search protocol described above was followed for each of the 200 chemicals
included in the Phase II screening-level review with one exception. This protocol was slightly
modified for inorganic arsenic. The modified literature search protocol is described in detail in
the chemical summary for inorganic arsenic (Appendix F).
EndNote, a reference managing software program, was used to manage and organize results
obtained from the literature search. For each chemical, results from searching TOXLINE,
MEDLINE, and CANCERJLIT were automatically imported into an EndNote file and sorted by
publication date. The Find Duplicates tool was used to identify and delete references that
appeared in multiple search results. Results from the CCRIS, TSCATS, and OPP Web site
cannot be automatically entered into EndNote. References found when searching these sources
were manually entered into the EndNote file for a chemical if the reference had not been
captured when searching TOXLINE, MEDLINE, or CANCERLIT and the reference presented
data relevant to the toxicity of the chemical under review (as described under Task 4). In many
instances, results from the TSCATS search provided additional information, such as study
completion date and author, for studies identified in TOXLINE. (TOXLINE captured the date
that unpublished studies were submitted to EPA for review under TSCA rather than the date that
these studies were completed.) This additional information was manually entered into EndNote.
The resulting EndNote file then served as the collection of references used to conduct the
literature screening under Task 4. The EndNote files for each chemical are provided
electronically in Appendix C.
2.4 Task 4: Sorting Literature Search Results
Individual references obtained in the literature search were sorted by their relevance to the
development of a given IRIS toxicity value. For the purpose of this screening-level review, this
sorting process was limited only to the information contained in the literature search records
(e.g., study titles and abstracts). Reviewing full-text articles and conducting in-depth data
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Screening-Level Review of the IRIS Database Phase II September 2002
reviews were outside the scope of the screening-level review. Individual references were sorted
into the following nine categories:
1. Potential to produce a significant change in an existing noncancer toxicity value
2. Potential to produce a significant change in an existing cancer toxicity value
3. Potential to produce a significant change in an existing cancer WOE designation
4. Physiologically-based pharmacokinetic (PBPK) modeling studies
5. Other toxicity studies not directly useful for establishing IRIS toxicity values
6. Studies with information on health effects in young populations
7. Compilations of health effects studies
8. Not useful
9. Unknown relevance
Each of these categories and the criteria used to assign categories are described in more detail in
Appendix O.
An individual reference may contain information relevant to more than one category. For
example, a multigeneration reproductive toxicity study would fall in category 1 (potential to
produce a change m an existing noncancer toxicity value) and category 6 (studies with
information on health effects in young populations). In sorting references, references were coded
with all appropriate categories.
For the majority of the 200 randomly selected chemicals, all references identified during the
literature search were screened and coded. When the literature search retrieved a large number of
references (i.e., greater than 300), EndNote functions were used to identify those reference most
likely relevant to the development of IRIS toxicity values. For some chemicals, the literature
searches identified a large number of references unrelated to the chemical of interest because
chemical synonyms are also common words. For example, the literature search for the pesticide
with the trade name "Assure" identified over 1,100 references. References not relevant to an
IRIS assessment for Assure were identified through a search of EndNote and were coded N/A in
the EndNote file. Other chemicals, such as Dicamba, have been the subject of extensive toxicity
testing in both plants and animals. In these instances, references containing common laboratory
species and toxicological terms (Table 3) were identified and coded. Remaining references were
retained in EndNote and coded N/A. Literature searches for some chemicals identified large
numbers of references because of chemical-specific characteristics. Strychnine, for example, has
been studied for its use as an anticonvulsant. Therefore, studies related to strychnine as a
treatment for seizures were found using a search of EndNote and coded N/A. The use of the
additional search terms, such as those listed in Table 3, to refine literature searches with large
numbers of records was documented in the chemical-specific summaries prepared under Task 5.
The EndNote files for each chemical are provided electronically in Appendix C.
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Table 3: Laboratory Species and Toxicological Terms
rat(s)
mouse/mice
gerbil(s)
hamster(s)
beagle(s)
dog(s)
human(s)
rabbit(s)
pig(s)
monkey(s)
primate(s)
worker(s)
epidemiol
genotox
mutat
mutag
2.5 Task 5: Evaluating Health Effects Information
In the final phase of the screening-level review, summary information contained in available
literature compilations and in the sorted literature searches was evaluated to determine if recent
health effects information could potentially produce a significant change in existing IRIS toxicity
values or WOE designations. Judgements about the potential impact of the more recent literature
on existing IRIS toxicity values were guided by a set of decision rules developed by the EPA.
These judgements considered both the basis for current toxicity values or WOE designations and
the nature of more recent toxicity literature. These decision rules are described in a set of
decision trees for noncancer RfDs and RfCs, CSFs and ILJRs, and WOE designations. Decision
trees are provided in Appendix E. Each IRIS toxicity value (i.e., RfD, RfC, CSF, or IUR) and
WOE designation currently contained in IRIS was evaluated separately. Such evaluations were
not performed if an assessment in support of an individual toxicity value or WOE designation
was absent from the existing IRIS assessment for a given chemical.
The literature screening conducted in Task 4 served to focus evaluations during Task 5.
References coded as category 1 (potential to produce a change in an existing noncancer toxicity
value) were evaluated against current RfDs and RfCs and principal studies used to derive these
values. References coded as category 2 (potential to produce a change in an existing cancer
toxicity value) were evaluated against current CSFs and IlJRs and principal studies used to
derive these values. References coded as category 2 and category 3 (potential to produce a
change in an existing cancer toxicity value or WOE designation) were evaluated in light of the
evidence used to derive the WOE designations. References coded as category 4 (PBPK modeling
studies) were evaluated for their potential to influence uncertainty factors for interspecies
extrapolation. References assigned a code of 5, 6, or 7 were those that would not typically be
used as the basis for a toxicity value, but might be considered more generally in developing an
IRIS summary. References coded as category 9 (unknown relevance) contained insufficient
information to evaluate their relevance to the development of toxicity values or WOE
designations. Further examination of these studies may be warranted in the future.
The findings of the screening-level review for each of the 200 chemicals were summarized in
brief narratives (1 or 2 pages). These narratives are provided in Appendix F. Narratives briefly
characterized the basis of toxicity values and WOE designations in existing IRIS summaries and
the nature of new health effects information. Narratives also included conclusions regarding the
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likelihood that new health effects information identified in authoritative literature compilations
or the literature search could produce a significant change in existing IRIS toxicity values.
Conclusions were drawn for each toxicity value and WOE designation. When no assessment of
the health effects literature for a given toxicity value or WOE designation has been conducted,
similar conclusions could not be drawn. Nonetheless, relevant information identified during the
screening-level review was noted in the narratives. A brief statement summarizing the number of
references coded as category 9 (unknown relevance) was also included in each narrative.
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3.0 RESULTS AND CONCLUSIONS
A screening-level review of 200 chemicals randomly selected from the IRIS database was
conducted to address questions about whether or not current health effects literature could
potentially produce a change in the existing IRIS toxicity values or WOE designation. The
results of this review are summarized in the following text and Table 4. Results for individual
chemicals are provided in Appendix G.
For 121 (60%) of the 200 chemicals reviewed, no significant new health effects information that
would likely produce a significant change in existing IRIS toxicity values or the WOE
designation was identified. For 79 chemicals (40%) new health effects information was
identified that, if evaluated in detail, could possibly result in a change to an existing IRIS
toxicity value or WOE designation.
Results relevant to the specific toxicity values and WOE designations are as follows:
• RfDs were available for 141 of the chemicals reviewed. New health effects information
that could potentially result in a significant change in the RfD was identified for 61 of the
141 chemicals.
• RfCs were available for 40 of the chemicals reviewed. New health effects information
that could potentially result in a significant change in the RfC was identified for 9 of the
40 chemicals.
• CSFs were available for 30 of the chemicals reviewed. New health effects information
that could potentially result in a significant change in the CSF was identified for 6 of the
30 chemicals.
• ILJRs were available for 21 of the chemicals reviewed. New health effects information
that could potentially result in a significant change in the IUR was identified for 6 of the
21 chemicals.
• WOE designations were available for 80 of the chemicals reviewed. New health effects
information that could potentially result in a significant change in the WOE designations
was identified for 11 of the 80 chemicals.
For most chemicals in IRIS, one or more toxicity values are not available in the IRIS database
(e.g., for dibutyl phthalate, an RfD, RfC and WOE are available in IRIS, but not a CSF or IUR).
In some instances, the lack of a toxicity value or WOE designation reflects the fact that EPA has
not yet undertaken a determination of a toxicity value or WOE designation. In other cases, a
chemical-specific toxicity value or WOE designation is not present in IRIS because its derivation
is inappropriate. For example, 1,1-methylphenol and trichloroacetic acid have been assigned a
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WOE classification of Group C—possible human carcinogen. Deriving a CSF or IUR for these
chemicals was not supported by the available data. As previously noted, screening-level reviews
were not specifically conducted when no assessment of the health effects literature for a toxicity
value or WOE designation had been conducted; however, relevant studies identified in the
literature screen were noted in the chemical-specific narratives. Of the 200 chemicals evaluated,
information relevant to a toxicity value not assessed in the current IRIS summary was identified
for 107 chemicals (54%). Because the literature search for these toxicity values was not intended
to be comprehensive and because a detailed review of new study literature was outside the scope
of this review, it cannot be determined whether the available toxicity information would support
the derivation of a toxicity value not currently available in IRIS.
Table 4: Results of Screening-Level Review of IRIS
Summary of Assessments
Available in the existing IRIS summary
Not available in the existing IRIS summary
No literature likely to produce a significant
change in the IRIS summary was identified
New literature was identified that could
potentially produce a significant change in the
IRIS summary
Not available in the IRIS summary, but
potentially relevant information was identified
RfD
141
59
80
61
23
RfC
40
160
31
9
20
CSF
30
170
24
6
18
IUR
21
179
15
6
9
WOE
80
120
69
11
75
Notes:
CSF oral cancer slope factor
IRIS Integrated Risk Information System
IUR inhalation unit risk
RfD oral reference dose
RfC inhalation reference concentration
WOE cancer weight-of-evidence
Given the application of a screening-level methodology to evaluate current IRIS assessments,
certain limitations and uncertainties are inherent in the results of the assessment. These
limitations and uncertainties are as follows:
• The screening-level review involved screening, coding, and evaluating studies identified
(1) in the literature compilations based on available study summaries and (2) in the
literature searches based only on study titles and abstracts. The literature was not
subjected to an in-depth assessment or independent critical evaluation. As such, no
conclusions regarding the validity of new toxicity information or appropriateness for its
use in developing toxicity values could be drawn. In general, it was conservatively
14
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Screening-Level Review of the IRIS Database Phase II September 2002
assumed that the more recent toxicity literature that passed the initial Task 4 screen had
the potential to produce a change in an existing IRIS value. It is expected that toxicity
values for some chemicals for which new toxicity information was identified would not
be subject to change upon a more detailed, critical examination of the study data.
• No literature search can be assured of capturing all relevant literature. The screening-
level review sought to capture the majority of potential new health effects studies;
however, some information, such as unpublished toxicology studies, may have been
overlooked. This is a specific concern when identifying new health effects literature for
pesticides, which comprise approximately 40% of the IRIS chemicals evaluated in the
current screening-level review. Many studies of pesticides are directly submitted to EPA
OPP and are considered confidential business information. Although OPP REDs, which
include reviews of all toxicity studies submitted to EPA, were one of the literature
compilations relied on, these documents were not available for all the pesticides
undergoing the screening-level review. For the pesticides, a search of the OPP Web site
was conducted to identify additional information possibly available through OPP.
• The literature search records for some studies contained insufficient information to
permit a determination of the relevance of the reference to a health assessment for a given
chemical (e.g., the record did not provide a complete citation or sufficient information on
the chemical(s) under study, endpoints measured, or date that the study was conducted).
The numbers of studies categorized as being of unknown relevance are provided in the
individual chemical narratives (Appendix F) and are summarized in Appendix G. Full
text review of these references, which was beyond the scope of this screening-level
review, would be required to determine their relevance to an updated health assessment
for a given chemical.
• Since the mid-1980s when the first IRIS summaries were developed, EPA has modified
some risk assessment methods for deriving toxicity values and WOE designations (e.g.,
benchmark dose approach, inter-species scaling factor, guidelines for carcinogen risk
assessment). Consideration of how the application of new methodologies might affect
existing IRIS values was beyond the scope of this screening-level review.
The TSCATS database contains unpublished technical reports submitted by industry to
EPA under TSCA. The TOXLINE database includes records from TSCATS and was the
preferred source of TSCATS records because TOXLINE search results could be
automatically downloaded into EndNote. The TSCATS information provided in
TOXLINE records, however, is incomplete. Therefore, some manual editing of the
TSCATS information was required. Two dates, one representing the date the study was
completed and one representing the date the study was submitted to EPA Office of Toxic
Substances (OTS), are reported in the TSCATS database. The TOXLINE database,
however, lists only the date that the study was submitted to EPA. Periodically, the date of
15
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Screening-Level Review of the IRIS Database Phase II September 2002
study completion predates the date of submission to EPA by 10 years or more. For
example, a study completed in 1970 may have a submission date to EPA of 1987.
TOXLINE would list the publication date for this study as 1987. In TSCATS, the
designation "00/00/00" is used if no submission date is available. TOXLINE incorrectly
converts this entry to a publication date of 2000.
To the extent possible, errors in TOXLINE were corrected by manually entering into the
EndNote databases for individual chemicals information regarding the actual study
completion date and study authors taken directly from TSCATS. However, not all
submissions to OTS that were contained in TOXLINE were also listed in TSCATS. As
such, information in these records could not be confirmed and the publication dates may
be erroneous. Therefore, unpublished technical reports submitted to OTS that were
lacking abstracts were generally coded as being of "unknown relevance." There exists the
possibility that unpublished OTS submissions that contained new study data may have
been dropped using this procedure.
16
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Screening-Level Review of the IRIS Database Phase II September 2002
APPENDICES
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Screening-Level Review of the IRIS Database Phase II September 2002
Appendix A: 200 Randomly Selected IRIS Chemicals
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Screening-Level Review of the IRIS Database Phase II
September 2002
Appendix
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
A: 200 Randomly Selected IRIS Chemicals
Chemical
Acetonitnle
Acrylonitnle
Adiponitrile
Aldicarb
Aldnn
Ally
Ally! alcohol
Ametryn
4-Aminopyndine
Amitraz
Ammonium acetate
Ammonium sulfamate
Aniline
Antimony
Antimony trioxide
Apollo
Arsenic (inorganic )
Arsine
Assure
Azobenzene
Barium cyanide
Baythroid
Benefm
Benomyl
Bidrm
Biphenthnn
1 , 1 -Biphenyl
Bis(2-chloroethoxy)methane
Bis(2-chloroisopropyl) ether
Bisphenol A
Bromodichloromethane
p-Bromodiphenyl ether
Bromoform
Bromoxynil octanoate
Cacodyhc acid
Captafol
CAS Number
75-05-8
107-13-1
111-69-3
116-06-3
309-00-2
74223-64-6
107-18-6
834-12-8
504-24-5
33089-61-1
631-61-8
7773-06-0
62-53-3
7440-36-0
1309-64-4
74115-24-5
7440-38-2
7784-42-1
76578-14-8
103-33-3
542-62-1
68359-37-5
1861-40-1
17804-35-2
141-66-2
82657-04-3
92-52-4
111-91-1
39638-32-9
80-05-7
75-27-4
101-55-3
75-25-2
1689-99-2
75-60-5
2425-06-1
A-l
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Screening-Level Review of the IRIS Database Phase II
September 2002
Number
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
Chemical
Carbaryl
Carbofuran
Carbon disulfide
Carbonyl sulfide
Carbosulfan
Carboxin
Chlorimuron-ethyl
Chlorine
1-Chlorobutane
2-Chlorobutane
2-Chlorophenol
p-Chlorophenyl methyl sulfide
Coke oven emissions
Cumene
Cyanazme
Cyanogen
Cyclohexanone
Cyclohexylamme
Dalapon (sodium salt)
Danitol
2,4-Diammotoluene
Dibenzofuran
Dibromochloromethane
Dibromodichloromethane
p,p'-Dibromodiphenyl ether
Dicamba
p,p'-Dichlorodiphenyltrichloroethane
1 , 1 -Dichloroethane
cis- 1 ,2-Dichloroethylene
trans- 1 ,2-Dichloroethylene
Dichloromethane
4-(2,4-Dichlorophenoxy)butyric acid
1 ,2-Dichloropropane
2,3-Dichloropropanol
Dicofol
Diethyl phthalate
Diethyl-p-mtrophenyl phosphate
Dimethipm
CAS Number
63-25-2
1563-66-2
75-15-0
463-58-1
55285-14-8
5234-68-4
90982-32-4
7782-50-5
109-69-3
78-86-4
95-57-8
123-09-1
8007-45-2
98-82-8
21725-46-2
460-19-5
108-94-1
108-91-8
75-99-0
39515-41-8
95-80-7
132-64-9
124-48-1
594-18-3
2050-47-7
1918-00-9
50-29-3
75-34-3
156-59-2
156-60-5
75-09-2
94-82-6
78-87-5
616-23-9
115-32-2
84-66-2
311-45-5
55290-64-7
A-2
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Screening-Level Review of the IRIS Database Phase II
September 2002
Number
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
Chemical
N,N-Dimethylformamide
2,4-Dimethylphenol
3 ,4-Dimethylphenol
2 ,4-Dimtrotoluene
Diphenamid
1 ,2-Diphenylhydrazme
Disulfoton
Endosulfan
Endothall
Epichlorohydnn
1 ,2-Epoxybutane
Ethephon
S-Ethyl dipropylthiocarbamate
Ethyl p-nitrophenyl phenylphosphorothioate
Ethylene glycol monobutyl ether (EGBE)
Ethylphthalyl ethylglycolate
Fluridone
Flurprimidol
Fluvalmate
Fomesafen
Formic acid
Furmecyclox
Glycidaldehyde
n-Heptane
alpha-Hexachlorocyclohexane
beta-Hexachlorocyclohexane
Hexachlorophene
1 ,6-Hexamethylene dnsocyanate
Hexazinone
Hydrazme/Hydrazine sulfate
Hydroquinone
Isobutyl alcohol
Lead and compounds (inorganic)
d-Limonene
Malathion
Maleic anhydride
Maleic hydrazide
Manganese
CAS Number
68-12-2
105-67-9
95-65-8
121-14-2
957-51-7
122-66-7
298-04-4
115-29-7
145-73-3
106-89-8
106-88-7
16672-87-0
759.94.4
2104-64-5
111-76-2
84-72-0
59756-60-4
56425-91-3
69409-94-5
72178-02-0
64-18-6
60568-05-0
765-34-4
142-82-5
319-84-6
319-85-7
70-30-4
822-06-0
51235-04-2
302-01-2
123-31-9
78-83-1
7439-92-1
5989-27-5
121-75-5
108-31-6
123-33-1
7439-96-5
A-3
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Screening-Level Review of the IRIS Database Phase II
September 2002
Number
113
114
US
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
Chemical
Mepiquat chloride
Mercuric chloride
Mercury, elemental
Merphos oxide
Methamidophos
Methyl isocyanate
Methyl methacrylate
2-Methyl-4-chlorophenoxyacetic acid
2-(2-Methyl-4-chlorophenoxy) propionic acid
Methylmercury
3-Methylphenol
4-Methylphenol
Metribuzm
Nitrate
Nitnte
N-Nitrosodimethylamme
N-Nitrosodi-N-propylamine
N-Nitrosodiphenylamme
Oxyfluorfen
Pentabromodiphenyl ether
Pentachlorocyclopentadiene
Pentafluoroethane
m-Phenylenediamine
Phenylmercunc acetate
Phosmet
Phthalic anhydnde
Picloram
Pinmiphos-methyl
Potassium silver cyanide
Prometon
Pronamide
Propaml
Propargyl alcohol
Propham
Propylene glycol monomethyl ether
Propylene glycol
Propyleneimme
Pyndme
CAS Number
24307-26-4
7487-94-7
7439-97-6
78-48-8
10265-92-6
624-83-9
80-62-6
94-74-6
93-65-2
22967-92-6
108-39-4
106-44-5
21087-64-9
14797-55-8
14797-65-0
62-75-9
621-64-7
86-30-6
42874-03-3
32534-81-9
25329-35-5
354-33-6
108-45-2
62-38-4
732-11-6
85-44-9
1918-02-1
29232-93-7
506-61-6
1610-18-0
23950-58-5
709-98-8
107-19-7
122-42-9
107-98-2
57-55-6
75-55-8
110-86-1
A-4
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Screening-Level Review of the IRIS Database Phase II
September 2002
Number
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
Chemical
Quinalphos
Quinoline
Quinone
Radium 226,228
Radon 222
Resmethnn
Savey
Selenious acid
Selenium sulfide
Selenium and Compounds
Selenourea
Silver cyanide
Simazine
Sodium diethyldithiocarbamate
Strychnine
Systhane
Tebuthiuron
Terbutryn
Tetrabromodiphenyl ether
1 ,2,4,5-Tetrachlorobenzene
Tetrachlorocyclopentadiene
1,1,1 ,2-Tetrachloroethane
1 , 1 ,2,2-Tetrachloroethane
2,3,4,6-TetrachIorophenol
Tetraethyl lead
Thallic oxide
Thallium carbonate
Thallium nitrate
Thallium(I) sulfate
Thiobencarb
Thiophanate-methyl
Toxaphene
1 ,2,4-Tnbromobenzene
Tnbutyltin oxide
Tnchloroacetic acid
Tnchlorocyclopentadiene
Trichlorofluoromethane
2,4,5-Trichlorophenol
CAS Number
13593-03-8
91-22-5
106-51-4
7440-14-4
14859-67-7
10453-86-8
78587-05-0
7783-00-8
7446-34-6
7782-49-2
630-10-4
506-64-9
122-34-9
148-18-5
57-24-9
88671-89-0
340)4-18-1
886-50-0
40088-47-9
95-94-3
695-77-2
630-20-6
79-34-5
58-90-2
78-00-2
1314-32-5
6533-73-9
10102-45-1
7446-18-6
28249-77-6
23564-05-8
8001-35-2
615-54-3
56-35-9
76-03-9
77323-84-3
75-69-4
95-95-4
A-5
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Screening-Level Review of the IRIS Database Phase II
September 2002
Number
189
190
191
192
193
194
I9S
196
197
198
199
200
Chemical
2,4,6-Tnchlorophenol
2 (2,4,5-Tnchlorophenoxy) propionic acid
1 ,2,3-Trichloropropane
1 , 1 ,2-Tnchloropropane
1 , 1 ,2-Tnchloro- 1 ,2,2-trifluoroethane
Tndiphane
Triethylene glycol monobutyl ether
Tnethylene glycol monoethyl ether
Tnfluralin
Uranium, soluble salts
Vanadium pentoxide
Vinclozolin
CAS Number
88-06-2
93-72-1
96-18-4
598-77-6
76-13-1
58138-08-2
143-22-6
112-50-5
1582-09-8
N.A
1314-62-1
50471-44-8
Notes:
CAS Number chemical abstracts registry service number
A-6
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Screening-Level Review of the IRIS Database Phase II September 2002
Appendix B: Sample Lotus Notes Report
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Appendix B: Sample Lotus Notes Report
Summary of Toxicity Information for Chemicals Listed in IRIS
Chemical Name: Acetonitrile CASRN: 75-05-8 Number: 1
Ims
RfD (mg/kg/day):
Date of Last Significant Revision: 01/26/99
Availability: Withdrawn
Critical Effect:
UF:
MF:
Was an UF assigned based on lack of supporting data?
What was the data gap?
Study Animal/Species:
Principal Study Description:
Principal Study Reference:
RfC (mg/m3): 0 06
Date of Last Significant Revision: 01/26/99
Availability:
Critical Effect: Mortality
UF: 100
MF: 10
Was an UF assigned based on lack of supporting data? Yes
What was the data gap? Limited data on reproductive endpomts involving exposure of laboratory animals before and
during mating through parturition, and the absence of hematological measurements in either mouse study
Study Animal/Species: Mouse
Principal Study Description: Subchromc/chronic inhalation sutides
Principal Study Reference: NTP. 1996
CSF(mg/kg/day)-1:
Date of Last Significant Revision:
Availability: Not available
Tumor Type:
Study Animal/Species:
Principal Study Reference:
IUR(ug/m3)-1:
Date of Last Significant Revision:
Availability: Not available
Tumor Type:
Study Animal/Species:
Principal Study Reference:
WOE Classification: D
Date of Last Significant Revision: 01/26/99
Information Available through the IRIS Submission Desk
Comments: Not Available
B-l
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Screening-Level Review of the IRIS Database Phase II September 2002
ATSDR
Toxlcologlcal Profile (date of most recent update): Not available
OralMRL(mg/kg/day):
Duration:
Critical Organ/Effect:
Study Animal/Species:
Principal Study Reference:
Inhalation MRL (mg/m3):
Duration:
Critical Organ/Effect:
Study Animal/Species:
Principal Study Reference:
ATSDR Supplemental Document:
Health Canada
Health Canada Assessment (date of assessment): Not available
TDI (mg/kg/day):
Critical Organ/Effect:
Study Animal/Species:
Principal Study Reference:
TC (mg/m3):
Critical Organ/Effect:
Study Animal/Species:
Principal Study Reference:
TD05 (mg/kg/day):
Tumor Type:
Study Animal/Species:
Principal Study Reference:
TC05 (mg/m3):
Tumor Type:
Study Animal/Species:
Principal Study Reference:
Cancer classification:
IARC
Date of Most Recent Monograph: Not available
Classification:
B-2
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Screening-Level Review of the IRIS Database Phase II September 2002
WHO
Publication Date: 1993
Publishing Organization: IPCS
NTP Cancer Bioassay (published since 1986)
Publication Date: 4/96
Route of exposure: Inhalation
Result: EE - Equivocal evidence of carcmogemcity
NTP Report on Carcinogens
Date Listed: Not available
Classification:
Reregistration Eligibility Decisions (RED)
Publication Date: Not available
RfD (mg/kg/day):
Critical Effect:
UF:
MR
Study Animal/Species:
Principal Study Description:
Principal Study Reference:
RfC (mg/m3):
Critical Effect:
UF:
IMF:
Study Animal/Species:
Principal Study Description:
Principal Study Reference:
CSF(mg/kg/day)-1:
Tumor Type:
Study Animal/Species:
Principal Study Reference:
IUR(ug/m3)-1:
Tumor Type:
Study Animal/Species:
Principal Study Reference:
B-3
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Screening-Level Review of the IRIS Database Phase II September 2002
NCEA Provisional Assessments
Publication Date: Not available
RfD (mg/kg/day):
Critical Effect:
UF:
MF:
Study Animal/Species:
Principal Study Description:
Principal Study Reference:
RfC (mg/m3):
Critical Effect:
UF:
MF:
Study Animal/Species:
Principal Study Description:
Principal Study Reference:
CSF(mg/kg/day)-1:
Tumor Type:
Study Animal/Species:
Principal Study Reference:
IUR(ug/m3)-1:
Tumor Type:
Study Animal/Species:
Principal Study Reference:
WOE Classification:
Comments: RfD Conduct literature search from 1998 to present
RfC Conduct literature search from 1998 to present
Carcinogenicity Conduct literature search from 1998 to present
Note A 14-day inhalation teratology study on rats, 13-week inhalation toxicity study on rats and mice, and a 90-day inhalation
toxicity study on rats and mice were found while searching the NTP Management Status Document
Note (2)- In the NTP Cancer Bioassay study, although equivocal evidence of carcinogenic activity was found in male F334/N rats,
there was no evidence found in female F344/N rats nor in male or female B6C3F1 mice
B-4
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Screening-Level Review of the IRIS Database Phase II September 2002
Appendix C: Electronic Files
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Appendix C: Electronic Files
The following electronic files are provided on the enclosed CD-ROM
1. Lotus Notes database
2. EndNote files for each of the 100 chemicals
3. WordPerfect narratives for each of the 200 chemicals
C-l
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Screenine-Level Review of the IRIS Database Phase II September 2002
Appendix D: Reference Sorting Criteria
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Screening-Level Review of the IRIS Database Phase II
September 2002
Appendix D: Reference Sorting Criteria
Code
Category
Criteria for Including in the Category
Potential to produce a
change in an existing
noncancer toxicity value
Animal studies
• subchronic toxicity study (usually minimum of 90-day exposure
duration)
• chronic toxicity study
• reproductive and developmental toxicity studies
• only studies involving oral and inhalation exposure routes (i.e , studies
involving dermal or injection administration would be considered
"Other")
Epidemiologic studies
• only studies that could potentially demonstrate a causal relationship, i.e.,
case-control and cohort studies only (e g, no case reports)
• studies examining effects associated with a single chemical exposure
only
Potential to produce a
change in an existing
cancer toxicity value
Animal studies
• cancer bioassay (involving lifetime or near lifetime exposures)
• only studies involving oral and inhalation exposure routes (i e., studies
involving dermal or injection administration would be considered
"Other")
Epidemiologic studies
only studies that could potentially demonstrate a causal relationship, i e ,
case-control and cohort studies only (e g., no case reports)
• studies examining effects associated with single chemical exposure only
Potential to produce a
change in an existing
cancer WOE designation
Studies that could be used in the determination of a cancer weight-of-
evidence (WOE) designation - other than those studies that fall into
Category 2 (in vivo cancer bioassays and epidemiological studies). Studies
in this category would include
• genotoxicity studies
DNA adduct studies
• other short-term in vivo assays, including tests for non-genotoxic agents
Studies in this category may include those that report results for a series of
chemicals, as long as the study includes the chemical of interest and the
results appear to be previously unreported in the peer-reviewed literature
PBPK modeling studies
Primarily complete physiologically-based pharmacokinetic (PBPK) models,
studies that compare the relationship between exposure and target tissue
dose in an animal species and humans, or other study that compares the
pharmacokmetics in an animal species and humans.
D-l
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Screening-Level Review of the IRIS Database Phase II
September 2002
Code
Category
Criteria for Including in the Category
Other toxicity studies
not directly useful for
establishing IRIS
toxicity values
Studies containing health effects information for the given chemical that
might appropriately be considered in a comprehensive review of the toxicity
of that chemical, but would not likely be considered in establishing a
toxicity value (RfD, RfC, or cancer slope factor/unit risk) or WOE
designation The following would be included in this category:
(1) Laboratory studies other than subchronic and chronic toxicity studies,
including studies of acute toxicity, dermal toxicity/sensitization, and various
short-term assays
(2) Studies involving exposure routes other than oral and inhalation (e g,
dermal, injection)
(3) Human studies not useful for demonstrating a causal association (e g ,
case study, cluster investigation) or meta analysis of previously published
studies
(4) Studies of the absorption, distribution, metabolism or excretion of the
chemical that do not fall into Category 4 (PBPK models or studies that
examine pharmacokmetic difference/similarities across species)
(5) Studies that address mechanism (mode) of action that do not fall into
other categories
Studies with information
on health effects in
young populations
Health effect studies in human or animal populations that specifically
examine the effects of a given chemical on early life stages
Studies in humans
• Epidemiological studies that look at effects associated with in utero or
childhood exposures
• Epidemiological studies that include children as cohorts
Experimental studies Examples of such studies would include-
• Cancer bioassays that include in utero exposure
• Developmental toxicity studies
Reproductive toxicity studies, especially multigeneration studies
• Special studies that include examination of effects on the developing
organism (e g , developmental neurotoxicity studies or developmental
immunotoxicity studies)
• Studies that examine transplacental transfer
• Studies that characterize the pharmacokinetic handling of a chemical at
different life stages
Compilations of health
effects studies
Reviews of the toxicity of the given chemical such as ATSDR, WHO,
IARC, NTP, and other review papers published in the peer-reviewed
literature
[In limited instances, a decision may be made to retrieve a review paper for
use in assessing the currency of a given IRIS assessment]
D-2
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Screening-Level Review of the IRIS Database Phase II
September 2002
Code
Category
Criteria for Including in the Category
Not useful
Including the following-
Studies that do not appear to address the chemical of interest
• Studies that address mixtures, such that an association between an effect
and the chemical of interest cannot be discerned
• Studies that do not address chemical toxicity
Studies not directly relevant to an assessment of mammalian toxicity
(e g, ecological toxicity studies)
• Studies already cited in an IRIS assessment
• Reviews, book chapters, symposia and conference proceedings, etc. that
address a large number of chemicals, an endpoint of toxicity (e g,
neurotoxicity of solvents), or an analysis based on previously reported
findings (e.g, correlations between carcinogenic potency and
mutagemcity for a series of chemicals)
Uncertain relevance
For a limited number of records, it may be essentially impossible to discern
from the literature search record whether or not a particular reference
contains relevant information on the toxicity of a given chemical. In some
cases it may be appropriate to identify such studies and to consider, based on
the literature search as a whole, retrieving and reviewing the full text copy
of the paper
D-3
-------
Screening-Level Review of the IRIS Database Phase 11 September 2002
Appendix E: Decision Trees
-------
IRIS Oral Reference Dose (RfD) or Inhalation Reference Concentration (RfC)
(1) Does a more recent health assessment suggest an alternative basis for the IRIS RfD/RfC?
Comparison of existing IRIS RfD/RfC to NCEA
provisional toxiaty values, pesticide RED RfD/RfC
values. ATSDR chronic MRLs. Health Canada assm.
Alternative toxicity value(s) identified (based
on alternative principal study or UFs)
Potential for new or alternative study data to
produce a change in the RfD/RfC
No new toxiaty values identified
No indication of significant new study data.
(2) Does a screen of the more recent literature reveal studies that could potentially support revision of the IRIS RfD/RfC?
Current RfD/RfC basis
Animal subchronic
toxiaty study
(or data judged to be
inadequate)
if yes
if yes
Human
epidemiologic
study
if yes _
Are new subchronic or chronic animal studies or
epidemiological studies (with adequate dose-response
information) available?
Are new chronic animal studies or epidemiological
studies (with adequate dose-response information)
available''
[Note, as long as an adequate chronic study is available,
it is unlikely that the principal study would be surplanted
by a subchronic study]
Are new epidemiological studies available7
[Note: Where adequate human dose-response data are
available and serve as the basis for the existing
RfD/RfC, it is unlikely that animal data would serve as
the basis for a revised RfD/RfC ]
yes
Potential for new data to directly change the
RfD/RfC
no
yes
No new study data appear to be available that
could potentially directly change the RfD/RfC.
Potential for new data to directly change the
RfD/RfC
no
No new study data appear to be available that
could potentially directly change the RfD/RfC
yes
Potential for new data to directly change the
RfD/RfC
no
No new study data appear to be available that
could potentially directly change the RfD/RfC
(3) Does a screen of the more recent literature reveal studies that could potentially support modification of uncertainty
factors!
Does the RfD/RfC
include a UF to
account for lack of
adequate supporting
data?
ArePBPK
modeling data
available?
yes
What is the identfied data gap? Do new study data appear
to fill that gap (including "Other" data)?
yes
no
If no, then further review of "Other" data is
not necessary.
1
no
Is it likely that PBPK data not previously considered could be
used to support a reduction in the UF for animal to human
extrapolation''
yes
no
no
Potential for new data to reduce/eliminate a UF
and thereby change the RfD/RfC
No new study data appear to be available that
could potentially change a UF.
Potential for new data to reduce/eliminate a UF
and thereby change the RfD/RfC
No new study data appear to be available that
could potentially change a UF.
-------
IRIS Oral Cancer Slope Factor (SF) or Inhalation Cancer Unit Risk (UR)
(1) Does a more recent health assessment suggest support for an alternative SF/UR?
Comparison of existing IRIS SF/UR to. NCEA
provisional SF/UR. pesticide RED SF/UR
SF/UR derived using alternative principal study
No new SF/UR identified
(changes based only on alternative risk assessment
models/procedures should not be considered)
Potential for new or alternative study data to
produce a change in the SF/UR
No indication of significant new study data
(2) Does a screen of the more recent literature reveal studies that could potentially support revision of the IRIS SF/UR?
Current SF/UR basis
if yes
Are new chronic animal studies or epidemiological
studies (with adequate dose-response information)
available?
ves
Potential for new data to directly change the
SF/UR
no
No new study data appear to be available that
could potentially directly change the SF/UR
Human
epidemiologic
study
if yes
Are new epidemiological studies available''
[Note- Where adequate human dose-response data
are available and serve as the basis for the existing
SF/UR, it is unlikely that animal data would serve as
the basis for a revised SF/UR ]
yes
P-
no
Potential for new data to directly change the
SF/UR
No new study data appear to be available that
could potentially directly change the SF/UR
(3) Does a screen of the more recent toxicokinetic data support a revision of interspecies extrapolation?
ArePBPK
modeling data
available?
yes
Is it likely that new PBPK data could be used to
refine the extrapolation of dose from animals to
humans?
no
ves _
no
Potential for new data to change the human
equivalent dose and thereby change the
SF/UR
extrapolation appear to be available
-------
IRIS Weight-of-Evidence (WOE) Classification as to Human Carcinogenicity
(1) Does a more recent health assessment suggest support for a different WOE classification?
Alternative WOE designation identified
Comparison of existing IRIS WOE classification to NCEA
provisional assessment, pesticide RED, (ARC monographs,
NTP Report on Carcinogens
No WOE designation identified that significantly
differed from IRIS
Potential for new study data to produce a
change in the WOE classification
No indication of significant new study
data that would change the WOE
classification
(2) Does a screen of the more recent literature reveal studies that could potentially support revision of the WOE classification?
Human Carcinogen
(sufficient evidence of carcmogenioty in
humans)
if yes
B1orB2
Probable Human Carcinogen
(B1 limited evidence of caranogeniaty in
humans,
B2: Sufficient evidence of caranogemcity in
animals with inadequate or lack of evidence
in humans)
if yes
Possible Human Carcinogen
(Limited evidence of Carcinogenicity in
animals and inadequate or lack of human
data)
if yes.
Are new epidemiological studies or extensive new
mechanistic data available?
[Note The existing animal bioassay data for "B"
carcinogens is generally sufficient to demonstrate
carcinogenic potential in animals Only adequate human
evidence or extensive mechanistic data would likely change
the WOE classification (e g, demonstration of
caranogeniaty in humans, or determination that
carcinogenic action in expenmental models is not relevant
to humans ]
Are new positive animal or epidemiological data or
extensive mechanistic data available?
[Note The evidence for caranogeniaty for "C" carcinogens
is generally equivocal Additional negative evidence is
unlikely to change the WOE classification to "D" Only
positive evidence of Carcinogenicity from animal bioassays
or epidemiological studies could potentially change the
designation from "C" to "B" or "A." Extensive mechanistic
data could "drop" the WOE designation to "D" or "E"]
Not Classifiable as to Human
Carcinogenicity
(inadequate or no evidence)
if yes
Are new animal or epidemiological data available?
[Note. ŁosillYŁ evidence could potentially change the WOE
classification to "C," "B," or even "A" Sufficient oegaliys
evidence could potentially change the designation to "E '1
Evidence for Noncarcmogeniaty for
Humans
if yes
Because sufficent positive evidence of human
caranogeniaty is required to classify a
chemcial as an "A" carcinogen, new
caranogeniaty studies are unlikely to change
EPA's cancer assessment
yes
New study data are available that could
potentially change the WOE classification.
no
No new study data appear to be available
that could potentially change the WOE
classification
yes;
no
New study data are available that could
potentially change the WOE classification
No new study data appear to be available
that could potentially change the WOE
classification.
no.
New study data are available that could
potentially change the WOE classification.
No new study data appear to be available
that could potentially change the WOE
classification
Because substantial negative evidence of human
caranogeniaty is required to classify a chemical as an "E"
carcinogen, it is unlikely that new positive studies will be
available to change EPA's existing cancer assessment
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Appendix F: Chemical Summaries
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Acetonitrile (CAS No. 7S-OS-8)
Oral Reference Dose (RfD)
An oral RfD for acetonitrile is not available because EPA determined that the data were insufficient to
support development of an RfD (latest assessment 1999). The oral RfD and supporting information
previously on IRIS were withdrawn. A literature search conducted for the years 1998 to 2002 does not
appear to contain study data that could be used to develop an RfD
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for acetonitrile was derived (1999) does not appear to
contain study data that could potentially produce a change in the RfC. A literature search conducted for
the years 1998 to 2002 identified no new studies that would be directly useful in the derivation of an RfC
for acetonitrile.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1999) does not appear to contain study data that could potentially produce a change in the
WOE. One micronucleus study (2001) found that acetonitrile did not increase the incidence of
micronucleated polychromatic erythrocytes in either mouse bone marrow or peripheral blood.
Unknown Relevance
Three documents were categorized as being of unknown relevance, including a study titled
"Auto-immune Diseases and Chronic Acetonitrile Exposure" (1998).
F-l
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Acrylonitrile (CAS No. 107-13-1)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A literature search conducted for the years 1997 to 2002 identified a 1998 update to a retrospective
cohort study of workers exposed to acrylonitrile and a 2001 National Toxicity Program (NTP) study in
which male and female B6C3F1 mice received acrylonitrile in water by gavage for 14 weeks or 2 years.
A 90-day gavage toxicity study was identified while searching the NTP Management Status Report.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for acrylonitrile was derived (1991) does not appear to
contain study data that could potentially produce a change in the RfC. A review of the Health Canada
Assessment (1998) and a literature search conducted for the years 1997 to 2002 identified no new studies
that would be directly useful in the derivation of an RfC for acrylonitrile.
Oral Slope Factor (CSF)
The literature published since the CSF for acrylonitrile was derived (1987) contains study data that could
potentially produce a change in the CSF.
The IRIS CSF is based on a 2-year study and two 18-month studies in which rats were exposed to
acrylonitrile in drinking water (1980) A 1998 Health Canada Assessment identified no new studies that
would be directly useful in the derivation of a CSF for acrylonitrile. A literature search conducted for the
years 1997 to 2002 identified a 2001 NTP study in which male and female B6C3F1 mice received
acrylonitrile in water by gavage for 2 years.
Inhalation Unit Risk (IUR)
The literature published since the IUR for acrylonitrile was derived (1987) appears to contain study data
that could potentially produce a change in the IUR.
The IRIS IUR is based on a study of respiratory cancer incidences in textile workers (1980). A review of
the Health Canada Assessment (1998) and a literature search conducted for the years 1997 to 2002
identified a 1998 study assessing cancer mortality and incidence among employees exposed to
acrylonitrile in a nitrogen fixation plant, a 1998 update to a retrospective cohort study of workers exposed
to acrylonitrile during fiber production, a 1998 epidemiology study of acrylonitrile workers, a 1999
historical cohort study of workers exposed to acrylonitrile in a chemical plant, and a 2001 reevaluation of
the 1999 historical cohort study A 1997 review paper noted that a follow-up to the 1980 study that served
as the basis for the IUR has been published.
F-2
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Acrylonitrile (CAS No. 107-13-1)
(continued)
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (Bl—probable human carcinogen) was derived
(1987) contains study data that could potentially produce a change in the WOE.
An NTP Cancer Bioassay (2001) concluded from a gavage study in B6C3F1 mice that there was clear
evidence of carcinogenicity. A literature search conducted for the years 1997 to 2002 identified two 1998
studies assessing cancer mortality and incidence among employees exposed to acrylonitrile, a 1998
review and meta-analysis of 25 epidemiologic studies of workers exposed to acrylonitrile, a 1998 study of
possible epigenetic mechanisms in the brain of rats exposed to acrylonitrile, a 1998 genotoxicological
monitoring study of workers exposed to acrylonitrile and/or dimethylformamide, a 1999 summary and
evaluation of 12 epidemiology studies that evaluate central nervous system cancer in workers exposed to
acrylonitrile, a 1999 genotoxicity study in male mice, a 1999 historical cohort study of cancer mortality in
workers exposed to acrylonitrile and other substances, a 2000 study of the ability of acrylonitrile to
induce morphological transformation and oxidative damage in Synan hamster cells, and a 2001
reevaluation of lung cancer risk in a cohort study of workers exposed to acrylonitrile.
Unknown Relevance
Eight documents were categorized as being of unknown relevance, including a study titled "Addendum to
Twenty Four Month Oral Toxicity Carcinogenicity Study of Acrylonitrile Administered in the Drinking
Water Fischer to 344 Rats" (2000).
F-3
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Adiponitrile (CAS No. 111-69-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1989 to 2002 identified a 13-week inhalation toxicity
study and fertility assessment in rats exposed to atmospheres containing adiponitrile (1990)
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1990) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1989 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
Twenty-four documents, many of which were submissions to EPA Office of Toxic Substances (OTS),
were categorized as being of unknown relevance, including a study titled "Thirteen-Week Inhalation
Toxicity of Adiponitrile Vapor-Aerosol to Sprague Dawley Rats" (2000). The majority of the OTS
submissions were studies conducted in the 1970s and early 1980s.
F-4
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Aldicarb (CAS No. 116-06-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for aldicarb was derived (1992) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for aldicarb was denved based on four acute oral exposure studies in humans (1971, 1987,
1990, 1992). A literature search conducted for the years 1991 to 2002 identified a 1991 subchronic
neurotoxicity study in male rats given aldicarb by oral gavage, a 1992 immunotoxicity study of aldicarb
in mice exposed for 28 or 90 days, and a 1993 study in which male rats were exposed to aldicarb for up to
16 weeks.
Note: 14-day and 13-week oral toxicity studies were identified while searching the NTP Management
Status Report; study dates were not provided.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogemcity)
was derived (1987) does not appear to contain study data that could potentially produce a change in the
WOE. An International Agency for Research on Cancer (IARC) Monograph (1991) characterized
aldicarb as Group 3—not classifiable as to carcinogenicity in humans A review of the World Health
Organization (WHO) Environmental Health Criteria (1991) and a literature search conducted for the years
1990 to 2002 identified two genotoxicity studies in animal and human cells (1996 and 1997).
Unknown Relevance
Seven documents were categorized as being of unknown relevance.
Note: The EPA Office of Pesticide Programs (OPP) Web site provides the "Index of Cleared Science
Reviews" for aldicarb, including a 1996 developmental neurotoxicity study in rats.
Note: Because of the large number of references found in the literature search (approximately 840),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-5
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Aldrin (CAS No. 309-00-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for aldrin was derived (198S) does not appear to contain study
data that could potentially produce a change in the RfD. A review of the ATSDR Toxicological Profile
(2000) and a literature search conducted for the years 1999 to 2002 identified no new studies that would
be directly useful in the derivation of an RfD for aldrin.
Note: 14-day and 13-week oral toxicity studies were identified while searching the NTP Management
Status Report; study dates were not provided.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for aldrin was derived (1987) does not appear to contain study data
that could potentially produce a change in the CSF. A review of the ATSDR Toxicological Profile (2000)
and a literature search conducted for the years 1999 to 2002 identified no new studies that would be
directly useful in the derivation of a CSF for aldrin.
Inhalation Unit Risk (IUR)
The literature published since the IUR for aldrin was derived (1987) contains study data that could
potentially produce a change in the IUR.
The IRIS IUR is based on a 2-year and an 80-month dietary study in mice (1965, 1978). A review of the
ATSDR Toxicological Profile (2000) identified two series of retrospective cancer mortality studies with
follow-ups, including studies published in 1991, 1992, 1995, 1997 A literature search conducted for the
years 1999 to 2002 identified no new studies that would be directly useful in the derivation of a IUR for
aldrin
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1987) contains study data that could potentially produce a change in the WOE. A review of the ATSDR
Toxicological Profile (2000) identified two series of retrospective cancer mortality studies with follow-
ups, including studies published in 1991, 1992, 1995, 1997. A literature search conducted for the years
1999 to 2002 identified no new studies that would be directly useful in establishing a WOE classification.
Note: The International Agency for Research on Cancer (IARC) Monograph (1987) classified aldrin as
Group 3—not classifiable as to carcmogenicity in humans.
Unknown Relevance
One document was categorized as being of unknown relevance.
F-6
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Ally (CAS No. 74223-64-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ally was derived (1987) does not appear to contain study
data that could potentially produce a change in the RfD. A literature search conducted for the years 1986
to 2002 identified no new studies that would be directly useful in the derivation of an RfD for ally.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Five documents were categorized as being of unknown relevance. Among these studies is an initial
submission to EPA Office of Toxic Substances (OTS) entitled "Embryo-Fetal Toxicity & Teratogenicity
Study of Metsulfuron-Methyl in Rats with Cover Letter Dated 08/20/92."
Note: Because of the large number of references found in the literature search (more than 1,100), search
results were limited with a secondary search in EndNote to identify references containing common
laboratory species and lexicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-7
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Allyl alcohol (CAS No. 107-18-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ally! alcohol was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for ally! alcohol was derived based on a subchronic oral study in rats (1978). A literature
search conducted for the years 1985 to 2002 found one reproductive toxicity study in rats (1990) and one
chronic carcmogenicity study in rats (1987).
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
Eleven studies were categonzed as being of unknown relevance.
Note: Because of the large number of references found in the literature search (approximately 400),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-8
-------
Screening-Level Review of the IRIS Database Phase II September 2002
lEvaluation of the Recent Literature and Determination of Currency for:
Ametryn (CAS No. 834-12-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ametryn was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1986 to 2002 identified no new studies that would be directly useful in the derivation of an oral RfD for
ametryn.
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: A literature search conducted for the years 1986 to 2002 identified a mammary tumorigenesis study
of ametryn in rats (1994).
Unknown Relevance
Five studies were categorized as being of unknown relevance, including one titled "Two Generation
Study on the Effect of the Triazine Herbicide Ametryne in Rats."
F-9
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
4-Aminopyridine (CAS No. 504-24-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogemcity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1988 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
Four documents were categorized as being of unknown relevance.
Note. Because of the large number of references found in the literature search (approximately 550),
search results were limited with a secondary search in EndNote to identify references containing both the
CAS number or common name of the chemical and common laboratory species and toxicological terms,
including: rat, mouse/mice, gerbil, hamster, beagle, dog, human, rabbit, pig, monkey, pnmate, worker,
subject, patient, epidemiol*, genotox*, mutat*, and mutag*. Any references not containing one of these
search terms were coded as N/A
Note: Much of the literature identified is centered around the effects of 4-aminopyridme in the
pharmacological dose range—looking at effects in central nervous and neuromuscular systems and
mechanism of action associated with those systems.
F-10
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Amitraz (CAS No. 33089-61-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for amitraz was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD.
The IRIS RfD for amitraz was derived based on a 2-year oral dietary study in dogs (1972). The EPA
Office of Pesticide Programs (OPP) Reregistration Eligibility Decision (RED) (1995) provides an RfD
derived from an unpublished 2-year oral toxiciry study in dogs (study date not provided). Comparison of
the summaries of the dog studies in IRIS and the RED suggest that they are the same study. A literature
search conducted for the years 1994 to 2002 identified no new studies that would be directly useful in the
derivation of an oral RfD for amitraz.
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: The OPP RED reported that EPA's Cancer Assessment Group and Health Effects Division Cancer
Peer Review Committee classified amitraz as Group C—possible human carcinogen (1986, 1990).
Unknown Relevance
Four studies were categorized as being of unknown relevance.
F-ll
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Ammonium acetate (CAS No. 631-61-8)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (1UR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcmogenicity)
was derived (1990) does not appear to contain information that could potentially produce a change in the
WOE classification. A literature search conducted for the years 1989 to 2002 identified no new studies
that would be directly useful in establishing a WOE classification.
Unknown Relevance
Four studies were categorized as being of unknown relevance.
F-12
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Ammonium sulfamate (CAS No. 7773-06-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ammonium sulfamate was derived (1988) does not appear
to contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1987 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for ammonium sulfamate.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-13
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Aniline (CAS No. 62-53-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: Health Canada developed a tolerable daily intake (TDI) (0.007 mg/kg/day) in 1993 based on CUT,
1982.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for aniline was derived (1990) does not appear to
contain study data that could potentially produce a change in the RfC. Review of Health Canada's 1993
assessment and a literature search conducted for the years 1992 to 2002 identified no new studies that
would be directly useful in the derivation of an RfC for aniline.
Oral Slope Factor (CSF)
The literature published since the CSF for aniline was derived (1987) does not appear to contain study
data that could potentially produce a change in the CSF. Review of Health Canada's 1993 assessment and
a literature search conducted for the years 1992 to 2002 identified no new studies that would be directly
useful in the derivation of a CSF for aniline.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1990) does not appear to contain study data that could potentially produce a change in the WOE
classification. Review of Health Canada's 1993 assessment, which classified aniline as a Group III—
possibly carcinogenic to humans—and a literature search conducted for the years 1992 to 2002 identified
no new studies that would be directly useful in establishing a WOE classification.
Unknown Relevance
Four documents were categorized as being of unknown relevance. Among these studies are an initial
submission to EPA Office of Toxic Substances (OTS) titled "Final Report & Addendum, Aniline -
Dominant Lethal Study in the Rat" and a study titled "Profound methemoglobmemia induced by dermal
and inhalation exposure to aniline dye."
Note: Because of the large number of references found in the literature search (more than 1,000), search
results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A. References addressing
aniline hydrochloride or other chemicals with aniline in their name were coded 8.
F-14
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Antimony (CAS No. 7440-36-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for antimony was derived (1985) appears to contain study data
that could potentially produce a change in the RfD. Review of the ATSDR Toxicological Profile (1992), a
literature search conducted for the years 1991 to 2002, and submissions to the IRIS Submissions Desk
identified new studies that would be potentially useful in the derivation of an RfD for antimony.
The IRIS RfD for antimony was derived based on a chronic oral bioassay in rats (1970). The ATSDR
Toxicological Profile (1992), literature search conducted for the years 1991 to 2002, and submissions to
the IRIS Submissions Desk included a 90-day drinking water study of potassium antimony tartrate in rats
(1998), a 90-day dietary study of antimony trioxide in rats (1999), a 13-week intraperitoneal study of
potassium antimony tartrate in rats and mice conducted by the National Toxicology Program (NTP)
(1992), and a 90-day feeding study of antimony trioxide in rats (1997; unpublished).
Note: ATSDR, in its 1992 Toxicological Profile, evaluated the noncancer oral toxicity data for antimony,
but did not derive a chronic oral minimal risk level (MRL) because, at the lowest dose tested in animals,
decreased lifespan was observed. ATSDR does not consider this an appropriate basis for a chronic-
duration MRL. The National Center for Environmental Assessment (NCEA) (1999) developed a
provisional subchronic RfD for antimony (2 x 10"* milligrams per kilogram body weight per day
[mg/kg/day]) based on a 90-day drinking water study of antimony potassium tartrate in the rat.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: Review of the ATSDR Toxicological Profile (1992), a literature search conducted for the years
1991 to 2002, and submissions to the IRIS Submission Desk identified a 90-day and 12-month inhalation
study of antimony trioxide in the rat (1994) and a mortality study of antimony smelter workers (1995).
ATSDR, in its 1992 Toxicological Profile, evaluated the noncancer inhalation toxicity data for antimony,
but did not derive a chronic inhalation MRL because, at the lowest dose tested in animals and humans, the
effects were considered to be serious and ATSDR does not consider this an appropriate basis for a chronic
MRL. NCEA (1999) developed a provisional subchronic inhalation RfC for antimony (4 x 10"4 milligrams
per cubic meter [mg/m3]) based on a 13-week inhalation study of antimony trioxide in the rat.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: A literature search conducted for the years 1991 to 2002 identified two mortality studies of
antimony smelter workers (1994, 1995).
F-15
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Antimony (CAS No. 7440-36-0)
(continued)
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In a 1999 Provisional Assessment prepared by NCEA, the evidence for carcinogenicity of antimony
was was characterized as inconsistent and insufficient. A literature search conducted for the years 1991 to
2002 identified a comparison of the clastogenic effects of antimony trioxide in mice in vivo following
acute and chronic exposure (1992).
Unknown Relevance
Five documents were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (approximately 1,100),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species or toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog, human,
rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*. Any
references not containing one of these search terms were coded as NA. References containing laboratory
species or toxicological terms were coded "labanimal". Because a large number of references remained,
references coded "labanimal" were searched to identify those references containing the CAS number for
antimony. References identified in this search were coded. The current IRIS RfD for antimony is based on
a study of potassium antimony tartrate. As such, the search in EndNote for antimony's CAS number may
have excluded studies of antimony compounds. As such, a third search in EndNote identified the
references coded "labanimal" that also contained "chronic," "subchronic," or "subacute," and "antimony"
References identified in this search were coded.
F-16
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Antimony trioxide (CAS No. 1309-64-4)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A literature search conducted for the years 1993 to 2002 identified a 90-day feeding study of
antimony trioxide in rats (1999).
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for antimony trioxide was denved (1995) does not
appear to contain study data that could potentially produce a change in the RfC. A literature search
conducted for the years 1993 to 2002 identified no new studies that would be directly useful in the
derivation of an RfC for antimony trioxide.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1989) classified antimony
trioxide as group B2—possibly carcinogenic to humans. A literature search conducted for the years 1993
to 2002, identified three studies which could potentially influence the derivation of a WOE classification.
A 1994 study of antimony trioxide administered to mice by gavage monitored for chromosomal
aberrations in bone marrow and sperm head abnormalities in germ cells. A 1997 study measured RNA
activity following exposure to antimony trioxide in human hepatoma cells. A 1998 study assessed genetic
toxicity of antimony trioxide in mice and rats after exposure by gavage.
Unknown Relevance
Two documents were categorized as being of unknown relevance, including a study titled
"Carcinogenicity and Toxicity of Inhaled Antimony Trioxide and Antimony Ore Concentrate in Rats"
(2000).
F-17
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Screening-Level Review of the IRIS Database Phase II . September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Apollo (CAS No. 74115-24-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for apollo was derived (1986) does not appear to contain study
data that could potentially produce a change in the RfD. A literature search conducted for the years 1985
to 2002 identified no new studies that would be directly useful in the derivation of an RfD for apollo.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1990) does not appear to contain study data that could produce a change in the WOE. A literature search
conducted for the years 1989 to 2002 identified no new studies that would be directly useful in
establishing a WOE classification.
Unknown Relevance
One document was categorized as being of unknown relevance.
F-18
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Screening-Level Review of the IRIS Database Phase 11 September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Arsenic, inorganic (CAS No. 7440-38-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for arsenic was derived (1990) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for arsenic was derived based on chronic oral exposure studies in humans (1968, 1977).
EPA published in the Federal Register (January 22, 2001) a summary of health effects studies considered
in revising the National Primary Drinking Water Regulations for arsenic. Of these, ten studies published
between 1990 and 2000 considered noncancer effects of drinking water exposure in humans and two
studies discussed noncancer effects of occupational exposures to arsenic (1995,1998).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the oral slope factor was derived (1994) contains study data that could
potentially produce a change in the WOE.
The IRIS CSF for arsenic was derived based on studies of the development of skin cancers after exposure
to arsenic in drinking water (1968, 1977). EPA published in the Federal Register (January 22, 2001) a
summary of health effects studies considered in revising the National Primary Drinking Water
Regulations for arsenic. Of these, six studies published between 1996 and 1998 considered the
carcinogenicity in humans of drinking water exposure to arsenic. As noted in the Federal Register, EPA
chose to develop quantitative risk estimates based on the Taiwan studies published between 1989 and
1992.
Inhalation Unit Risk (IUR)
The literature published since the IUR was derived (1994) contains study data that could potentially
produce a change in the IUR.
The IRIS IUR for arsenic was derived based on studies of the development of lung cancers in humans
after exposure to arsenic (1982, 1983). Review of the ATSDR Toxicological Profile (2000) identified a
number of epidemiology studies examining inhalation exposures to arsenic and increases in the risk of
lung cancer, including six studies completed between 1995 and 1997. A literature search conducted for
the years 1999 to 2002 identified a quantitative risk assessment of health risks (including cancer)
associated with occupational exposure to arsenic (1997) and a study of the exposure-response curve for
respiratory cancer in copper smelter workers exposed to arsenic (2000).
F-19
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Arsenic, inorganic (CAS No. 7440-38-2)
(continued)
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (A—human carcinogen) was derived (1994) does
not appear to contain study data that would likely support a change in the WOE.
EPA published in the Federal Register (January 22, 2001) a summary of the evidence for human
carcmogenicity of arsenic in support of revisions to the National Primary Drinking Water Regulations for
arsenic. EPA concluded that "inorganic arsenic is a multi-site human carcinogen by the drinking water
route," and that "the weight of evidence for ingested arsenic as a causal factor of carcinogenicity is much
greater now than a decade ago."
Unknown Relevance
No documents were categorized as being of unknown relevance.
Note: The IRIS summary for inorganic arsenic included an RfD, CSF, IUR, and WOE designation. A
Federal Register notice, published by EPA, provided a summary of health effects studies considered in
revising the National Primary Drinking Water Standards. This summary included new study data relevant
to the derivation of the RfD, CSF, and WOE designation, but not the IUR Therefore, the literature search
targeted studies of inhalation exposures that might be relevant to the denvation of a revised IUR. As such,
TOXLINE, PUBMED, and CANCERLIT were searched using the CAS number for arsenic, "inhalation,"
and terms that apply to cancer endpomts, including cancer, carcinog*, tumor1", oncogen1", neoplasm*,
mutag*, mutat*, and genotox*. CCRIS and TSCATS were searched by CAS number alone, however,
only studies of inhalation exposures and cancer endpoints were entered into the EndNote database for
inorganic arsenic.
F-20
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Arsine (CAS No. 7784-42-1)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for arsine was derived (1993) contains study data that
could potentially produce a change in the RfC.
The IRIS RfC for arsine was derived based on a 13-week and 28-day inhalation study in rats, mice, and
hamsters (1989) and a 12-week inhalation study in mice (1990). A literature search conducted for the
years 1992 to 2002 identified a 1992 study of arsine gas toxicity in hamsters, mice, and rats after
inhalation exposures ranging from 0.5 hr to 90-days.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1987) characterized arsine as
Group 1—carcinogenic to humans.
Unknown Relevance
Three documents were categorized as being of unknown relevance.
F-21
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Assure (CAS No. 76578-14-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for assure was derived (1988) does not appear to contain study
data that could potentially produce a change in the RfD. A literature search conducted for the years 1987
to 2002 identified no new studies that would be directly useful in the derivation of an RfD for chemical.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1988) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1987 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification
Unknown Relevance
Seven documents were categorized as being of unknown relevance Among these, one study was titled
"Letter from Dupont Chem to USEPA Regarding Subchronic Dietary Toxicity of Propanoic Acid* in
Mice with Cover Letter and Attachments."
Note: Because of the large number of references found in the literature search (approximately 5,000),
search results were limited with a secondary search in EndNote to identify references containing both the
CAS number and common name of the chemical (reducing references to approximately 435). A tertiary
search, conducted in EndNote, to identify common laboratory species and toxicological terms, including:
rat, mouse/mice, gerbil, hamster, beagle, dog, human, rabbit, pig, monkey, primate, worker, subject,
patient, epidemiol*, genotox*, mutat*, and mutag* yielded approximately 240 references. Any references
not containing one of these search terms were coded as N/A.
F-22
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Azobenzene (CAS No. 103-33-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A 90-day dosed-feed toxicity study was identified during a search of the NTP Management Status
Report.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSV)
The literature published since the CSF for azobenzene was derived (1988) does not appear to contain
study data that could potentially produce a change in the CSF. A literature search conducted for the years
1987 to 2002 identified no new studies that would be directly useful in the derivation of a CSF for
azobenzene.
Inhalation Unit Risk (IUR)
The literature published since the IUR for azobenzene was derived (1988) does not appear to contain
study data that could potentially produce a change in the IUR. A literature search conducted for the years
1987 to 2002 identified no new studies that would be directly useful in the derivation of an IUR for
azobenzene.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1988) does not appear to contain study data that could potentially produce a change in the WOE.
The IRIS WOE for azobenzene was based on evidence of carcinogenicity in a rat bioassay, genotoxicity,
and potential for conversion in the stomach to the carcinogen benzidine A literature search conducted for
the years 1989 to 2002 identified additional studies of the mutagenic potential of azobenzene, including
the findings in micronucleus assays (1990) and in the Ames assay (1994). An International Agency for
Research on Cancer (IARC) Monograph (1987) characterized azobenzene as Group 3—not classifiable as
to carcinogenicity in humans.
Unknown Relevance
A 1991 study titled "Evaluation of Teratogenicity of Certain Azo and Azoxy Compounds through
Dominant Lethal Studies" was categorized as being of unknown relevance.
F-23
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Barium cyanide (CAS No. 542-62-1)
Oral Reference Dose (RfD)
The RfD for barium cyanide was withdrawn in 1993. The literature published since 1993 does not appear
to contain study data that would support the derivation of an RfD. A literature search conducted for the
years 1992 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
barium cyanide.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-24
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Baythroid (CAS No. 68359-37-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for baythroid was derived (1986) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
198S to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
baythroid.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Eleven documents were categorized as being of unknown relevance. Among these studies is "Four
Toxicity Studies with Cyfluthrin in Rats" (1992).
F-25
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Benefin (CAS No. 1861-40-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for benefin was derived (1985) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1984 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
benefin.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-26
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Benomyl (CAS No. 17804-35-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for benomyl was derived (1986) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for benomyl was derived based on a three-generation reproduction study in rats (1968).
The World Health Organization (WHO) Environmental Health Criteria (1993) for benomyl identified a
1990 two-generation reproduction study in rats fed diets containing benomyl. The WHO document also
identified studies published in 1988 and 1991 that evaluated the reproductive effects of benomyl
administered to male rats by gavage.
Inhalation Reference Concentration (RFC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In Table 1 of the Ninth Report on Carcinogens (2001), the National Toxicology Program (NTP)
classified benomyl as a probable carcinogen based on a 1995 study of Benlate DF with Flusilazole and
Chlorothalonil.
Unknown Relevance
No literature search was necessary.
F-27
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bidrin (CAS No. 141-66-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for bidrin was derived (1986) appears to contain study data
that could potentially produce a change in the RfD.
The IRIS RfD for bidrin (0.001 milligrams per kilogram body weight per day [mg/kg/day]) was derived
based on a three-generation rat reproduction study published in 1965. A literature search conducted for
the years 1985 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for bidrin. However, the EPA Office of Pesticide Programs (OPP) risk assessment (1999) produced for
the Reregistration Eligibility Decision (RED) presented an oral RfD of 0.00002 mg/kg/day based on a
combined chronic toxicity and carcinogenicity study in rats. The citation for the chronic toxicity study
that served as the basis for the RED RfD was not provided; however, a comparison of the principal
studies used to develop the IRIS and RED RfDs revealed differences in the lowest-observed-adverse-
effects-levels (LOAELs) (0.05 mg/kg/day and 0.02 mg/kg/day, respectively) and in the critical effects
(inhibition of plasma cholinesterase and inhibition of plasma, brain, and RBC cholinesterases,
respectively). This suggests that new study data were available to OPP for their assessment of bidrin.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-28
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Biphenthrin (CAS No. 82657-04-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for biphenthrin was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1987 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
biphenthrin
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: One study (1997) observed tumors of the urinary bladder (initially reported as leiomyosarcomas) in
Swiss Webster mice when fed biphenthrin in the diet for 604 to 644 days.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS
Unknown Relevance
Three documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance
F-29
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,1-Biphenyl (CAS No. 92-52-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 1,1-biphenyl was derived (1985) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1984 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for 1,1-biphenyl.
Inhalation Reference Concentration (RfC)
An IRIS RfC is not available because EPA determined that data were inadequate for derivation of an RfC
(latest assessment 1990). The literature published since 1990 does not appear to contain study data that
could be used to develop an RfC for 1,1-biphenyl.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcmogenicity)
was derived (1990) does not appear to contain study data that could produce a change in the WOE.
A literature search conducted for the years 1989 to 2002 identified a 1989 study investigating changes in
DNA synthesis levels and morphology in F344 rats following oral administration of biphenyl; a 1989
genotoxicity study using the rat hepatocyte DNA-repair test; a 1992 study investigating liver enzyme-
mediated mutagenicity detected in Salmonella typhimurium and Chinese hamster V79 cells; and a 1997
study of the in vivo genotoxicity of biphenyl in CD-I male mouse stomach, liver, kidney, bladder, lung,
brain, and bone marrow (positive and negative findings).
Unknown Relevance
Eight documents, three of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including a study titled "Initial Submission: 90-day
Inhalation Toxicity Study of Biphenyl (99+% purity) in Cdl Mice (final report)."
Note: Too many references to download were found while searching Toxline with "word variants" (over
8,500) or "exact words" (over 3,500) with chemical name searching Therefore, the search was conducted
using only the CAS number. Because of the large number of references found in the literature search
(approximately 900), search results were limited with a secondary search in EndNote to identify
references containing common laboratory species and toxicological terms, including: rat, mouse/mice,
gerbil, hamster, beagle, dog, human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*,
genotox*, mutat*, and mutag* Any references not containing one of these search terms were coded as
N/A.
F-30
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bis(2-chloroethoxy)methane (CAS No. 111-91-1)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A literature search conducted for the years 1989 to 2002 identified one subchronic toxicity study
(1990) in which bis(2-choroethoxy)methane was administered by gavage in com oil to Sprague-Dawley
rats for 90 days.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer \Veight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcmogenicity)
was derived (1990) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1989 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
Three documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-31
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bis(2-chloroisopropyl) ether (CAS No. 39638-32-9/108-60-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for bis(2-chloroisopropyl)ether was derived (1989) does not
appear to contain study data that could potentially produce a change in the RfD. A literature search
conducted for the years 1988 to 2002 identified no new studies that would be directly useful in the
derivation of an RfD for bis(2-chloroisopropyl)ether.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer \Veight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) characterized bis(2-
chloroisopropyl)ether as Group 3—not classifiable as to carcinogenicity in humans.
Unknown Relevance
Four documents, one of which was a submission to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
Note: The CAS number changed from 39638-32-9 to 108-60-1 on June 6,2000. Both CAS numbers were
considered in the literature search.
F-32
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bisphenol A (CAS No. 80-05-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for bisphenol A was derived (1988) appears to contain study
data that could potentially produce a change in the RfD.
The IRIS RfD for bisphenol A was derived based on a chronic oral bioassay in rats, published by NTP in
1982. A literature search conducted for the years 1987 to 2002 identified several chronic and subchronic
toxicity studies as well as several developmental and reproductive studies. Among these are a 13-week
subchronic toxicity study in male and female B6C3F1 mice fed bisphenol A in their diet (1994); a
lifetime exposure study in male Sprague-Dawley CD rats fed bisphenol A in their diet (1999); a two-
generation reproductive toxicity study in male and female Crj: CD (SD) IGS rats administered bisphenol
A via gastric intubation (2001); and a three-generation reproductive, oral toxicity study in Sprague-
Dawley rats that reported an adult systemic no-observable-adverse-effect-level (NOAEL) of 5 milligrams
per kilogram body weight per day (mg/kg/day) and reproductive/postnatal NOAEL of SO mg/kg/day
(2001). In addition, according to a letter submitted by the Society of the Plastics Industry, Inc. to the IRIS
Submission Desk a two-generation reproductive toxicity study (1999) exists.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note1 According to a letter submitted by the Society of the Plastics Industry, Inc. to the IRIS Submission
Desk a 13-week aerosol toxicity study with Fisher 344 rats (1988) exists.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (1UR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1987 to 2002 identified mutagenicity tests (with both
positive and negative findings). Several studies examined the relationship between estrogenicity and cell
transforming activity. Among these are studies evaluating sister chromatid exchange and chromosome
aberration assays in Chinese hamster ovary cells (1989); in vivo DNA adduct formation in CD1 male rats
(1995); aneuploidogenic potential in cultured Chinese hamster V79 cells (1997); cellular transformation,
aneuploidy, and DNA adduct formation in cultured Syrian hamster embryo cells (1998); cell-transforming
activity and estrogenicity in Syrian hamster embryo cells (2001); endocrine disruption in Chinese hamster
V79 cells and Sertoli cells in rats (2001); and mutagenicity in human RSa cells (2001).
F-33
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bisphenol A (CAS No. 80-05-7)
(continued)
Unknown Relevance
Twenty documents, eleven of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Among these studies are "Support: Final Report, 3-
Generation Reproductive Toxicity Evaluation of Bisphenol A Administered in Feed to Cd (Sprague-
Dawley) Rats," "Support: Evaluation of Reproductive Organ Development in Cf-1 Mice Following
Prenatal Exposure to Bisphenol A," "Initial Submission: Bisphenol A: 13-Week Aerosol Toxicity Study
with Fischer 344 Rats (Final Report) (1992)," and "Bisphenol A: 13-Week Aerosol Toxicity Study with
Fischer 344 Rats (Final Report) (1988)." The literature search also identified two ongoing listed in the
Computer Retrieval of Information on Scientific Projects (CRISP) database (a biomedical database of
research projects supported by the Department of Health and Human Services).
Note: Because of the large number of references found in the literature search (approximately 600),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*
Any references not containing one of these search terms were coded as N/A.
F-34
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bromodichloromethane (CAS No. 75-27-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for bromodichloromethane was derived (1987) may contain
study data that could potentially produce a change in the RfD.
The IRIS RfD for bromodichloromethane was derived based on a chronic gavage bioassay in mice
(1987). ATSDR updated the Toxicological Profile for bromodichloromethane in 1989. ATSDR derived
an oral minimal risk level (MRL) based on the same 1987 study used to derive the IRIS oral RfD. A
literature search conducted for the years 1988 to 2002, however, identified two 2-year feeding studies in
Wistar rats (1992, 1995), a 52-week drinking water study in F344 rats (1995), a prospective study of
pregnant women exposed to bromodichloromethane and other trihalomethanes (THMs) in drinking water
(1998), two retrospective cohort studies of women exposed to bromodichloromethane and other THMs in
drinking water (2000, 2001), and eight reproductive/developmental toxicity studies in rats (1999, 2000,
2001) and rabbits (2001) that could potentially produce a change in the RfD for bromodichloromethane.
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1998 to 2002 identified a 1-year bioassay in mice
exposed to bromodichloromethane vapor published in 2001.
Oral Slope Factor (CSF)
The literature published since the CSF for bromodichloromethane was derived (1992) may contain study
data that could potentially produce a change in the CSF.
The IRIS CSF for bromodichloromethane was derived based on a 2-year carcinogenicity study in mice
administered bromodichloromethane in corn oil by gavage (1987). The International Agency for Research
on Cancer (IARC) Monograph on bromodichloromethane (1999) cites two 2-year feeding studies in rats
(1992, 1995) and a 52-week drinking water study in rats (1995). A literature search conducted for the
years 1988 to 2002 identified a 2-year gavage study in rats and mice (1993) not cited in the IARC
Monograph. These studies could potentially produce a change in the CSF for bromodichloromethane.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: A literature search conducted for the years 1998 to 2002 identified a 1-year bioassay in mice
exposed to bromodichloromethane vapor published in 2001.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1992) does not appear to contain study data that could potentially produce a change in the WOE
classification. In 1999, consistent with the EPA's WOE designation, IARC classified
bromodichloromethane as a Group 2B—possibly carcinogenic to humans.
F-35
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bromodichloromethane (CAS No. 75-27-4)
(continued)
A literature search conducted for the years 1988 to 2002 identified no new studies that would likely
produce a change in the WOE classification. As was concluded in the IRIS assessment conducted in 1992,
there are no adequate epidemiologic studies to assess the carcinogenic potential of bromodichloromethane
in humans, and animal bioassays provide some positive evidence of carcinogenic potential. The literature
search identified the following additional studies of the carcinogenic and mutagenic potential of
bromodichloromethane: two 2-year feeding studies in Wistar rats (1992, 1995), a 2-year gavage study in
F344/N rats and B6C3F1 mice (1993); a 52-week drinking water study in rats (1995); a short-term
carcinogenicity study (1998); findings of sister-chromatid exchanges (1991, 1993) and chromosomal
aberrations (1996); and a study of genotoxic potential (1997). Some negative mutagenicity studies also
were identified (1995, 1996, 1997).
Unknown Relevance
Twenty-five studies, one of which was a submission to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Among these studies are "Chronic toxicity studies of Tbm,
Dbcm, and Bdcm in Wistar rats" (1988); "Carcinogenic activity of drinking water as related to the tumor
initiating and promoting activity of tnhalomethanes" (1988); "Public drinking water contamination and
birth weight, prematurity, fetal deaths, and birth defects" (1996); "The association of drinking water
source and chlorination by-products with cancer incidence among postmenopausal women in Iowa: a
prospective cohort study" (1997); and "Evaluation of the potential immunotoxicity of
bromodichloromethane in rats and mice" (1999). The literature search also identified one ongoing effort
listed in the Computer Retneval of Information on Scientific Projects (CRISP) database (a biomedical
database of research projects supported by the Department of Health and Human Services).
Note: A literature search conducted for the years 1988 to 2002 identified two studies carried out to
develop, apply, and validate a physiologically-based pharmacokinetic (PBPK) model for
bromodichloromethane (1997, 1998).
Note: Because of the large number of references found in the literature search (approximately 450),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species or toxicologies! terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog, human,
rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*. Any
references not containing one of these search terms were coded as N/A.
F-36
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
p-Bromodiphenyl ether (CAS No. 101-55-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcmogenicity)
was derived (1990) does not appear to contain study data that could potentially produce a change in the
WOE classification.
The World Health Organization (WHO) Environmental Health Criteria (1994) did not cite any new
studies since the IRIS WOE classification was derived. A literature search conducted for the years 1993
to 2002 identified no new studies that could potentially produce a change in the WOE classification.
Unknown Relevance
One study was categorized as being of unknown relevance.
F-37
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bromoform (CAS No. 75-25-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for bromoform was derived (1987) appears to contain study
data that could potentially produce a change in the RfD.
The IRIS RfD for bromoform was derived based on a subchronic oral gavage bioassay in F344/N rats
conducted by the National Toxicology Program (NTP) (1989). ATSDR published a toxicological profile
for bromoform in 1990. ATSDR derived an oral minimal risk level (MRL) based on a chronic study in
mice and rats published by NTP (1988). A literature search conducted for the years 1989 to 2002
identified the 2-year NTP gavage study in F344 rats and B6C3F1 mice (1989); a reproductive toxicity
study in Swiss CD-I mice administered bromoform in corn oil via gavage (1989); two developmental
toxicity studies in F344 rats (1992) and CD-I mice (2001); and a prospective study of pregnant women
exposed to bromoform and other trihalomethanes (THMs) in drinking water (1998).
Note: The IRIS RfD verification date is listed as August 13,1987, although the principal study (13-week
NTP study) was published in 1989. This apparent discrepancy reflects the fact that the IRIS summary was
based on a draft form of the NTP bioassay. In 1990, the citation was updated to reflect the final NTP
bioassay (NTP 1989).
Inhalation Reference Dose (RfC)
An IRIS RfC is not available because EPA determined that data were inadequate for denvation of an RfC
(latest assessment 1993). A literature search conducted for the years 1989 to 2002 identified no new
studies that would be directly useful in the derivation of an RfC for bromoform.
Oral Slope Factor (CSF)
The literature published since the CSF for bromoform was derived (1989) does not appear to contain
study data that could potentially produce a change in the CSF.
The IRIS CSF for bromoform was derived based on a draft 2-year NTP bioassay in rats (1988). [The final
bioassay was published in 1989.] The International Agency for Research on Cancer (IARC) Monograph
on bromoform (1999) does not cite new study data that would appear to produce a change in the CSF for
bromoform. A literature search conducted for the years 1989 to 2002 identified no new studies that would
be directly useful in the derivation of a CSF for bromoform. Two publications (1989, 1993) related to a 2-
year gavage study in F344 rates and B6C3F1 mice are reanalyses of data from the NTP bioassay.
Inhalation Unit Risk (IUR)
The literature published since the IUR for bromoform was derived (1989) does not appear to contain
study data that could potentially produce a change in the IUR. The IARC Monograph (1999) does not cite
new study data that would appear to produce a change in the IUR for bromoform. A literature search
conducted for the years 1989 to 2002 identified no new studies that would be directly useful in the
derivation of a IUR for bromoform.
F-38
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bromoform (CAS No. 75-25-2)
(continued)
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1989) may contain study data that could potentially produce a change in the WOE classification. In
1999, IARC classified bromoform as Group 3—not classifiable as to carcinogenicity in humans. A
literature search conducted for the years 1989 to 2002 identified a number of genotoxicity studies; both
positive and negative responses were reported.
Unknown Relevance
Twenty-three studies, four of which were submissions to EPA's Office of Toxic Substances (OTS), were
categorized as being of unknown relevance Among these studies are "Reproductive risks from
contaminants in drinking water" (1993); "Chlorination of drinking water and cancer incidence" (1994);
"Reproductive and developmental effects of disinfection by-products in drinking water" (1996); "The
association of drinking water source and chlonnation by-products with cancer incidence among
postmenopausal women in Iowa: a prospective cohort study" (1997); "Exposure to tnhalomethanes and
adverse pregnancy outcomes" (1998); and "Chlorination disinfection byproducts in water and their
association with adverse reproductive outcomes: a review" (2000). For many sources, it was unclear
whether bromoform was evaluated individually (many of these sources only note that trihalomethanes
were studied)
F-39
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Bromoxynil octanoate (CAS No. 1689-99-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for bromoxynil octanoate was derived (1987) appears to
contain study data that could potentially produce a change in the RfD.
The IRIS RfD for bromoxynil octanoate was derived based on a 2-year dietary study in rats (1982). A
Reregistration Eligibility Decision (RED) (for bromoxynil: see note below) was published in 1998. The
RfD derived for the RED was based on a 1-year chronic oral toxicity study in dogs (using bromoxynil
phenol as the test material) (1988, 1989). A literature search conducted for the years 1986 to 2002
identified developmental toxicity studies (using bromoxynil as the test material) in CD rats and CD-I
mice (1990), in Sprague-Dawley rats and Swiss-Webster mice (1991), and CD-I mice (199S) not cited in
the RED.
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: The RED presented a CSF for bromoxynil based on an 18-month dietary study of bromoxynil in
mice (1980) and a carcinogenicity study of bromoxynil phenol in mice (1994)
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
Six studies, one of which was a submission to EPA Office of Toxic Substances (OTS), were categorized
as being of unknown relevance.
Note: The IRIS summary states the following concerning bromoxynil: "Bromoxynil exists as an acid but
also as esters (e.g. octanoate). Subchronic studies indicate that there is no toxicological difference
between these different forms of bromoxynil The RfDs for all bromoxynil compounds will be based on
the toxicity of bromoxynil alone, unless evidence to the contrary is found " As a result, the literature
search for bromoxynil octanoate was expanded to include bromoxynit (CAS No. 1689-84-5).
F-40
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Cacodylic acid (CAS. No. 75-60-5)
Oral Reference Dose (RID)
No assessment of the RfD is included in IRIS.
Note: A literature search conducted for the years 1990 to 2002 identified a 2-year dietary study of the
mechanism of action of bladder tumor induction in rats following a 10-week exposure to cacodylic acid
(1999) and a developmental study in Sprague-Dawley rats (oral gavage) (1990).
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A literature search conducted for the years 1990 to 2002 identified one 50-week drinking water
study in mice (1998), a 2-year drinking water bioassay in male F344 rats (1999), and a study of the
mechanism of action of bladder tumor induction following 10-week exposure of F344 rats to cacodylic
acid (1999).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE (D—not classifiable as to human carcmogenicity) was derived
(1991) may contain study data that could potentially produce a change in the WOE classification.
A literature search conducted for the years 1990 to 2002 identified several carcinogenicity bioassays (see
description under oral CSF) and a number of genotoxicity studies, including evidence of DNA damage in
in vivo studies of rats (1997) and mice (1999); genotoxicity in Chinese hamster cells (1992,1997, 1998);
mutagemcity in mouse cells (1993, 1997, 1998); and DNA single-strand breaks, DNA-protein cross-links,
and chromosomal aberrations in human cells (1993, 1994, 1995, 1996, 1997).
Unknown Relevance
Twelve studies, one of which was a submission to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. For many sources, it was unclear whether cacodylic acid (a
primary metabolite of arsenic) was evaluated individually (many of these sources only note that arsenic
was studied).
F-41
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Captafol (CAS No. 2425-06-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for captafol was derived (1987) appears to contain study data
that could potentially produce a change in the RfD.
The IRIS RfD for captafol was derived based on a 1-year dietary study in dogs (1985). A literature search
conducted for the years 1986 to 2002 identified a 1989 study of renal effects in F344 rats exposed to
captafol in their diet for 2 years and a 1991 study of F344/DuCrj rats exposed to captafol in their diet for
13 weeks.
Inhalation Reference Concentration (RFC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: The literature search conducted for the years 1986 to 2002 revealed two studies that might
contribute to the development of a CSF for captafol: a 1990 study of dietary exposure to captafol for 104
weeks and a 1996 study of dietary exposure to captafol for 32 weeks.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: The Health Effects Division of EPA Office of Pesticide Programs (OPP) assessed the
carcinogenicity of captafol and categorized it as a Group 2B—probably human carcinogen (1993). An
International Agency for Research on Cancer (IARC) Monograph (1991) listed captafol as Group
2A—probably carcinogenic to humans.
Unknown Relevance
Eight documents were categorized as being of unknown relevance, including four listings in OPP's
"Index of Cleared Science Reviews" and two studies (1990, 1992) listed on the Computer Retrieval of
Information on Scientific Projects (CRISP) database (a biomedical database of research projects
supported by the Department of Health and Human Services).
F-42
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Screening-Level Review of the IRIS Database Phase TI September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Carbaryl (CAS No. 63-25-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for carbaryl was derived (1985) appears to contain study data
that could potentially produce a change in the RfD.
The IRIS RfD for carbaryl was derived based on a chronic dietary study in rats published in 1961. A
review of the World Health Organization (WHO) Environmental Health Criteria for carbaryl (1994)
identified four toxicity studies published after the derivation of the RfD for carbaryl: a 1-year dietary
study in beagles that examined primarily hematological effects (1987); a 1-year dietary study in rats in
which changes to body weight, food consumption, total cholesterol, liver weight, and kidney weight were
observed (1991); and a developmental toxicity study in mice (1991).
A literature search conducted for the years 1993 to 2002 identified a 1995 study of reproductive effects in
male albino rats exposed to carbaryl in their diets for 90 days; two 1997 studies of adult neural, immune,
and reproductive function after perinatal exposure to carbaryl; and a 2001 study of bone ossification in
juvenile rats exposed to carbaryl during pregnancy and lactation.
Inhalation Reference Concentration (RfC)
An inhalation RfC is not available because EPA determined that data were inadequate for derivation of an
RfC (latest assessment 1991). The literature published since 1991 does not appear to contain study data
that could be used to develop an RfC for carbaryl. A review of the WHO Environmental Health Criteria
for carbaryl (1994) and a literature search conducted for the years 1993 to 2002 identified no new studies
that would be directly useful in the derivation of an RfC for carbaryl.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (LARC) Monograph (1987) listed carbaryl as
Group 3—not classifiable as to carcinogenicity in humans.
Unknown Relevance
Seven documents, including five listings in the EPA Office of Pesticide Programs (OPP) "Index of
Cleared Science Reviews," were categorized as being of unknown relevance.
F-43
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Carbaryl (CAS No. 63-25-2)
(continued)
Note: Because of the large number of references found in the literature search (approximately 1,000),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species or toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog, human,
rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*. Any
references not containing one of these search terms were coded as N/A.
F-44
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Screening-Level Review of the IRIS Database Phase 11 September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Carbofuran (CAS No. 1563-66-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for carbofuran was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1986 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
carbosulfan. The literature search identified two 1997 letters in EPA's public docket relating to a peer
review of the carbofuran RfD, as well as two 1998 studies on the pregnancy outcome of rats exposed to
carbofuran during days 1 to 5 or days 7 to 14 of gestation.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: The literature search conducted for the years 1986 to 2002 identified one study of the genotoxicity
of carbofuran in human peripheral blood lymphocytes (1989); a study of non-genotoxic effects of
carbofuran in rat liver epithelial cells (1997); a study of the cytotoxicity and genotoxicity of carbofuran in
hamster V79 cells (1998); and a study of genotoxicity, cell growth, cell cycle, and apoptosis in hamster
lung fibroblast cells (2001)
Unknown Relevance
Fifteen documents were categorized as being of unknown relevance. Among these are "Hepatorenal
Toxicity of Nuvacron and Furadan in Mice," "Effect of Carbamates on Some Enzymes of Rat Liver and
Kidney," "Carbofuran Toxicity and Clearance in the Isolated Perfused Rat Lung," and "Studies on
Carcinogenicity of Furadan in ICR Mice by Chronic Ingestion." Several documents listed in the EPA
Office of Pesticide Programs (OPP) "Index of Cleared Science Reviews" also were identified.
Note: Because of the large number of references found in the literature search (approximately 1,800),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species or lexicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog, human,
rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*. Any
references not containing one of these search terms were coded as N/A.
F-45
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Carbon disulfide (CAS No. 75-15-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for carbon disulfide was derived (1985) does not appear to
contain study data that could potentially produce a change in the RfD. The IRIS RfD was derived based
on an inhalation teratology study in rabbits (1981). A review of the Health Canada Assessment (1999)
and a literature search conducted for the years 1998 to 2002 identified no new studies of oral exposure to
carbon disulfide. New studies of inhalation exposure to carbon disulfide that might be used to derive an
oral RfD are discussed below.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for carbon disulfide was derived (1995) appears to
contain study data that could potentially produce a change in the RfC.
The IRIS RfC for carbon disulfide was derived based on an occupational study (1983). In 1999, Health
Canada derived a tolerable concentration (TC) based on the same principal study used to derive the IRIS
RfC. A review of the Health Canada Assessment revealed an epidemiologic study of the effects of carbon
disulfide on the peripheral nerves (1995) and an investigation of nerve function in workers exposed to
carbon disulfide occupationally.
A literature search conducted for the years 1998 to 2002 identified a number of epidemiology studies of
workers occupationally exposed to carbon disulfide (1998, 2000, 2001). The literature search also
identified four studies of neurological effects and neurobehavioral effects in F344 rats exposed to carbon
disulfide by inhalation for up to 13 weeks (1998), a study of atherogenic effects in C57BL6 mice (1999),
and a study of neurotoxic effects in C57BL/6 mice exposed to carbon disulfide by inhalation for up to 20
weeks (2000).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Eleven documents were categorized as being of unknown relevance, including a submission to EPA
Office of Toxic Substances (OTS) entitled "Internal Memorandum Regarding Mutagenicity Testing with
Attachment" and nine documents pertaining to carbon disulfide and adduct formation, cytotoxicity,
artherosclerosis, and inhalation toxicity listed in the Computer Retrieval of Information on Scientific
Projects (CRISP) database (a biomedical database of research projects supported by the Department of
Health and Human Services).
F-46
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Carbonyl sulfide (CAS No. 463-58-1)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An inhalation RfC is not available because EPA determined that data were inadequate for derivation of an
RfC (latest assessment 1991). The literature published since 1991 does not appear to contain study data
that could be used to develop an RfC for carbonyl sulfide. A literature search conducted for the years
1990 to 2002 identified no new studies that would be directly useful in the derivation of an RfC for
carbonyl sulfide.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Nine documents were categorized as being of unknown relevance. Five of these were submissions to EPA
Office of Toxic Substances (OTS), and the other four were listed in the Computer Retrieval of
Information on Scientific Projects (CRISP) database (a biomedical database of research projects
supported by the Department of Health and Human Services).
F-47
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Carbosulfan (CAS No. 55285-14-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for carbosulfan was derived (1986) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1985 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
carbosulfan.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: Five genotoxicity studies were identified in a literature search conducted for the years 1985 to
2002 Among these were a study of genotoxicity in an in vivo mouse bone marrow assay, two studies of
chromosomal aberrations and sister chromatid exchanges in human lymphocytes, a study of in vivo
chromosomal aberrations in rat bone marrow cells, and a study of mutagenic effects of carbosulfan in the
Ames-test and yeast assay.
Unknown Relevance
Four documents were categorized as being of unknown relevance. Among these studies is "A Subchronic
Feeding Study with Fmc 35001 in Rats."
F-48
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Carboxin (CAS No. 5234-68-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for carboxin was derived (1986) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1985 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
carboxin.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: One genotoxicity study (1988) was identified.
Unknown Relevance
Two documents were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (approximately 280),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-49
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Chlorimuron-ethyl (CAS No. 90982-32-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for chlorimuron-ethyl was derived (1989) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1988 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for chlorimuron-ethyl.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (1UR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Seven documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (approximately 500),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
This search yielded approximately 360 references, so search results were limited with a tertiary search in
EndNote to identify references containing the CAS number and any synonym of chlorimuron-ethyl. Any
references not containing one of these search terms were coded as N/A.
F-50
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Chlorine (CAS No.7782-50-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for chlorine was derived (1993) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1992 to 2002 identified no new studies that would be directly useful in the denvation of an RfD for
chlorine.
Note: The EPA Office of Pesticide Programs (OPP) Reregistration Eligibility Decision (RED) RfD
(1995) for chlorine was derived based on the same National Toxicology Program (NTP) chronic drinking
water study in F344/N rats, published in 1992, as the IRIS RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1992 to 2002 identified a 2-year inhalation toxicity
study of chlorine gas in mice and rats (1995). In addition, the National Center for Environmental
Assessment (NCEA) released an issue paper deriving a chronic RfC in 1999.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: Three studies were identified which examined the carcinogenic potential of chlorinated water in rats
and mice (1992, 1993,1997).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: One study (1995) was identified which evaluated the carcinogenicity of 2-year exposures to
chlorine gas in mice and rats.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: The 1995 RED for chlorine gas reports a WOE classification of Group D—not classifiable as to
human carcinogenicity. An issue paper deriving a subchronic RfC was released by NCEA in 1999 and
concluded that chlorine gas is not likely to be a human carcinogen. A 2000 International Agency for
Research on Cancer (IARC) Monograph of disinfectants and disinfectant by-products reviewed the
carcinogenicity of chlorinated water. A 2001 study of chlorinated water carcinogenicity, through
examination of chromosomal aberrations, was also identified.
F-51
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Chlorine (CAS No.7782-50-5)
(continued)
Unknown Relevance
Eleven documents were categorized as being of unknown relevance. Among these studies are "Letter
from the Chlorine Inst Inc to USEPA Regarding a Two-year Chlorine Bioassay in Rats and Mice," "A
Chronic Inhalation Toxicity Study of Chlorine in Female and Male B6C3F1 Mice and Fischer 344 Rats,"
"Support: Information Regarding a Chronic Inhalation Study in Rats and Mice," "Chronic Inhalation
Toxicity Study on Chlorine in Non Human Primate," and "Acute and Long Term Pulmonary Toxicity
after Accidental Chlorine Exposure "
Note: Because of the large number of references found in the literature search (approximately 3,200),
search results were limited with a secondary search in EndNote to identify references containing the CAS
number and any synonym of chlorine, yielding approximately 680 references. Because of the continued
large number of references, search results were limited with a tertiary search in EndNote to identify
references containing common laboratory species and toxicological terms, including: rat, mouse/mice,
gerbil, hamster, beagle, dog, human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*,
genotox*, mutat*, and mutag*. Any references not containing one of these search terms were coded as
N/A.
F-52
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1-Chlorobutane (CAS No. 109-69-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could potentially produce a change in the
WOE. A literature search conducted for the years 1988 to 2002 identified no new studies that would be
directly useful in establishing a WOE classification. One mutagenicity study (1990) was identified that
studied the effects of chlorobutane on chromosome aberration and sister chromatid exchange in Chinese
hamster ovary cells.
Unknown Relevance
Nine documents were categorized as being of unknown relevance.
F-53
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2-Chlorobutane (CAS No. 78-86-4)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1988 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-54
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2-Chlorophenol (CAS No. 95-57-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2-chlorophenol was derived (1988) does not appear to
contain study data that could potentially produce a change in the RfD. Review of the ATSDR
Toxicological Profile (1999) and a literature search conducted for the years 1998 to 2002 identified no
new studies that would be directly useful in the derivation of an RfD for 2-chlorophenol. the ATSDR
Toxicological Profile addresses eight chlorophenols. The intermediate minimal risk level (MRL) is based
on 1984 and 1985 drinking water studies of 2,4-dichlorophenol in Sprague-Dawley rats.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) classified 2-
chlorophenol as Grou 2B—possibly carcinogenic to humans.
Unknown Relevance
Two documents were categorized as being of unknown relevance, both of which were submissions to
EPA Office of Toxic Substances (OTS).
F-55
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
p-Chlorophenyl methyl sulfide (CAS No. 123-09-1)
Oral Reference Dose (RfD)
An oral RfD for p-chlorophenyl methyl sulfide is not available because EPA determined that the data
were insufficient to support the development of an RfD (latest assessment 1992). The literature published
since 1992 does not appear to contain study data that could be useful in the development of an RfD. A
literature search conducted for the years 1991 to 2002 identified a 91-day dietary toxicity study in rats
and mice (1993). An unpublished version of this study was evaluated by EPA in 1992 and was
determined to be inadequate as the basis for the RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1991) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1990 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-56
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Coke oven emissions (CAS No. 8007-45-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
The literature published since the IUR for coke oven emissions was derived (1989) contains study data
that could potentially produce a change in the IUR.
The IRIS IUR for coke oven emissions was derived based on an occupational study examining respiratory
cancer in a cohort of steel workers exposed to coke oven emissions (benzene-soluble organics extracted
from the paniculate phase of coal tar pitch volatiles) (1975, 1976).
A literature search conducted for the years 1988 to 2002 identified nine additional mortality and cancer
morbidity studies in aluminum workers (1991, 1994, 1995), coke gas plant workers (1992), steelworkers
(1995), carbon workers (1997), and tar distillery workers and roofers (1997) that could potentially
produce a change in the IUR; however, the extent to which exposure data are available and causal
relationships identified in these studies is unknown.
Nonhuman data include a carcinogenicity study in rats exposed to coal tar pitch (1992), a study of rumor
rates in rats exposed to coal tar pitch condensation aerosol (1994), and studies of skin cancer in mice
exposed to coal tar pitch smoke (1996, 1997).
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (A—human carcinogen) was derived (1989) does
not appear to contain study data that could produce a change in the WOE. The National Toxicology
Program (NTP) (1981) and International Agency for Research on Cancer (IARC) Monograph (1987) also
classify coke oven emissions as a known human carcinogen. A literature search conducted for the years
1988 to 2002 identified carcinogenicity studies (in humans and animals) as cited above, as well as
multiple positive genotoxicity studies.
Unknown Relevance
Thirty-four documents, three of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including studies titled "Basal cell epitheliomatosis of the
face in a man who had handled pitch" and "The influence of the working environment on the respiratory
system in coke factory workers."
F-57
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Coke oven emissions (CAS No. 8007-45-2)
(continued)
Note: Coke oven emissions are a mixture of chemicals that are formed as a result of the distillation of
coke from coal and other carbon products. Coke oven emissions include the synonyms coal tar and coal
tar pitch. The IRIS summary identifies coal tar pitch volatiles (CASRN 65996-93-2) as the primary
synonym for coke oven emissions. Therefore, the literature search reviewed studies related to coke oven
emissions, coal tar, coal tar pitch, and coal tar pitch volatiles. Also, researchers quantify the toxicity of
coke oven emissions by using exposure concentrations of certain components of coke oven emissions,
frequently benzo(a)pyrene (BaP). This literature search includes studies that use BaP as a marker for coke
oven emissions exposures, but not studies strictly related to the toxicity of BaP.
Multiple studies were identified evaluating health effects associated with dermal exposure to coal tar in
the treatment of psoriasis. While not directly relevant to the IRIS IUR or WOE classification, study data
may be useful in supporting IRIS evaluations.
Note: Because of the large number of references found in the literature search (approximately 730),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-58
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Cumene (CAS No. 98-82-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for cumene was derived (1997) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1996 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
cumene.
Inhalation Reference Concentration (RfC)
The literature published since the RfC for cumene was derived (1997) does not appear to contain study
data that could potentially produce a change in the RfC.
The IRIS RfC for cumene was derived based on a 13-week inhalation study in rats (1995). A literature
search conducted for the years 1996 to 2002 identified a 1997 developmental toxicity study in pregnant
CD (Sprague-Dawley) rats and pregnant New Zealand white rabbits exposed to cumene vapor. An
unpublished version of this study was considered in the 1997 IRIS assessment for cumene.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1997) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1996 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
Six documents, five of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including studies titled "Preliminary Results in Mouse
Prechromc Inhalation Study of Cumene" and "An Analysis of Genotoxicity Assays Performed on
Cumene" and a letter submitting information about a 14-week cumene study in rats.
F-59
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Cyanazine (CAS No. 21725-46-2)
Oral Reference Dose (RfD)
An oral RfD for cyanazine is not available (latest assessment 1992). The oral RfD and supporting
information previously on IRIS were withdrawn in 1992; according to the IRIS summary, a new RfD was
in preparation by the RfD/RfC Work Group. A literature search conducted for the years 1991 to 2002
identified study data that may be useful in developing an RfD, specifically, a 2-year dietary study in
Sprague-Dawley rats (2000) and a development toxicity study in rats (1999).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A literature search conducted for the years 1991 to 2002 identified a 2-year dietary study in
Sprague-Dawley rats evaluating the oncogenic potential of cyanazine.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1991 to 2002 identified several in vitro and in vivo
mutagenicity studies, reporting no genotoxic effects in most systems tested (1993, 1996, 1998, 2000, and
2001), as well as one animal bioassay (mentioned in the CSF note above).
Unknown Relevance
Three documents, two of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
Note: A secondary search in EndNote identified references containing: phytotox*, aquatic"1, and ecotox*.
References containing one of these search terms were coded as N/A.
Note: The EPA Office of Pesticide Programs (OPP) Reregistration Eligibility Decision (RED) for
cyanazine was voluntarily canceled in September 199S.
F-60
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Cyanogen (CAS No. 460-19-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for cyanogen was derived (1985) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1984 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
cyanogen.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1984 to 2002 identified a 1984 study investigating
behavioral, physiologic, and pathologic effects in male rhesus monkeys and male Charles River rats
exposed to cyanogen by inhalation for 6 hours/day, 5 days/week, for 6 months.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-61
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Cyclohexanone (CAS No. 108-94-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for cyclohexanone was derived (1986) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1985 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for cyclohexanone.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1985 to 2002 identified a two-generation reproductive
toxicity study in CD Sprague-Dawley albino rats exposed to cyclohexanone vapors (1986) ; two
inhalation developmental toxicity studies (1989 and 1992) in pregnant Sprague-Dawley rats and mated
CD rats (1989,1992) ; and a study evaluating development of spines on olfactory granule cells in rats
exposed to cyclohexanone vapors (1988).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) assigned
cyclohexanone a cancer classification of Group 3—not classifiable as to carcmogenicity in humans. A
literature search conducted for the years 1985 to 2002 identified an in vitro study of cyclohexanone
mutagenicity in Chinese hamster ovary cells (1985).
Unknown Relevance
Eighteen documents, 12 of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Among these studies are "Two-generation Rat Reproduction
Study with Cyclohexanone via Inhalation," "Inhalation Teratogenicity with Cyclohexanone in Mice,"and
"A Summary of the Results of 55 Chemicals Screened for Developmental Toxicity in Mice."
F-62
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Cyclohexylamine (CAS No. 108-91-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for Cyclohexylamine was derived (1987) does not appear to
contain study data that could potentially produce a change in the RfD.
The IRIS RfD for Cyclohexylamine was derived based on two chronic studies in rats (1976). A literature
search conducted for the years 1986 to 2002 identified a study of morphological changes in male Wistar
rats fed Cyclohexylamine for up to 13 weeks (1990) and a 13-week dietary study investigating the
metabolism and testicular toxicity of Cyclohexylamine in rats and mice (1989). Both the 1989 and 1990
studies involved a single study group exposed at 400 milligrams per kilogram body weight per day
(mg/kg/day), which was more than 10-fold higher than the lowest dose adminstered in the studies selected
as the basis for the current RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSV)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1986 to 2002 identified two genotoxicity/mutagemcity
studies (1986, 1989).
Unknown Relevance
Eight documents, four of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Among these studies are "Initial Submission: Toxicity
Studies on Cyclohexylamine (final report)" and "Cyclamate, Cyclohexylamine and Cardiovascular
Toxicity in Man: an Initial Population Study."
F-63
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dalapon (sodium salt) (CAS No. 75-99-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dalapon was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1987 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
dalapon.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categorized as being of unknown relevance.
Note: A secondary search in EndNote identified references containing: phytotox*, aquatic"1, and ecotox*.
References containing one of these search terms were coded as N/A.
F-64
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Danitol (CAS No. 39515-41-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for danitol was derived (1993) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1992 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
danitol.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted from 1992 to 2002 identified three genotoxicity studies: one study
(1995) testing the ability of danitol to induce micronuclei in both whole-blood and isolated human
lymphocyte cultures; a second study (1996) testing for genotoxicity in Salmonella typhimunum,
chromosome aberrations in Chinese hamster lung fibroblasts, and the induction of micronuclei in mouse
cells; and a third study (1997) investigating the induction of micronuclei in rat bone marrow cells.
Negative, weak, and positive genotoxic responses were reported.
Unknown Relevance
Nine studies, three of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-65
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,4-Diaminotoluene (CAS No. 95-80-7)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An inhalation RfC for 2,4-diaminotoluene (2,4-DAT) is not available because EPA determined that the
data were inadequate for derivation of an RfC (latest assessment 1990). The literature published since
1990 does not appear to contain study data that could be used to develop an RfC. A literature search
conducted for the years 1990 to 2002 identified no new studies that would be directly useful in the
derivation of an RfC for 2,4-DAT.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (1UR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1987) characterized 2,4-
DAT as Group 2B—possible human carcinogen. The National Toxicology Program (NTP) Ninth Report
on Carcinogens (2001) classified 2,4-DAT as "reasonably anticipated to be a human carcinogen." In
addition, a literature search conducted for the years 1989 to 2002 identified several genotoxicity and
mutagemcity studies, including in vivo genotoxicity testing using the rat micronucleus test (1991);
analysis of DNA adduct formation (1992, 1993, 1994, 1995, 1996); chromosomal aberration induction
studies (1990, 1991); microbial mutagenicity studies (1990, 1992, 2000); and Big Blue transgenic mouse
mutation assays (1995, 1996). Overall, reported findings were positive for genotoxicity and mutagenicity.
In addition, several studies evaluated possible mechanisms of carcinogenic action of 2,4-DAT (1990,
1992, 1995, 1996).
Unknown Relevance
Twenty documents, five of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Among these studies are "Determination of the Reproductive
Effects in Mice of Nine Selected Chemicals" and "The Carcinogenicity of Hair Dyes and Permanent
Wave Preparations."
F-66
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dibenzofuran (CAS No. 132-64-9)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A Provisional Assessment deriving a provisional RfD was released by the National Center for
Environmental Assessment (NCEA) in 1999. The provisional RfD was based on a 1940 repeat-dose
toxicity study in rats. This study was identified as the only available toxicity study of dibenzofuran. A
literature search conducted by NCEA for the period 1992 to January 1999 confirmed the absence of
current toxicity data for dibenzofuran.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE. NCEA
released an issue paper in 1999 which concluded that the carcinogenicity of dibenzofuran cannot be
determined. A literature search conducted for the years 1998 to 2002 identified no new studies that would
be directly useful in establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
Note: The literature search identified multiple references related to polychlorinated dibenzofurans,
however, the IRIS summary specifically stated that polychlorinated dibenzofurans are not appropriate as a
surrogate for assessing risks associated with dibenzofuran.
F-67
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dibromochloromethane (CAS No. 124-48-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dibromochloromethane was derived (1987) contains study
data that could potentially produce a change in the RfD.
The IRIS RfD for dibromochloromethane was derived based on a 13-week gavage bioassay in F344/N
rats and B6C3F1 mice (1985). The ATSDR Toxicological Profile (1990) presented an oral minimal risk
level (MRL) for dibromochloromethane based on the same study as the IRIS RfD. A literature search
conducted for the years 1989 to 2002, however, identified a 90-day oral toxicity study in Sprague-Dawley
rats (1990), a short-term reproductive and developmental toxicity screen using Sprague-Dawley rats
(1996), and an epidemiologic study of spontaneous abortion in pregnant women exposed to
dibromochloromethane and other tnhalomethanes (THMs) via chlorinated drinking water (1998) that may
be useful in the derivation of an RfD for dibromochloromethane.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the oral CSF for dibromochloromethane was derived (1989) does not
appear to contain study data that could potentially produce a change in the CSF.
The IRIS CSF for dibromochloromethane was derived based on a 104-week National Toxicology
Program (NTP) gavage study in F344/N rats and B6C3F1 mice (1985). An International Agency for
Research on Cancer (IARC) Monograph (1999) did not present new study data. A literature search
conducted for the years 1989 to 2002 identified no new studies that would be directly useful in the
derivation of a CSF for dibromochloromethane.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1989) may contain study data that could produce a change in the WOE.
The IRIS WOE for dibromochloromethane was derived based on inadequate human data and limited
evidence of carcinogenicity in animals (a 104-week gavage study in F344/N rats and B6C3F1 mice
[1985]), together with positive mutagemcity data, and structural similarity to other tnhalomethanes,
which are known animal carcinogens. However, an IARC Monograph (1999) characterized
dibromochloromethane as Group 3—not classifiable as to carcinogenicity in humans.
F-68
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dibromochloromethane (CAS No. 124-48-1)
(continued)
In addition, a literature search conducted for the years 1989 to 2002 identified new studies not included in
the IARC Monograph that may be useful in establishing a WOE classification. These included an analysis
of the NIP cancer bioassay findings for various chlorination byproducts (including
dibromochloromethane) (1993) and several genotoxicity and mutagenicity studies, mostly reporting
positive findings including chromosomal aberration induction studies (1990, 1991), a sister chromatid
exchange induction study (1990), a DNA strand break study (1996), microbial mutagenicity studies
(1998, 1999), and an in vitro genotoxicity study using the Comet assay in human whole blood cultures
(1999). In addition, three studies evaluated possible mechanisms of carcinogenic action for
dibromochloromethane (1996, 1997, 1998), including a liver tumor induction study (1998) in female
B6C3F1 mice exposed to dibromochloromethane via gavage in com oil for three weeks.
Unknown Relevance
Fifteen documents were categorized as being of unknown relevance. For many studies, it was impossible
to determine if dibromochloromethane was tested separately from other THMs. Among these studies are
"Assessment of the Toxic and Carcinogenic Potential of Disinfecting Water Supplies, Long-Term Rodent
Studies of Chlorine, Chloramine, and Trihalomethanes," "Trihalomethanes in Drinking Water and Cancer
Risk Assessment and Integrated Evaluation of Available Data in Animals and Humans," "The
Association of Drinking Water Source and Chlorination By-Products with Cancer Incidence Among
Postmenopausal Women in Iowa," and "Exposure to Trihalomethanes and Adverse Pregnancy
Outcomes."
F-69
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dibromodichloromethane (CAS No. 594-18-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSV)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1991) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1990 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
Two documents were categorized as being of unknown relevance, "Toxicology of halogenated aliphatic
hydrocarbons: Structural and molecular determinants for the disturbance of chromosome segregation and
the induction of lipid peroxidation" and "The detection and evaluation of aneugenic chemicals."
F-70
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
p,p'-Dibromodiphenyl ether (CAS No. 2050-47-7)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcmogenicity)
for p,p'-dibromodiphenyl ether was derived (1990) does not appear to contain study data that could
potentially produce a change in the WOE classification. A literature search conducted for the years 1989
to 2002 identified no new studies that would be directly useful in the derivation of a WOE classification
for p,p'-dibromodiphenyl ether.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-71
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dicamba (CAS No. 1918-00-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dicamba was derived (1988) appears to contain study data
that could potentially produce a change in the RfD.
The IRIS RfD for dicamba was derived based on a developmental study in rabbits (1978). A 1999 Federal
Register1 notice published by EPA Office of Pesticide Programs (OPP) related to the pesticide tolerance
for dicamba on agricultural commodities includes a summary of the available toxicity studies for
dicamba, including several studies not cited in the IRIS summary (a mouse carcmogenicity study, a
second rabbit teratology study, and two-generation rat reproduction study). Also in the Federal Register
notice, EPA presents an RfD of 0.045 milligrams per kilogram body weight per day (mg/kg/day), based
on the 2-generation rat study not apparently considered in the IRIS summary.
A literature search conducted for the years 1987 to 2002 identified a number of studies whose relevance
to the derivation of an RfD for dicamba could not be determined because of the limited information
contained in each study record These studies were coded as "unknown relevance."
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In the 1999 Federal Register notice, OPP reached the following conclusion regarding the
carcinogenic potential of dicamba:
1 Two Federal Register notices regarding dicamba were identified:
58 FR 62039, November 24, 1993 [Pesticide Tolerances for Dicamba]
64 FR 759, January 6,1999 [Dicamba (3,6-dichloro-o-anisic acid); Pesticide Tolerance].
F-72
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dicamba (CAS No. 1918-00-9)
(continued)
"In accordance with the EPA Proposed Guidelines for Carcinogen Risk Assessment (10-APR-
1996), the EPA classified dicamba as a "not classifiable" human carcinogen. This was based on
the mouse carcinogenicity study and the rat combined chronic toxicity/carcinogenicity study,
being classified as supplemental because a [maximum tolerated dose] (MTD) was not achieved in
both studies. However, these studies were adequate to indicate that dicamba has either a low or no
cancer potential in mammals. A pharmacokinetics study pending EPA review indicates that the
MTD for both the rat and mouse studies was reached. If this is corroborated by EPA's review, a
quantitative cancer risk will not be made for dicamba and its metabolites, on the other hand, if the
review does not corroborate this indication, replacement studies will be required" (64 FR 759,
January 6,1999).
A literature search conducted for the years 1987 to 2002 identified five genotoxicity studies potentially
relevant to the derivation of a WOE classification: a structural chromosome aberration study in Chinese
hamster ovary cells listed the EPA OPP "Index of Cleared Science Reviews" (1987); two mutagenicity
studies using the Ames test and the SOS-Chromotest (1988, 1989, respectively); in vivo and in vitro test
systems in which sister chromatid exchange (SCE) and unscheduled DNA synthesis (UDS) were
measured in cultured human peripheral blood lymphocytes and the unwinding rate of liver DNA was
measured in intrapentoneally treated rats (1990); and a mutagenicity study using SCE and UDS assays in
human peripheral lymphocytes and of chromosome aberration analysis in rat bone marrow (1994). Both
positive and negative findings were reported
Unknown Relevance
Twenty documents were categorized as being of unknown relevance, including nineteen listings in the
OPP "Index of Cleared Science Reviews." Among these listings were two memoranda (1993, 1996)
regarding "Dicamba: RfD Peer Review Report," a 1996 letter regarding "September 9, 1996, Request for
New Chronic Toxicity/Carcinogenicity Study in Rats - RfD Committee Recommendations," a 1998
memorandum titled "Dicamba - Report of the Hazard Identification Assessment Review Committee," and
a 1987 memorandum entitled "Banvel Herbicide (Dicamba): Amended Registration."
Also included among these listings were documents entitled "Dicamba: One-year Toxicity Study in
Dogs" (1987), "Mutagenicity: In Vitro Chromosomal Aberrations" (1987), "Oncogenicity Study in Mice
with Dicamba Technical and 21-Day Dermal Toxicity in Rabbits with Banvel Herbicide" (1989),
"Dicamba: Developmental Toxicity Study in Rabbits" (1993), "Dicamba: Acute Neurotoxicity Study in
Rats" (1993), "Dicamba - Review of Subchronic Neurotoxicity Study (82-7)" (1995), and "Dicamba:
Reproductive Toxicity Study Submitted in Response to DCI" (1995).
Note: Because of the large number of references found in the literature search (approximately 500),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species or toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog, human,
rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*. Any
references not containing one of these search terms were coded as N/A.
F-73
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
p,p'-Dichlorodiphenyltrichtoroethane (CAS No. 50-29-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for p.p'-dichlorodiphenyltrichloroethane (DDT) was derived
(1985) contains study data that could potentially produce a change in the RfD.
The IRIS RfD for DDT was derived based on a 27-week rat dietary study published in 1950. ATSDR
updated the Toxicological Profile for DDT in 2000. ATSDR did not derive a chronic oral minimal risk
level (MRL) for DDT due to insufficient data. ATSDR derived an intermediate oral MRL for DDT based
on the same 1950 rat study used to derive the IRIS RfD in 1985.
A literature search conducted for the years 1999 to 2002 identified a 130-month dietary study in rhesus
monkeys (1999), an oral toxicity study in Sprague Dawley rats exposed for up to 18 months (1999), a
study of reproductive/developmental toxicity in rabbits (2000), and a teratogenicity study in rats and
rabbits (2000).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS
Oral Slope Factor (CSF)
The literature published since the CSF for DDT was derived (1987) does not appear to contain study data
that could produce a change in the CSF. A review of the ATSDR Toxicological Profile (2000) and a
literature search conducted for the years 1999 to 2002 identified no new studies that would be directly
useful in the derivation of a CSF for DDT.
Inhalation Unit Risk (IUR)
The literature published since the IUR for DDT was derived (1987) does not appear to contain study data
that could produce a change in the IUR. A review of the ATSDR Toxicological Profile (2000) and a
literature search conducted for the years 1999 to 2002 identified no new studies that would be directly
useful in the derivation of an IUR for DDT.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification for DDT (B2—probable human carcinogen) was
derived (1987) contains study data that could potentially produce a change in the WOE classification. In
1991, consistent with the EPA's WOE designation, International Agency for Research on Cancer (IARC)
characterized DDT as Group 2B—possibly carcinogenic to humans.
F-74
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
p,p'-Dichlorodiphenyltrichloroethane (CAS No. 50-29-3)
(continued)
The 1987 IRIS WOE classification was based on animal carcinogenicity assays; IRIS concluded that there
were inadequate epidemiologic studies to assess the carcinogenic potential of DDT. A review of the
ATSDR Toxicological Profile (2000) identified eight studies published in the 1990s evaluating the cancer
risk to individuals who may have had relatively high exposures to DDT, four prospective studies
characterizing past DDT exposure in groups of cancer patients, five case-control studies of the association
between DDT levels in the body and the occurrence of cancer, and several reviews of the role of DDT in
the etiology of breast cancer. ATSDR notes, however, that evidence of DDT carcinogenicity in humans is
inconclusive. A literature search conducted for the years 1999 to 2002 identified no new studies that
would be directly useful in the derivation of a WOE classification for DDT.
Unknown Relevance
Three documents were categorized as being of unknown relevance.
Note: The literature search also identified two studies of serum DDT levels in human mothers who had
experienced spontaneous abortions (2000,2001).
Note: Because of the large number of references found in the literature search (approximately 1,000),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A. In addition, a synonym for
DDT is "Detox " Because both chemical name and word variants were used as search parameters for the
literature search, a number of studies unrelated to DDT were found (due to the common use of the word
"detox*"). These studies were identified by a secondary search in EndNote and coded as N/A.
F-75
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,1-Dichloroethane (CAS No. 75-34-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: An issue paper evaluating oral exposures to 1,1-dichloroethane was issued by the National Center
for Environmental Assessment (NCEA) in 1998 and concluded that insufficient information was available
to derive an RfD. A literature search conducted for the years 1997 to 2002 identified no new studies that
would be directly useful in establishing an RfD for 1,1-dichloroethane.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: An issue paper evaluating inhalation exposures to 1,1-dichloroethane was issued by NCEA in 1998
and concluded that insufficient information was available to derive an RfC. A literature search conducted
for the years 1997 to 2002 identified no new studies that would be directly useful in establishing an RfC
for 1,1-dichloroethane.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) for 1,1-
dichloroethane was denved (1989) does not appear to contain study data that could produce a change in
the WOE classification. An NCEA Provisional Assessment (1998) classified 1,1-dichloroethane as Group
C—possible human carcinogen. A literature search conducted for the years 1997 to 2002 identified no
new studies that would be directly useful in the derivation of a WOE classification for 1,1-dichloroethane.
Unknown Relevance
Five documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-76
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
cis-l,2-Dichloroethylene (CAS No. 75-34-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: In the 1996 Toxicological Profile, ATSDR derived an intermediate minimal risk level (MRL) for
cis-l,2-dichloroethylene. A literature search conducted for the years 199S to 2002 identified a 14- and 90-
day gavage study in Sprague-Dawley rats (199S) that appears to be the published version of the study that
served as the basis for the ATSDR intermediate MRL.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
for cis-l,2-dichloroethylene was derived (1989) does not appear to contain study data that would produce
a change in the WOE classification.
The ATSDR Toxicological Profile (1996) cites several in vivo and in vitro mutagemcity/genotoxicity
studies for cis-l,2-dichloroethylene, with both positive and negative findings reported. A literature search
conducted for the years 1995 to 2002 identified no new studies that would be directly useful in the
derivation of a WOE classification for cis-l,2-dichloroethylene.
Unknown Relevance
Two documents, both submissions to EPA Office of Toxic Substances (OTS) regarding inhalation studies
in rats, were categorized as being of unknown relevance.
F-77
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
trans-l,2-Dichloroethylene (CAS No. 156-60-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for trans-1,2-dichloroethylene was derived (1988) does not
appear to contain study data that could potentially produce a change in the RfD. Review the ATSDR
Toxicological Profile (1996) and a literature search conducted for the years 1995 to 2002 identified no
new studies that would be directly useful in the derivation of an RfD for trans-1,2-dichloroethylene. The
principle study used to derive the IRIS RfD and the ATSDR oral minimal risk level (MRL) are the same.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: The ATSDR Toxicological Profile for dichloroethylene (1996) includes an intermediate inhalation
MRL for trans-1,2-dichloroethylene.
Oral Slope Factor (CSV)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS
Unknown Relevance
One document, a submission to EPA Office of Toxic Substances (OTS), was categorized as being of
unknown relevance.
Note: A literature search conducted for the years 1995 to 2002 identified one paper presenting a
pharmacokinetic model of the kinetics of metabolism of trans-1,2-dichloroethylene, vinyl chloride, and
trichloroethylene
F-78
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dichloromethane (CAS No. 75-09-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dichloromethane was derived (1985) does not appear to
contain study data that could potentially produce a change in the RfD. Review of the ATSDR
Toxicological Profile (2000) and a literature search conducted for the years 1999 to 2002 identified no
new studies that would be directly useful in the derivation of an RfD. The principal studies used to derive
the IRIS RfD and the ATSDR oral minimal risk level (MRL) appear to be unpublished and published
versions of the same study.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: ATSDR published a chronic inhalation MRL in the 2000 toxicological profile based on a 2-year
inhalation toxicity and oncogenicity study of dichloromethane in rats (1988). In addition, two studies of
inhalation exposure to dichloromethane in Fischer 344 rats were identified: a two-generation reproductive
toxicity study (produced in 1985) and a 13-week neurotoxicity study (produced in 1988).
Oral Slope Factor (CSF)
The literature published since the CSF for dichloromethane was derived (1989) does not appear to contain
study data that could potentially produce a change in the CSF Review of the ATSDR Toxicological
Profile (2000) and a literature search conducted for the years 1999 to 2002 identified no new studies that
would be directly useful in the derivation of a CSF.
Inhalation Unit Risk (1UR)
The literature published since the ITJR for dichloromethane was derived (1989) does not appear to contain
study data that could potentially produce a change in the IUR. Review of the ATSDR Toxicological
Profile (2000) and a literature search conducted for the years 1999 to 2002 identified no new studies that
would be directly useful in the derivation of an IUR.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1989) does not appear to contain study data that could produce a change in the WOE. In 1999, consistent
with EPA's WOE designation, the International Agency for Research on Cancer (IARC) classified
dichloromethane as Group 2B—possibly carcinogenic to humans.
Review of the ATSDR Toxicological Profile (2000) and a literature search conducted for the years 1999
to 2002 identified no new studies that would likely produce a change in the WOE classification. As was
concluded in the IRIS assessment conducted in 1989, there are no adequate epidemiologic studies to
assess the carcinogenic potential of dichloromethane in humans, and animal bioassays provide some
positive evidence of carcinogenic potential. The literature search identified a positive DNA adduct study
(2001).
F-79
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dichloromethane (CAS No. 75-09-2)
(continued)
Unknown Relevance
Thirteen documents, most of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-80
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
4-(2,4-Dichlorophenoxy)butyric acid (CAS No. 94-82-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 4-(2,4-dichlorophenoxy)butyric acid was derived (198S)
contains study data that could potentially produce a change in the RfD.
The IRIS RfD for 4-(2,4-dichlorophenoxy)butyric acid was derived based on a subchronic oral bioassay
in dogs (1969). A literature search conducted for the years 1984 to 2002 identified two chronic dietary
toxicity studies (1998)—one in rodents and one in dogs. A 1999 publication reported results of
developmental toxicity studies in rats and rabbits and a two-generation reproduction study in rats
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS
Note: A literature search conducted for the years 1984 to 2002 identified a chronic dietary study in rats
reporting no oncogenic response (1998).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1984 to 2002 identified one study that evaluated the in
vitro genotoxicity of 4-(2,4-dichlorophenoxy)butyric acid in the Ames test, mammalian cell cultures,
chromosomal aberration assay, and induction of DNA damage and repair in rat hepatocytes (2000).
4-[2,4-Dichlorophenoxy]butyric acid was found not to be genotoxic in mammals.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-81
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,2-Dichloropropane (CAS No. 78-87-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: ATSDR derived a chronic oral minimal risk level (MRL) in its 1989 toxicological profile for 1,2-
dichloropropane based on a 1986 National Toxicology Program (NTP) bioassay. A literature search
conducted for the years 1992 to 2002 identified a 1992 two-generation reproductive toxicity study in male
and female Sprague-Dawley rats and a developmental toxicity study in rats and rabbits (1995)
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for 1,2-dichloropropane was derived (1991) does not
appear to contain study data that could potentially produce a change in the RfC. Review of the World
Health Organization (WHO) Environmental Health Critena (1993) and a literature search conducted for
the years 1992 to 2002 identified no new studies that would be directly useful in the derivation of an RfC
for 1,2-dichloropropane.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) assigned 1,2-
dichloropropane a cancer classification of Group 3—not classifiable as to carcmogenicity in humans. An
NTP bioassay revealed no evidence of carcinogenicity in male rats, equivocal evidence in female rats, and
some evidence in male and female mice.
Unknown Relevance
Twelve documents, five of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-82
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,3-Dichloropropanol (CAS No. 616-23-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,3-dichloropropanol was derived (1990) does not appear
to contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1989 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for chemical.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Three documents were categorized as being of unknown relevance. Among these studies is a submission
to EPA Office of Toxic Substances (OTS) titled "A Five Week Feeding Study of Cardura E10 in Rats"
(1991)
F-83
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dicofol (CAS No. 115-32-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: EPA Office of Pesticide Programs (OPP) derived an oral RfD in its 1998 Reregistration Eligibility
Decision (RED) based on a 1-year chronic dietary study in dogs (1988). A literature search conducted for
the years 1997 to 2002 identified a reproductive toxicity study in rats following dietary administration
(1999).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
A CSF for dicofol is not available because EPA determined that the data were insufficient to support
development of a CSF (latest assessment 1992). The CSF and supporting information previously on IRIS
were withdrawn. Review of the OPP RED (1998) and a literature search conducted for the years 1997 to
2002 identified no new studies that would be directly useful in the derivation of a CSF for dicofol.
Inhalation Unit Risk (IUR)
An IUR for dicofol is not available because EPA determined that the data were insufficient to support
development of an IUR (latest assessment 1992). The IUR and supporting information previously on IRIS
were withdrawn. Review of the OPP RED (1998) and a literature search conducted for the years 1997 to
2002 identified no new studies that would be directly useful in the derivation of an IUR for dicofol.
Cancer Weight-of-Evidence (WOE) Classification
A carcinogenicity assessment is not available. The carcinogen assessment summary was withdrawn by the
CRAVE Agency Work Group pending further review (latest assessment 1992)
In the 1998 RED, EPA's Carcinogenicity Peer Review Committee classified dicofol as Group
C—possible human carcinogen—based on a 1978 National Cancer Institute bioassay in rats and mice
(MRID 41037801). A literature search conducted for the years 1997 to 2002 identified no new studies
that would be directly useful in establishing a WOE classification.
Unknown Relevance
One document, "Dicofol stimulation of cell proliferation," was categorized as being of unknown
relevance.
F-84
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Diethyl phthalate (CAS No. 84-66-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for diethyl phthalate was derived (1987) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for diethyl phthalate was derived based on a subchronic oral dietary study in rats (1978).
ATSDR derived an intermediate minimal risk level (MRL) in the 1995 Toxicological Profile based on a
different 1978 subchronic (3-week) feeding study in rats. A literature search conducted for the years 1994
to 2002 identified a 120-day drinking water study (2000) in Sprague-Dawley rats. Two additional studies
(2000) evaluated the effects of perinatal exposures to diethyl phthalate in Sprague-Dawley rats.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1987) does not appear to contain study data that could potentially produce a change in the
WOE. A National Toxicology Program (NTP) 2-year dermal cancer bioassay published in 1995
characterized diethyl phthalate as exhibiting equivocal evidence of carcinogenicity in male and female
B6C3F1 mice and no evidence of carcinogenicity in male or female F334/N rats. A literature search
conducted for the years 1994 to 2002 identified no new studies that would be directly useful in
establishing a WOE classification.
Unknown Relevance
Nine documents, seven of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Among these studies are "Determination of Diethyl Phthalate
in Blood," "Diethyl Phthalate: Reproduction and Fertility Assessment in Cd-1 Mice When Administered
in the Feed," and "Genetic Evaluation of Molykote Pene-Lube, Diethyl Phthalate, in Bacterial Reverse
Mutation Assays."
F-85
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Diethyl-p-nitrophenyl phosphate (paraoxon) (CAS No. 311-45-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1991) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1990 to 2002 identified one mutagenicity study (1995) of
metabolites of organothiophosphorus pesticides that included paraoxon.
Unknown Relevance
Three documents were categorized as being of unknown relevance.
Note: The IRIS summary notes that paraoxon has been extensively used as a deacetylase inhibitor in the
study of the mechanism of mutagenesis. Several studies identified by the literature search evaluate the
inhibition patterns of various esterases following paraoxon exposure, including studies examining cross-
species differences.
Note: Paraoxon is a major metabolite of the pesticide, parathion. As a metabolite of parathion, studies and
models of parathion poisoning also discuss the effects of paraoxon and include them in the group of
effects caused by parathion. Studies identified as such were reviewed during this literature search, and the
potential relevance of each study was evaluated individually.
Note: A literature search conducted for the years 1990 to 2002 found one study (1994) carried out to
develop, apply, and validate a comprehensive pharmacokinetic model for parathion and its major
metabolites (including paraoxon). Another study (1996) examined the interspecies differences in enzymes
reacting with organophosphates and their inhibition by paraoxon. A third study (1996) compared
parathion and paraoxon toxicokinetics, lung metabolic activity, and cholinesterase inhibition in guinea
pigs and rabbit lungs. A fourth study (1993) compared the cytotoxic sensitivities of mouse and human
cells to organophosphate insecticides, including paraoxon.
F-86
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Diethyl-p-nitrophenyl phosphate (paraoxon) (CAS No. 311-45-5)
(continued)
Note: Because of the large number of references found in the literature search (approximately 375),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-87
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Dimethipin (CAS No. 55290-64-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dimethipin was derived (1986) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1985 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
dimethipin.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1987) does not appear to contain study data that could produce a change in the WOE. A literature search
conducted for the years 1986 to 2002 identified no new studies that would be directly useful in
establishing a WOE classification.
Unknown Relevance
Seven documents were categorized as being of unknown relevance. All seven documents were listed on
the EPA Office of Pesticide Programs (OPP) "Index of Cleared Science Reviews" for dimethipin,
including "Harvade: Statistical Tests on Rat (Hazleton, Squire and EPL Evaluations) and Mouse
(Hazelton and EPL Evaluations) Data for Selected Tumors," "Harvade: EPA Reg. No. 400-155:
Subchronic mouse study," three peer reviews of documents submitted to OPP, and one response to peer
review.
F-88
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
N,N-Dimethylformamide (CAS No. 68-12-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A continuous breeding dosed-water study was identified in the National Toxicology Program
(NTP) Management Status Report.
Inhalation Reference Concentration (RfC)
The literature published since the RfC for N,N-dimethylformamide was derived (1990) contains study
data that could potentially produce a change in the RfC.
The IRIS RfC for N,N-dimethyIformamide was derived based on two occupational studies (1984). A
2000 Health Canada Assessment reports an inhalation tolerable concentration (TC) based on liver effects
as reported in a 1997 occupational study and a 1984 study. [The 1984 study, but not the 1987 study,
served as a basis for the current RfC.] In addition, a 13-week inhalation study in Fisher rats and BB63F1
mice was found while searching the NTP Management Status Report.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) characterized N,N-
dimethylformamide as Group 3—not classifiable as to carcinogenicity in humans.
Unknown Relevance
No literature search was necessary.
F-89
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,4-Dimethylphenol (CAS No. 105-67-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,4-dimethylphenol was derived (1990) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for 2,4-dimethylphenol was denved based on a subchronic oral gavage study in mice
(1989). A literature search conducted for the years 1989 to 2002 identified one 90-day corn oil gavage
study in Sprague-Dawley rats (1993).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS
Unknown Relevance
No documents were categorized as being of unknown relevance
F-90
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
3,4-DimethyIphenol (CAS No. 95-65-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 3,4-dimethylphenol was derived (1986) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 198S to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for 3,4-dimethylphenol.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
One submission to EPA Office of Toxic Substances (OTS) was categorized as being of unknown
relevance.
F-91
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,4-Dinitrotoluene (CAS No. 121-14-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,4-dinitrotoluene was derived (1991) does not appear to
contain study data that could potentially produce a change in the RfD. Review of the ATSDR
Toxicological Profile (1998) and a literature search conducted for the years 1997 to 2002 identified no
new studies that would be directly useful in the derivation of an RfD for 2,4-dinitrotoluene. ATSDR
derived a chronic oral minimal risk level (MRL) for 2,4-dinitrotoluene based on the same 198S dog study
used to derive the IRIS RfD.
Inhalation Reference Concentration (RfC)
An oral RfC for 2,4-dinitrotoluene is not available because EPA determined that the data were insufficient
to support development of an RfC (latest assessment 1990). Review of the ATSDR Toxicological Profile
(1998) and a literature search conducted for the years 1997 to 2002 identified no new studies that would
be directly useful in the derivation of an RfC. According to the ATSDR Toxicological Profile (1998),
data were insufficient for the derivation of an acute, intermediate, or chronic inhalation MRL.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1996) characterized 2,4-
dinitrotoluene as Group 2B—possibly carcinogenic to humans. A literature search conducted for the years
1997 to 2002 identified one mutagenicity study (1998) and one genotoxicity study (1999), which reported
both positive and negative results.
Unknown Relevance
Three submissions to EPA Office of Toxic Substances (OTS) were categorized as being of unknown
relevance.
F-92
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Diphenamid (CAS No. 957-51-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for diphenamid was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1986 to 2002 identified no new studies that would be directly useful in the denvation of an RfD for
diphenamid.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Two documents, one of which was a submission to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-93
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,2-Diphenylhydrazine (CAS No. 122-66-7)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An oral RfC for 1,2-diphenyIhydrazine is not available because EPA determined that the health effects
data were inadequate to support development of an RfC (latest assessment 1991). A literature search
conducted for the years 1990 to 2002 identified no new studies that would be directly useful in the
derivation of an RfC for 1,2-diphenylhydrazine.
Oral Slope Factor (CSF)
The literature published since the CSF for 1,2-diphenylhydrazine was derived (1986) does not appear to
contain study data that could potentially produce a change in the CSF. Review of the ATSDR
Toxicological Profile (1990) and a literature search conducted for the years 1989 to 2002 identified no
new studies that would be directly useful in the derivation of an CSF for 1,2-diphenylhydrazine.
Inhalation Unit Risk (IUR)
The literature published since the IUR for 1,2-diphenylhydrazine was derived (1986) does not appear to
contain study data that could potentially produce a change in the IUR. Review of the ATSDR
Toxicological Profile (1990) and a literature search conducted for the years 1989 to 2002 identified no
new studies that would be directly useful in the derivation of an IUR for 1,2-diphenyIhydrazine.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1986) does not appear to contain study data that could produce a change in the WOE. Review of the
ATSDR Toxicological Profile (1990) and a literature search conducted for the years 1989 to 2002
identified one study (2000) investigating the nature of the DNA damage in rats and mice induced by 1,2-
diphenylhydrazine
Unknown Relevance
Two documents were categorized as being of unknown relevance.
F-94
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Disulfoton (CAS No. 298-04-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for disulfoton was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for disulfoton was derived based on a 2-year oral toxicity (diet) study in F344/N rats
(1985). In the Revised Health Effects Risk Assessment (2000) prepared as part of its Reregistration
Eligibility Decision (RED), EPA Office of Pesticide Programs (OPP) identified a two-generation
reproductive toxicity study in rats administered disulfoton in their diets (1997) and a 1-year toxicity
dietary study in dogs (1997). OPP used the 1-year toxicity study in dogs as the basis for its RfD. The
RED has not been finalized. ATSDR's minimal risk level (MRL), presented in its 199S toxicological
profile for disulfoton, appears to be based on the same 1985 study used in the derivation of the IRIS RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: ATSDR derived an intermediate inhalation MRL for disulfoton (1995) based on an neurotoxicity
study in rats published in 1980.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
No literature search was necessary.
F-95
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Endosulfan (CAS No. 115-29-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for endosulfan was derived (1993) does not appear to contain
study data that could potentially produce a change in the RfD.
A review of the EPA Office of Pesticide Programs (OPP) Reregistration Eligibility Decision (RED)
(2002), the ATSDR Toxicological Profile (2000), and a literature search conducted for the years 1999 to
2002 identified no new studies that would be directly useful in the derivation of an RfD for endosulfan.
The RED RfD and ATSDR's oral minimal risk level (MRL) are based on the same 2-year dietary study in
rats (1989) used in the derivation of the IRIS RfD. The literature search did identify two reproductive and
developmental toxicity studies in rats (1999, 2000); however, administered dose levels and the only
reported observed effect level (decreased sperm production in male offspring) were at levels comparable
to those in the 1989 study on which the IRIS RfD is based.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
Eight documents were categorized as being of unknown relevance.
F-96
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Endothall (CAS No. 145-73-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for endothall was derived (1986) may contain study data that
could potentially produce a change in the RfD.
The IRIS RfD for endothall was derived based on a 2-year dietary study in dogs (using disodmm
endothall) (1965). EPA Office of Pesticide Programs (OPP) has initiated a reassessment of the health
risks resulting from exposure to endothall; to what extent this reassessment was prompted by new effects
information is unknown2. A literature search conducted for the years 198S to 2002 identified a
developmental toxicity study in rats (1995) that may be useful in the derivation of an RfD for endothall.
Only an abstract with summary findings of this developmental toxicity study has been published.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
Nine documents were categorized as being of unknown relevance.
2EPA. 2002. Six-Year Review, Chemical Contaminants, Health Effects Technical Support
Document. Office of Water, Office of Science and Technology. EPA Publication No. 822-R-01-001.
February 2002.
F-97
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Screening-Level Review of the IRIS Database Phase 11 September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Epichlorohydrin (CAS No. 106-89-8)
Oral Reference Dose (RfD)
An oral RfD for epichlorohydrin is not available because EPA determined that the data were inadequate
for derivation of an RfD (latest assessment 1992). The oral RfD and supporting information previously on
IRIS were withdrawn pending further review by the RfD/RfC work group. The literature made available
since 1992 contains study data that could potentially be used to develop an RfD.
A literature search conducted for the years 1991 to 2002 identified a 90-day oral toxicity study in
Sprague-Dawley rats (1996) and a 2-year toxicity study (oral gavage) in SPF Wistar RJV:Tox(M) rats
(completed in 1982 and later submitted to EPA). A published version of this 1982 2-year study was
considered by EPA in the cancer assessment; however, it is not clear if the study was included in the
evaluation of noncancer effects.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for epichlorohydrin was derived (1991) contains study
data that could potentially produce a change in the RfC.
The IRIS RfC for epichlorohydrin was derived based on a 90-day inhalation study in B6C3F1 mice,
F344/N rats, and Sprague-Dawley rats published in 1979. A literature search conducted for the years 1990
to 2002 identified five cohort studies (1990, 1994, 1996) and an occupational exposure study (1993) of
workers exposed to epichlorohydrin. The abstracts for the epidemiologic studies are not explicit,
however, about the nature and extent of the dose-response data.
Note: Most of the epidemiologic studies identified in this literature search are also cited in the
International Agency for Research on Cancer (IARC) Monograph (1999).
Oral Slope Factor (CSF)
The literature published since the oral CSF for epichlorohydrin was derived (1986) does not appear to
contain study data that could potentially produce a change in the CSF A literature search conducted for
the years 1998 to 2002 identified no new studies that would be directly useful in the derivation of an CSF
for epichlorohydrin. No oral carcinogenicity studies were identified in the IARC Monograph (1999).
Inhalation Unit Risk (IUR)
The literature published since the inhalation IUR for epichlorohydrin was derived (1986) contains study
data that could potentially produce a change in the IUR.
The IRIS IUR for epichlorohydrin was derived based on a 30-day inhalation study in Sprague-Dawley
rats published in 1980 and a retrospective cohort study of workers from epichlorohydrin-producing plants
published in 1981. The IARC Monograph (1999) identified six new epidemiologic studies.
F-98
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Epichlorohydrin (CAS No. 106-89-8)
(continued)
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1986) contains study data that could potentially produce a change in the WOE.
The IRIS WOE for epichlorohydrin was derived based on inadequate human data and sufficient evidence
of carcinogenicity in animals. The IARC Monograph (1999) identified six new epidemiologic studies and
characterized epichlorohydrin as Group 2A—probably carcinogenic to humans.
In addition, a literature search conducted for the years 1990 to 2002 identified studies not included in the
IARC Monograph; however, it does not appear that any of these studies would produce a change in the
WOE classification. Studies include: an in vitro sister chromatid exchange induction study in human
lymphocytes (2000), evaluations of DNA adducts and other genetic effects in workers exposed to
epichlorohydrin (1997, 1999, 2000), a DNA adduct induction study in Wistar rats (1999), in vitro DNA
strand break (and repair) studies in human diploid fibroblasts (1997, 1998), genotoxicity studies using the
micronucleus test in mice (1991, 1992), a DNA adduct induction study using calf thymus DNA (1996),
and microbial genotoxicity studies (1990, 1991, 1992, 1993 [two studies], 1994). Overall, the studies
reported positive findings.
Unknown Relevance
Seventy-eight documents, 39 of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Among these studies are "Epichlorohydrin, Subchronic
Studies: IV. The Effects of Maternally Inhaled Epichlorohydrin on Rat and Rabbit Embryonal and Fetal
Development, 8(d) Submission," "Initial Submission: Inhalation Carcinogenicity of Epichlorohydrin with
Cover Letter Dated 10/19/92," "Initial Submission: Carcinogencitiy Study of Epichlorohydrin in Rats
(Final Report) with Cover Letter Data 05/27/92," "A Case-Control Study of Lung Cancer and Central
Nervous System Neoplasms among Chemical Workers, with Cover Letter Data 10/20/92," and
"Epichlorohydrin, Subchronic Studies: LA. 90-Day Inhalation Study in Laboratory Rodents (Final
Report) 8(d) Submission."
F-99
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,2-Epoxybutane (CAS No. 106-88-7)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC was derived (1991) does not appear to contain study
data that could potentially produce a change in the RfC. A literature search conducted for the years 1990
to 2002 identified no new studies that would be directly useful in the derivation of an RfC for 1,2-
epoxybutane.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) characterized 1,2-
epoxybutane as Group 2B—possibly carcinogenic to humans. Carcinogenesis studies published by the
National Toxicology Program (NTP) (1988) indicated clear evidence of carcinogenicity in male F344/N
rats, equivocal evidence of carcinogenicity in female F344/N rats, and no evidence of carcinogenicity in
male or female B6C3F1 mice.
Unknown Relevance
Thirteen documents, four of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-100
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Ethephon (CAS No. 16672-87-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ethephon was denved (1988) does not appear to contain
study data that could potentially produce a change in the RfD. A review of the EPA Office of Pesticide
Programs (OPP) Reregistration Eligibility Decision (RED) (1995) and a literature search conducted for
the years 1994 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for ethephon. The principal study used to derive the RED RfD was considered an additional study in
establishing the IRIS RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In the 1995 RED, OPP classified ethephon as Group D—not classifiable as to human
carcinogenicity.
Unknown Relevance
Three documents (1997, 1998, 1999) listed in the Computer Retrieval of Information on Scientific
Projects (CRISP) database (a biomedical database of research projects supported by the Department of
Health and Human Services) were categorized as being of unknown relevance.
F-101
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
S-Ethyl dipropylthiocarbamate (CAS No. 759-94-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for S-ethyl dipropylthiocarbamate was derived (1987) does
not appear to contain study data that could potentially produce a change in the RfD. A review of the EPA
Office of Pesticide Programs (OPP) Reregistration Eligibility Decision (RED) (1999) and a literature
search conducted for the years 1998 to 2002 identified no new studies that would be directly useful in the
derivation of an RfD for S-ethyl dipropylthiocarbamate. The RED RfD is based on the same two-
generation reproductive toxicity study in rats (1986) that was used to derive the IRIS RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: The 1999 RED notes that S-ethyl dipropylthiocarbamate "was not mutagenic and did not exhibit
any oncogenic potential in a mouse oncogemcity study and two combined chronic toxicity/oncogenicity
studies in rat."
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-102
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Ethyl p-nitrophenyl phenylphosphorothioate (CAS No. 2104-64-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ethyl p-nitrophenyl phenylphosphorothioate was derived
(1986) does not appear to contain study data that could potentially produce a change in the RfD. A
literature search conducted for the years 1985 to 2002 identified no new studies that would be directly
useful in the derivation of an RfD for ethyl p-nitrophenyl phenylphosphorothioate.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Seven documents, five of which were submissions to EPA's Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including "Effects of Some Organophosphate Pesticides on
the Murine Immune System Following Subchronic Exposure "
F-103
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Ethylene glycol monobutyl ether (CAS No. 111-76-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ethylene glycol monobutyl ether was derived (1999) does
not appear to contain study data that could potentially produce a change in the RfD. A literature search
conducted for the years 1998 to 2002 identified no new studies that would be directly useful in the
derivation of an RfD for ethylene glycol monobutyl ether.
Inhalation Reference Concentration (RfC)
The literature published since the RfC for ethylene glycol monobutyl ether was derived (1999) does not
appear to contain study data that could potentially produce a change in the RfD. The IRIS RfC for
ethylene glycol monobutyl ether was derived based on the application of a benchmark dose assessment
and physiologically-based pharmacokinetic (PBPK) model to the results of a subchronic rat inhalation
study in which the critical effect was changes in red blood cell count (1998). A literature search
conducted for the years 1998 to 2002 identified two publications (1999,2000) that appear to contain
findings from the National Toxicology Program (NTP) subchronic inhalation study considered in the
IRIS assessment. The 1999 publication reported disseminated thrombosis and bone infarction in exposed
female F344/N rats and the 2000 publication reported dental pulp infarction in female rats.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1999) does not appear to contain study data that could produce a change in the WOE classification. A
literature search conducted for the years 1998 to 2002 identified no new studies that would be directly
useful in the derivation of a WOE for ethylene glycol monobutyl ether.
Unknown Relevance
Twenty-two documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance These included "Effects of Exposure to Glycol Ethers on
Shipyard Painters: Hematologic Effects and Male Production and Evaluation of Exposure to Ethylene
Glycol Ether in Shipyard Painting," "Pathology Working Gp Report and Summary Pathology Tables for
Ongoing Chronic Inhalation Study on Ethylene Glycol Monobutyl Ether," two reports on "A Teratologic
Evaluation of Ethylene Glycol Monobutyl Ether in Fischer 344 Rats & New Zealand White Rabbits
Following Inhalation Exposure," "Inhalation Teratologic Potential of Ethylene Glycol Monobutyl Ether
in the Rat," and four documents related to studies of reproductive effects.
F-104
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Ethylene glycol monobutyl ether (CAS No. 111-76-2)
(continued)
Note: A literature search conducted for the years 1998 to 2002 identified a 2000 NTP technical report on
"Toxicology and carcinogenesis studies of 2-Butoxyethanol [CAS No 111-76-2] in F344/N rats and
B6C3F1 mice (inhalation studies)." However, the IRIS RfC and WOE classification are based on a 1998
draft publication of the same report, and the 1998 NTP report is cited as an additional study for the IRIS
RfD assessment.
F-105
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Ethylphthalyl ethylglycolate (CAS No. 84-72-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ethylphthalyl ethylglycolate was derived (1985) does not
appear to contain study data that could potentially produce a change in the RfD. A literature search
conducted for the years 1984 to 2002 identified no new studies that would be directly useful in the
derivation of an RfD for ethylphthalyl ethylglycolate.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categonzed as being of unknown relevance.
F-106
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Fluridone (CAS No. 59756-60-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for fluridone was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1987 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
fluridone.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Five documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Although reported as having a submission date of 1992, these
studies were likely part of the series of toxicity studies conducted by Eli Lilly and Company between
1978 and 1986 and considered by EPA in the IRIS assessment.
Note: Because of the large number of references found in the Toxline literature search using standard
protocol (over 6,900 results for search: CAS number, toxic*), in the custom search screen, fluridone's
CAS number (59756-60-4) and relevant search term were entered and searching was conducted with the
"singular and plural forms" search option, rather than the "word variants" search option. Because a
synonym of fluridone is "sonar", many of the studies identified were not related to the chemical sonar.
Only studies containing the CAS number were retained in the EndNote database.
F-107
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Flurprimidol (CAS No. 56425-91-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for flurprimidol was derived (1989) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1988 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
flurprimidol.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Fifteen documents, all of which were submissions to EPA Office of Toxic Substances (OTS) and appear
to contain laboratory findings from acute toxicity studies, were categorized as being of unknown
relevance
F-108
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Fluvalinate (CAS No. 69409-94-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for fluvalinate was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1986 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
fluvalinate.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Ten documents were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (approximately 435),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-109
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Fomesafen (CAS No. 72178-02-0)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF was derived (1987) does not appear to contain study data that
could potentially produce a change in the CSF. A literature search conducted for the years 1986 to 2002
identified no new studies that would be directly useful in the derivation of a CSF for fomesafen.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1987) contains study data that could potentially produce a change in the WOE.
The IRIS WOE for fomesafen was derived based on a 2-year dietary study in mice (1985). A literature
search conducted for the years 1986 to 2002 identified two studies by Czech investigators (1998 [in
Czech], 1999) that examined hepatocellular carcinoma and preneoplastic and morphologic changes in the
liver of mice administered fomesafen for 3 to 14 months.
Unknown Relevance
Two documents, both submissions to EPA Office of Toxic Substances (OTS), were categorized as being
of unknown relevance.
F-110
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Formic acid (CAS No. 64-18-6)
Oral Reference Dose (RfD)
An oral RfD for formic acid is not available because EPA determined that the data were insufficient to
support development of an RfD (latest assessment 1990). The oral RfD and supporting information
previously on IRIS were withdrawn. The literature published since 1990 does not appear to contain study
data that could be used to develop an RfD.
A literature search conducted for the years 1989 to 2002 identified no new studies that would be directly
useful in the derivation of an RfD for formic acid. The literature search identified a study (1995) that
examined the role of formate in the development of exencephaly in pregnant and embryonic CD-I mice,
following methanol exposure by gavage3. Nine developmental toxicity studies of formic acid on embryos
in culture were also identified (1993, 1994, 1995, 1996, 1998).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1989 to 2002 identified a National Toxicology Program
(NTP) technical report of the toxicity of formic acid on F344/N rats and B6C3F1 mice following 2- and
13-week whole body/inhalation exposures (1992). A 1995 study examined the role of formate in the
development of exencephaly in pregnant and embryonic CD-I mice, following methanol exposure by
inhalation1.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1989 to 2002 identified three mutagenicity studies of
formic acid. None of these studies provided evidence that formic acid is genotoxic.
Unknown Relevance
Five documents were categorized as being of unknown relevance.
3Formic acid, also called formate, is the primary metabolite of methanol and is often the subject
of methanol toxicity studies. Therefore, the literature search reviewed studies related to methanol toxicity,
generally coding relevant studies as 5, "other toxicity studies not directly useful for establishing IRIS
toxicity values."
F-lll
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Formic acid (CAS No. 64-18-6)
(continued)
Note: A biopesticide registration eligibility document (1999) concluded that chronic toxicity tests,
"designed to assess mammalian mutagenic potential and impacts on the immune system, chronic feeding
studies, and carcinogenicity studies, have been waived because formic acid is a naturally occurring
substance in honey and other foods, and is cleared under 21 CFR 172.515 as a Direct Food Additive for
use as a flavoring agent in a wide range of processed foods."
Note: A literature search conducted for the years 1989 to 2002 identified one study carried out to develop,
apply, and validate a physiologically-based pharmacokinetic (PBPK) model for formic acid (1996).
Note: Because of the large number of references found in the literature search (approximately 800),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*
Any references not containing one of these search terms were coded as N/A.
F-112
-------
Screening-Level Review of the IRIS Database Phase [I September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Furmecyclox (CAS No. 60568-05-0)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for furmecyclox was derived (1987) does not appear to contain
study data that could potentially produce a change in the CSF. A literature search conducted for the years
1986 to 2002 identified no new studies that would be directly useful in the derivation of a CSF for
furmecyclox.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1987) does not appear to contain study data that could produce a change in the WOE. A literature search
conducted for the years 1986 to 2002 identified no new studies that would be directly useful in
establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-113
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Glycidaldehyde (CAS No. 765-34-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for glycidaldehyde was derived (1987) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1986 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for glycidaldehyde.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1991) does not appear to contain study data that could produce a change in the WOE. An International
Agency for Research on Cancer (IARC) Monograph (1999) characterized glycidaldehyde as Group
2B—possibly carcinogenic to humans. A literature search conducted for the years 1986 to 2002 identified
no new studies that would be directly useful in establishing a WOE classification.
Unknown Relevance
One document, "Identification of DNA Adducts in Mouse Skin Treated with Glycidaldehyde in-Vivo,"
was categorized as being of unknown relevance
F-114
-------
Screenme-Level Review of the IRIS Database Phase H September 2002
Evaluation of the Recent Literature and Determination of Currency for:
n-Heptane (CAS No. 142-82-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1991) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1990 to 2002 identified one genotoxicity study (1992) that
investigated the gene mutation, chromosome aberrations, and DNA repair associated with numerous
industrial solvents, including n-heptane.
Unknown Relevance
Seven documents, two of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-115
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
alpha-Hexachlorocyclohexane (CAS No. 319-84-6)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: The ATSDR Toxicological Profile (1999) derived a chronic oral minimal risk level (MRL) based
on hepatic effects reported in a lifetime dietary study in Wistar rats (1950).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for alpha-hexachlorocyclohexane was derived (1986) does not
appear to contain study data that could potentially produce a change in the CSF. Review of the ATSDR
Toxicological Profile (1999) and a literature search conducted for the years 1998 to 2002 identified no
new studies that would be directly useful in the derivation of a CSF for alpha-hexachlorocyclohexane.
Inhalation Unit Risk (IUR)
The literature published since the IUR for alpha-hexachlorocyclohexane was derived (1986) does not
appear to contain study data that could potentially produce a change in the IUR. Review of the ATSDR
Toxicological Profile (1999) and a literature search conducted for the years 1998 to 2002 identified no
new studies that would be directly useful in the derivation of an IUR for alpha-hexachlorocyclohexane.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1986) does not appear to contain study data that could produce a change in the WOE. An International
Agency for Research on Cancer (IARC) Monograph (1987) classified alpha-hexachlorocyclohexane as
Group 2B—possibly carcinogenic to humans—and the National Toxicology Program (NTP) Second
Annual Report on Carcinogens (1981) lists alpha-hexachlorocyclohexane as reasonably anticipated to be
a human carcinogen. Review of the ATSDR Toxicological Profile (1999) and a literature search
conducted for the years 1998 to 2002 identified no new studies that would be directly useful in
establishing a WOE classification.
Unknown Relevance
Four documents were categorized as being of unknown relevance. Among these studies are
"Organochlorine exposure and risk of breast cancer" and "Differential toxicity and environmental fates of
hexachlorocyclohexane isomers."
F-116
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
beta-Hexachlorocyclohexane (CAS No. 319-85-7)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: The ATSDR Toxicological Profile (1999) derived an intermediate oral minimal risk level (MRL)
based on hepatic effects reported in a 13-week dietary study in Wistar rats (1986).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for beta-hexachlorocyclohexane was derived (1986) does not
appear to contain study data that could potentially produce a change in the CSF. The IRIS CSF for beta-
hexachlorocyclohexane was derived based on a 110-week dietary study in CF1 mice published in 1973. A
review of the ATSDR Toxicological Profile (1999) and a literature search conducted for the years 1998 to
2002 identified two epidemiology studies of beta-hexachlorocyclohexane exposure and breast cancer
(1998, 1999). Neither study found statistically significant increases in breast cancer associated with
exposure to beta-hexachlorocyclohexane.
Inhalation Unit Risk (IUR)
The literature published since the IUR for beta-hexachlorocyclohexane was derived (1986) does not
appear to contain study data that could potentially produce a change in the IUR A review of the ATSDR
Toxicological Profile (1999) and a literature search conducted for the years 1998 to 2002 identified no
new studies that would be directly useful in the derivation of an IUR for beta-hexachlorocyclohexane.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1986) contains study data that could potentially produce a change in the WOE.
The IRIS WOE for beta-hexachlorocyclohexane was derived based on a 110-week dietary study in CF1
mice published in 1973. An International Agency for Research on Cancer (IARC) Monograph (1987)
classified beta-hexachlorocyclohexane as Group 2B—possibly carcinogenic to humans—and the National
Toxicology Program (NTP) Second Annual Report on Carcinogens (1981) lists beta-
hexachlorocyclohexane as reasonably anticipated to be a human carcinogen. A review of ATSDR
Toxicological Profile (1999) and a literature search conducted for the years 1998 to 2002 identified an
epidemiology study that found a slight, but not statistically significant, increase in breast cancer
associated with exposure to beta-hexachlorocyclohexane (1998). A case-control study comparing beta-
hexachlorocyclohexane levels in breast adipose tissue from incident breast carcinoma cases and controls
concluded that increasing adipose tissue levels of beta-hexachlorocyclohexane are not associated with
increased risk of breast carcinomas (1999).
F-117
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
beta-Hexachlorocyclohexane (CAS No. 319-85-7)
(continued)
Unknown Relevance
Five documents were categorized as being of unknown relevance. Among these studies are "Differential
toxicity and environmental fates of hexachlorocyclohexane" and "Partitioning coefficients of
organochlorine pesticides between mother blood serum and umbilical blood serum."
F-118
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Hexachlorophene (CAS No. 70-30-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for hexachlorophene was derived (1988) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for hexachlorophene was derived based on a 13-week dietary study in dogs (1974). A
literature search conducted for the years 1987 to 2002 identified another subchronic (90-day) oral toxicity
study in male weanling Sprague-Dawley rats (1991).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: A literature search conducted for the years 1987 to 2002 found one chronic inhalation
carcmogenicity study in albino noninbred rats exposed to hexachlorophene (1987; published in Russian).
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1987) characterized
hexachlorophene as Group 3— not classifiable as to carcinogenicity in humans. A literature search
conducted for the years 1987 to 2002 identified one chronic inhalation carcinogenicity study in albino
noninbred rats exposed to hexachlorophene (1987; published in Russian).
Unknown Relevance
Eight documents, two of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance Among these studies are "Concerning the Carcinogenicity of
Hexachlorophene,""Neurotoxicity of Hexachlorophene in Mice," and "Hexachlorophene Intoxication in
F344 Rats."
F-119
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,6-Hexamethylene diisocyanate (CAS No. 822-06-0)
Oral Reference Dose (RID)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
The literature published since the oral RfC for 1,6-hexamethylene diisocyanate was derived (1992) does
not appear to contain study data that could potentially produce a change in the RfC.
The IRIS RfC for 1,6-hexamethylene diisocyanate was derived based on a chronic inhalation study in rats
published in 1989. Review of the ATSDR Toxicological Profile (1998) and a literature search conducted
for the years 1997 to 2002 identified no new chronic toxicity studies, but identified a subchronic, whole-
body inhalation study in adult male Sprague-Dawley rats (1998) and two
reproductive/developmental/neurotoxicity studies in Sprague-Dawley rats exposed via whole-body
inhalation (20004). The two developmental and reproductive toxicity studies reported no developmental
toxicity at any dose and maternal effects only at levels above the lowest-observed-adverse-effects-level
(LOAEL) found in the principal study for the IRIS RfC. In addition, in its 1998 Toxicological Profile,
ATSDR derived a chronic inhalation minimal risk level (MRL) based on the principal study used for the
IRIS RfC.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1997 to 2002 identified two genotoxicity studies (1997,
2000).
Unknown Relevance
Twenty-three studies, all of which were either submissions to EPA Office of Toxic Substances (OTS) or
to the Computer Retrieval of Information on Scientific Projects (CRISP) database (a biomedical database
of research projects supported by the Department of Health and Human Services), were categorized as
being of unknown relevance. Among these studies are "A Developmental Toxicity Study with 1,6-
Hexamethylene Diisocyanate (Hdi) in the Sprague-Dawley Rat,""Chronic Inhalation Study with Hdi (1,6-
Hexamethylene Diisocyanate) in the Rat," and "Toxicological Investigations of Desmodur H
(Hexamethylene Diisocyanate)."
4It is unclear from the abstract whether these are the same or separate studies.
F-120
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Hexazinone (CAS No. 51235-04-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for hexazinone was derived (1987) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for hexazinone was derived based on a 2-year dietary study in rats completed in 1977. An
uncertainty factor was assigned based on the lack of a chronic exposure study in an apparently more
sensitive species (dogs). In the 1994 Reregistration Eligibility Decision (RED), EPA Office of Pesticide
Programs (OPP) derived an RfD based on a chronic (1-year) dietary study in dogs (1991).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS
Note: In the 1994 RED, the OPP Carcinogenicity Peer Review Committee classified hexazinone as Group
D—not classifiable as to human carcinogenicity.
Unknown Relevance
No literature search was necessary.
F-121
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Hydrazine/Hydrazine sulfate (CAS No. 302-01-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: ATSDR derived an intermediate inhalation minimal risk level MRL in its 1997 lexicological
Profile.
Oral Slope Factor (CSF)
The literature published since the CSF for hydrazine was derived (1987) contains study data that could
potentially produce a change in the CSF
The IRIS CSF for hydrazine was derived based on a gavage study in mice (1970). An International
Agency for Research on Cancer (IARC) Monograph (1999) identified three 2-year drinking-water studies
in NMRI mice (1990), Wistar rats (1988), and Syrian hamsters (1987).
Inhalation Unit Risk (IUR)
The literature published since the IUR for hydrazine was derived (1987) contains study data that could
potentially produce a change in the IUR.
The IRIS IUR for hydrazine was derived based on a 1-year study in rats published in 1981. An IARC
Monograph (1999) identified a subchronic study in Fisher 344 rats (1995) and a cancer mortality study in
male workers at a hydrazine plant (1995).
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1987) does not appear to contain study data that could produce a change in the WOE. An IARC
Monograph (1999) characterized hydrazine as Group 2B—possibly carcinogenic to humans.
Unknown Relevance
No literature search was necessary.
F-122
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Hydroquinone (CAS No. 123-31-9)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A review of the World Health Organization (WHO) Environmental Health Criteria (1994) and a
literature search conducted for the years 1993 to 2002 identified a developmental toxicity gavage study in
female rats (1992), a reproductive toxicity study in rabbits (1992), a two-generation reproductive toxicity
study in CD Sprague-Dawley rats exposed to hydroquinone via gavage (1993), and a 2-year dietary study
in male 344 rats (1996).
Inhalation Reference Concentration (RfC)
An inhalation RfC for hydroquinone is not available because EPA determined that the data were
insufficient to support development of an RfC (latest assessment 1990). A review of the WHO
Environmental Health Criteria (1994) and the literature published conducted for the years 1993 to 2002
identified no new studies that would be directly relevant in the derivation of an RfC.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A review of the WHO Environmental Health Criteria (1994) and a literature search conducted for
the years 1993 to 2002 identified a 2-year dietary study in male F344 rats (1996) and a shorter term (6-
week) study to better characterize the early development of renal toxicity in male and female F344 rats
and male SD rats (1994).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: A literature search conducted for the years 1993 to 2002 identified a cancer mortality study of male
and female employees exposed to hydroquinone dust and vapor (1995).
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) characterized
hydroquinone as Group 3—not classifiable as to carcinogenicity in humans. A review of the WHO
Environmental Health Criteria (1994) and a literature search conducted for the years 1993 to 2002
identified the animal assays described under the CSF discussion above, as well as several genotoxicity
assays, including studies of DNA adduct formation, induction of micronuclei, sister chromatid exchange,
chromosomal loss/breakage, cell transformation, gene mutations, and aneuploidy. Most studies reported
positive results; a few studies demonstrated hydroquinone's ability to inhibit the induction of micronuclei.
F-123
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Hydroquinone (CAS No. 123-31-9)
(continued)
Unknown Relevance
Forty-three documents, 8 of which were submissions to EPA Office of Toxic Substances (OTS) and 25 of
which were submissions to the Computer Retrieval of Information on Scientific Projects (CRISP)
database (a biomedical database of research projects supported by the Department of Health and Human
Services), were categorized as being of unknown relevance.
Note: A literature search conducted for the years 1993 to 2002 identified many studies that examined the
cytotoxic mechanisms and the mechanisms of tumor induction of hydroquinone and parent compounds
(e g., benzene)5. In addition, the search identified one study that developed a physiologically-based
pharmacokinetic (PBPK) model for hydroquinone (2000).
Note: Because of the large number of references found in the literature search (approximately 850),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
3 Hydroquinone is a primary metabolite of benzene and is often the subject of benzene toxicity
studies. Therefore, the literature search identified studies related to benzene toxicity; relevant studies were
generally assigned a code of 5, "other toxicity studies not directly useful for establishing IRIS toxicity
values."
F-124
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Isobutyl alcohol (CAS No. 78-83-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for isobutyl alcohol was derived (1986) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for isobutyl alcohol was derived based on a subchronic oral toxicity study in rats (1986). A
literature search conducted for the years 1985 to 2002 identified one new subchronic toxicity study—a
90-day drinking water study in Wistar rats (1997).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1985 to 2002 identified a prenatal inhalation toxicity
study in Wistar rats and Himalayan rabbits (1995) and a 90-day neurotoxicity study in Sprague-Dawley
rats exposed to isobutyl alcohol vapors (1999).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
Thirty-four documents, 23 of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance Among these studies are "Lymphocyte Subpopulations in
Solvent-Exposed Workers," "Mutagenicity Evaluation of Isobutanol Alcohol in the Ames
Salmonella/Microsome Plate Test (Final Report)," "Mutagenicity Evaluation of Isobutyl Alcohol in the
Mouse Lymphoma Forward Mutation Assay (Final Report)," "Initial Submission: Experimental
Investigation of Carcinogenic Effects of Solvents Exemplified by 1-Propanol, 2-Methyl-l-Propanol, and
3-Methyl-l-Butanol," and "Rat Oral Subchronic Toxicity Study with Isobutyl Alcohol (Final Report)"
F-125
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Lead and compounds (inorganic) (CAS No. 7439-92-1)
Oral Reference Dose (RfD)
An oral RfD is not available because EPA considered deriving an RfD inappropriate since some health
effects occur at blood lead levels so low as to be essentially without a threshold (latest assessment 1985).
The literature published since 1985 contains study data that could be relevant to the development of an
RfD. In its 1999 Toxicological Profile, ATSDR identified numerous studies relating exposure to lead and
internal lead doses in humans and several post-1985 systemic, neurological, developmental, and
reproductive toxicity studies in rats (primarily) and monkeys. ATSDR did not derive a minimal risk level
(MRL) for lead, but did develop an approach for assessing lead exposures using regression analysis with
multi-route uptake parameters to estimate blood lead levels. In addition, EPA's Integrated Exposure
Uptake Biokinetic Model (IEUBK) was developed and refined since the last IRIS update.
Inhalation Reference Concentration (RFC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Risk Factor (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1988) does not appear to contain study data that would produce a change in the WOE.
The IRIS WOE for lead and compounds (inorganic) was derived based on sufficient evidence of
carcinogenicity in animals (ten rat bioassays and one mouse assay have shown statistically significant
increases in renal tumors with dietary and subcutaneous exposure to several soluble lead salts) and
inadequate human evidence. An International Agency for Research on Cancer (IARC) Monograph (1987)
characterized lead as Group 2B—possibly carcinogenic to humans. The World Health Organization
(WHO) Environmental Health Criteria (1995) and the ATSDR Toxicological Profile (1995) identified no
new animal or human carcinogenicity studies.
Unknown Relevance
No literature search was necessary.
F-126
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
d-Limonene (CAS No. 5989-27-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An inhalation RfC for d-limonene is not available because EPA determined that the data were inadequate
for derivation of an RfC (latest assessment 1993). The literature published since 1993 does not appear to
contain study data that could be used to develop an RfC.
EPA Office of Pesticide Programs (OPP) issued a Reregistration Eligibility Decision (RED) for limonene
in 1994 but did not derive an RfC. (The RED considers limonene the same as d-limonene for toxicity
assessment purposes.) A literature search conducted for the years 1993 to 2002 identified no new studies
that would be directly useful in the derivation of an RfC for d-limonene.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) characterized d-
limonene as Group 3—not classifiable as to carcinogenicity in humans.
Unknown Relevance
Six documents were categorized as being of unknown relevance.
F-127
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Malathion (CAS No. 121-75-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for malathion was derived (1987) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for malathion was derived based on a subchronic dietary study in humans (1962). In its
2000 Reregistration Eligibility Decision (RED), EPA Office of Pesticide Programs (OPP) derived an RfD
for malathion based on a chronic (2-year) oral toxicity/oncogenicity study in Fischer-344 rats (1996;
unpublished). In its 2001 Toxicological Profile, ATSDR derived a chronic oral minimal risk level (MRL)
based on the same 2-year study. (RED Status: as of February 2001, the 60-day public participation period
was completed.)
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1987) classified malathion
as not classifiable as Group 3—to carcinogenicity in humans. In addition, EPA OPP Cancer Assessment
Review Committee classified malathion as having "suggestive evidence of carcinogenicity, but not
sufficient to assess human carcinogenic potential," as reported in the preliminary risk assessment (2000)
for the RED.
Unknown Relevance
No literature search was necessary.
F-128
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Maleic anhydride (CAS No. 108-31-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD was derived (1988) contains study data that could potentially
produce a change in the RfD.
The IRIS RfD for maleic anhydride was derived based on two chronic studies in rats (1982,1983). A
literature search conducted for the years 1987 to 2002 identified a teratology and multigeneration
reproduction study in rats completed by Monsanto Co. in 1991 and submitted to EPA Office of Toxic
Substances (OTS) in 1992.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1987 to 2002 identified a 6-month inhalation toxicity
study in Engle hamsters, CD rats, and Rhesus monkeys (1988) and a retrospective cohort study of
workers at resin and cushion flooring factories exposed to maleic anhydride in the air (1995). The
literature search also identified a number of clinical studies related to asthmatic, allergic, and other
immune responses following exposure to maleic anhydride.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
Thirteen documents, seven of which were submissions to EPA OTS, were categorized as being of
unknown relevance.
F-129
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Maleic hydrazide (CAS No. 123-33-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for maleic hydrazide was derived (1986) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for maleic hydrazide was derived based on a 2-year dietary study in SPF Wistar rats
(1981). In its 1994 Reregistration Eligibility Decision (RED), EPA Office of Pesticide Programs (OPP)
derived an oral RfD based on the 1993 recommendations of the OPP RfD/Peer Review Committee. The
RED RfD was based on a 104-week chronic feeding study in Sprague-Dawley rats (1991; an addendum
to the study was published in 1993) and a co-critical 52-week chronic feeding study in beagle dogs (1991;
with supplemental information furnished in 1991). These studies used the potassium salt of maleic
hydrazme (which OPP considers equivalent to maleic hydrazine with respect to applicable toxicity study
requirements).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1987) characterized maleic
hydrazide as Group 3—not classifiable as to carcmogenicity in humans. The 1994 RED reported both
negative and positive mutagenicity assay findings and negative chronic feeding carcinogenicity studies in
rats and mice.
Unknown Relevance
No literature search was necessary.
F-130
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Manganese (CAS No. 7439-96-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for manganese was derived (1995) does not appear to contain
study data that could potentially produce a change in the RfD.
The IRIS RfD for manganese was derived based three human chronic ingestion studies published in 1973,
1987, and 1989. A review of the ATSDR Toxicological Profile (2000) and a literature search conducted
for the years 1999 to 2002 identified no new human chronic studies, but identified developmental and
reproductive toxicity studies in rats (1999, 2000) and mice (2001). In the 2000 Toxicological Profile,
ATSDR indicated that health effects data are not sufficient to derive a chronic oral minimal risk level
(MRL).
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for manganese was derived (199S) contains study data
that could potentially produce a change in the RfC.
The IRIS RfC for manganese was derived based on a study of occupational exposure to several different
forms of manganese (manganese dioxide, manganese oxides, and manganese salts). In the 2000
Toxicological Profile, ATSDR derived an inhalation MRL based on the same study, but used a
benchmark dose (BMD) approach. ATSDR also cites more recent studies: a longitudinal follow-up study
by the same author of the principal RfC and MRL study (1999); a study of exposures at a metal producing
plant (reporting a no-observed-adverse-effects-level [NOAEL] consistent with the ones derived using the
ATSDR BMD approach) (1999); and two studies by the same author of neurobehavioral effects in
workers exposed to manganese dusts (1 to 28 years) (199S, 1999). A literature search conducted for the
years 1999 to 2002 identified additional human studies: one study of nervous system function and levels
of total manganese in blood samples of residents exposed from various environmental sources (1999) and
a study of neurological and neurophysiological effects in workers in the ship and electrical industries
(2001).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1988) does not appear to contain study data that could produce a change in the WOE
classification. A review of (1995, 1999) and a literature search conducted for the years 1999 to 2002
identified no new studies that would be directly useful in establishing a WOE classification for
manganese.
F-131
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Manganese (CAS No. 7439-96-5)
(continued)
Unknown Relevance
Six documents were categorized as being of unknown relevance, including a 1999 study entitled,
"Neurotoxic effects of low level exposure to manganese in human populations."
Note: A literature search conducted for the years 1999 to 2002 identified one study carried out to develop,
apply, and validate a biologically-based, dose-response (BBDR) model for manganese (1999), as well as
several other studies of the pharmacokinetics of manganese Several studies evaluated the uptake and
distribution of manganese administered within the olfactory system.
Note: Because of the large number of references found in the literature search (approximately 1,250),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A. Because the literature search
identified a number of studies evaluating the movement of Mn+2 within cells, references containing the
following terms were coded as N/A: MN(2+), Mn(+2), Mn+2, Mn2+, MnDPDP, and MnSOD. In
addition, a number of studies containing the following terms were also coded as N/A: trace metal, trace
element, and nutrition.
F-132
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Screening-Level Review of the IRIS Database Phase II September 2002
' Evaluation of the Recent Literature and Determination of Currency for:
Mepiquat chloride (CAS No. 24307-26-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for mepiquat chloride was derived (1988) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for mepiquat chloride was derived based on a 90-day dietary study in dogs (1977). In the
1997 Reregistration Eligibility Decision (RED), EPA Office of Pesticide Programs (OPP) derived an oral
RfD based on the 1996 recommendations of the OPP RfD/Peer Review Committee. The RED RfD was
based on a 1-year dietary study in dogs (1989 and a supplemental 1994 study)
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: According to the 1997 RED, OPP's RfD/Peer Review Committee classified mepiquat chloride as
Group E—evidence of noncarcinogenicity for humans—in 1996.
Unknown Relevance
No literature search was necessary.
F-133
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Mercuric chloride (CAS No. 7487-94-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for mercuric chloride was derived (1988)6 does not appear to
contain study data that could potentially produce a change in the RfD.
The IRIS RfD for mercuric chloride was derived based on subchronic dietary and subcutaneous studies in
Brown Norway rats, as recommended by a 1987 peer review panel. In the 1999 Toxicological Profile,
ATSDR derived an intermediate oral minimal risk level (MRL) for mercuric chloride based on a 1993
National Toxicity Program (NTP) assay considered in the IRIS assessment. A literature search conducted
for the years 1998 to 2002 identified no chronic toxicity studies, but identified a two-generation
reproductive and fertility study in Sprague-Dawley rats (1998; 2001); reproductive toxicity studies in
C57/BL6 mice (1999) and in Sprague-Dawley rats (1999); and developmental toxicity studies in MRL/lpr
mice (2000) and in post-natal rats (2001). The lowest doses administered in these studies (0.25 to 0.5
milligrams per kilogram body weight per day [mg/kg/day]) were similar to the lowest-observed-adverse-
effects-levels (LOAELs) used to derive the IRIS RfD. As such, data from these studies is unlikely to
produce a change in the IRIS RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
A CSF for mercuric chloride is not available because EPA determined that the data were insufficient to
support development of a CSF (latest assessment 1994). The literature published since 1994 does not
appear to contain study data that could potentially produce a change in the CSF status. A review of the
ATSDR Toxicological Profile (1999) and a literature search conducted for the years 1998 to 2002
identified no new studies that would be directly useful in the derivation of a CSF for mercuric chloride.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1994) does not appear to contain study data that could produce a change in the WOE classification.
A review of the ATSDR Toxicological Profile (1999) and a literature search conducted for the years 1998
to 2002 identified no human studies, but identified several genotoxicity studies of mercuric chloride, as
well as studies of the mechanisms by which mercuric chloride damages DNA.
'The IRIS RfD verification date is listed in the IRIS summary as 11/16/88. A note is also
provided indicating that the IRIS summary was included in the Mercury Study Report to Congress and
that peer review and public comments (1995) were evaluated and considered in the revision and
finalization of the IRIS summary.
F-134
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Mercuric chloride (CAS No. 7487-94-7)
(continued)
Unknown Relevance
Eleven documents were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (approximately 425),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A. In addition, references
containing the term aquatic were also coded as N/A.
F-135
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Screenme-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Elemental mercury (CAS No. 7439-97-6)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for elemental mercury was derived (1990)7 contains
study data that could potentially produce a change in the RfC.
The IRIS RfC for elemental mercury was derived based on human occupational studies published
between 1983 and 1993. In the 1999 Toxicological Profile, ATSDR derived a chronic inhalation minimal
risk level (MRL) for mercury vapor based on one of the studies on which the IRIS RfC is based. A
literature search conducted for the years 1998 to 2002, however, identified additional human study data,
including several studies of chloralkali workers: studies comparing urinary mercury concentration to
effects on thyroid function (2000), renal and immunologic markers (2000), and neuropsychological
effects (1999, 2001), as well as an additional study of a variety of long-term health effects in workers
whose exposure was assessed with historical measurements and personnel records (2001). Other human
studies identified include: a study of reversible color vision loss in workers (1998); a follow-up study of
neurological effects to workers who had past occupational exposures (2000); a study of mercury
exposures and microdamage to kidneys in Venezuelan workers (2001); a study of changes in the
monocyte-macrophage system in workers with low-level exposures (2001); two studies of auditory neuro-
sensory responses (1998) and neuro-otological effects (2002) in adults and children in gold mining areas
of Ecuador; a study of the effects on the activity of red cell enzymes and peripheral blood indices in
workers with chronic exposure (7 months to 32 years) to mercury vapors (2000); and a study of
neurobehavioral effects in Zulu chemical workers (2000). The extent to which useful exposure/dose-
response data are available for a number of these studies is uncertain based on the information provided in
the abstracts.
A review of the ATSDR Toxicological Profile (1999) and a literature search conducted for the years 1998
to 2002 also identified developmental toxicity studies (a noted data gap in the IRIS assessment) in rats
(1992, 2001), in addition to the two studies of Ecuadorian children noted above.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
7The IRIS RfC verification date is listed in the IRIS summary as 4/19/90. A note is also provided
indicating that the IRIS summary was included in the Mercury Study Report to Congress and that peer
review and public comments (199S) were evaluated and considered in the revision and finalization of the
IRIS summary.
F-136
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Elemental mercury (CAS No. 7439-97-6)
(continued)
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1994) does not appear to contain study data that could produce a change in the WOE
classification. A review of the ATSDR Toxicological Profile (1999) and a literature search conducted for
the years 1998 to 2002 identified three genotoxicity studies: a positive micronuclei study in mercury-
exposed workers (1999); a study of chromosomal aberrations (positive) and sister-chromatid exchanges
(inconclusive) in individuals exposed to mercury and other chemical contaminants (1999); and a positive
mutagenicity study that also examined the mechanism by which mutations were induced (1999). The
abstracts of the latter two studies do not reveal the form of mercury investigated.
Unknown Relevance
Thirty-three documents were categorized as being of unknown relevance, including 21 records from the
Computer Retrieval of Information on Scientific Projects (CRISP) database (a biomedical database of
research projects supported by the Department of Health and Human Services) and a study entitled
"Influence of prenatal mercury exposure upon scholastic and psychological test performance: benchmark
analysis of a New Zealand cohort." The documents listed in the CRISP database include descriptions of
proposed or ongoing studies of mercury's immunotoxicity, a study of exposure to dentists entitled
"Chronic Disease Risks Associated with Mercury Vapor Exposure," and "Cellular and Molecular
Toxicity in Human Mammary Cells."
Note: A literature search conducted for the years 1998 to 2002 identified one study carried out to develop,
apply, and validate a physiologically-based pharmacokinetic (PBPK) model for inhaled mercury vapor
(2001).
Note: Because of the large number of references found in the literature search (approximately 2,050),
search results were limited with a secondary search in EndNote to identify references containing terms
related to human studies and carcinogenicity assessments, including: human, worker, subject, patient,
occupa*, epidemiol*, genotox*, mutat*, and mutag*. Any references not containing one of these search
terms were coded as N/A. In addition, references containing the CAS number for mercuric chloride
and/or methylmercury, but not the CAS number for elemental mercury were coded N/A. Studies
containing the terms phytox*, ecotox*, aquatic, sediment, ocean, watershed, ecosystem, patch, or allergy
were also coded as N/A.
F-137
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Merphos oxide (CAS No. 78-48-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for merphos oxide was derived (1987) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for merphos oxide was derived based on a 90-day delayed neurotoxicity study in hens
(1979). An uncertainty factor was assigned based on the lack of a complete database. In its 2000 Interim
Reregistration Eligibility Decision (IRED) and 2000 Human Health Risk Assessment for Tributes
(merphos oxide), EPA Office of Pesticide Programs (OPP) derived an RfD based on a 1-year dietary
study in dogs (1991). In addition, a literature search conducted for the years 1986 to 2002 identified four
multi-generational reproductive and developmental dietary toxicity studies of merphos oxide in Sprague-
Dawley rats (1996, 1998)8.
Inhalation Reference Concentration (RfC)
An inhalation RfC for merphos oxide is not available because EPA determined that the data were
insufficient to support development of an RfD (latest assessment 1992). A literature search conducted for
the years 1986 to 2002 identified no new studies that would be directly useful in the derivation of an RfC
for merphos oxide.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In its 2000 Interim IRED and 2000 Human Health Risk Assessment for Tribufos, OPP's Cancer
Peer Review Committee classified tribufos as an "unlikely human carcinogen" at low doses, but a "likely
carcinogen" at high doses A 1993 hepatocarcinogenicity bioassay in rats found merphos oxide negative
in both number and area analyses.
Unknown Relevance
One document was categorized as being of unknown relevance.
8Note: A literature search for the years 1986 to 2002 was conducted prior to the identification of
the 2000 IRED document for tribufos.
F-138
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Methamidophos (CAS No. 10265-92-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for methamidophos was derived (1987) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for methamidophos was derived based on a 1-year dietary study in dogs completed in
1984. A Registration Eligibility Decision (RED) is being prepared by EPA Office of Pesticide Programs
(OPP), but has not been finalized. In its 2000 Health Effects Risk Assessment, OPP derived an RfD based
on an 8-week toxicity study in rats (1991). (The RED status states that a 60-day public participation
period for risk management decisions has been completed as of April 2000 )
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In its Health Effects Risk Assessment (2000), OPP's Hazard Identification Assessment Review
Committee classified methamidophos as "not likely" to be a human carcinogen
Unknown Relevance
No literature search was necessary.
F-139
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Methyl isocyanate (CAS No. 624-83-9)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An inhalation RfC for methyl isocyanate is not available because EPA determined that the data were
insufficient to support development of an RfC (latest assessment 1990). The literature published since
1990 does not appear to contain study data that could be used to develop an RfC.
A literature search conducted for the years 1989 to 2002, however, identified developmental toxicity
studies: a maternal and fetal toxicity study in Swiss-white mice and Sprague-Dawley rats that received a
single 3-hour exposure to methyl isocyanate (1990) and two teratological studies in Charles Foster rats
that appeared to involve exposure prior to mating only (1994, 1996). In addition, the literature search
identified the findings of a survey of the pregnancy outcomes and health status of 200 children whose
pregnant mothers were exposed to methyl isocyanate vapor during an accidental factory spill in 1984, in
Bhopal, India(1991)9.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1989 to 2002 identified six studies of methyl isocyanate
genotoxicity and one study of its carcinogenicity. A genotoxicity test of the effects of inhalation exposure
on the somatic cells of mice, by means of an in vivo micronucleus test and chromosomal analysis of bone
marrow cells, revealed few structural and numerical abnormalities (1989). A 1992 study demonstrated the
positive genotoxic response of methyl isocyanate-modified DNA in E. coll. A study of germ cell
mutagenicity in inhalation-exposed rats concluded that the observed failure of methyl isocyanate to cause
germ cell mutagenicity was related to its poor biodistribution to the target sites (1992).
'Note: Several follow-up studies (1990 to 1997) report the effects of exposure to high levels of
methyl isocyanate accidentally released in 1984, in Bhopal, India.
F-140
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Screening-Level Review of the IRIS Database Phase I! September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Methyl isocyanate (CAS No. 624-83-9)
(continued)
Two studies of peripheral blood leucocyte cultures, from people exposed to methyl isocyanate gas at
Bhopal, India, were negative for chromosomal aberrations, effects on sister chromatid exchanges, and cell
cycle effects (1992, 1996). One chromosomal survey using standard lymphocyte cultures found that
people exposed to methyl isocyanate repeatedly showed chromosomal translocations at particular
chromosomes (1990). A 1999 study of cancer patterns of the lung, oropharynx, and oral cavity in relation
to methyl isocyanate gas exposure at Bhopal, India, concluded that the full potential of excess risk, if any,
may not manifest for 15 to 20 years after the accident.
Unknown Relevance
Twenty-seven documents, many of which were submissions to EPA Office of Toxic Substances (OTS),
were categorized as being of unknown relevance, including a study titled "An Assessment of Pulmonary
Effects from Long Term Low Level Exposure to Methyl Isocyanate" (1992), and five studies related to
the effects of a high level accidental release of methyl isocyanate in Bhopal, India, in 1984.
F-141
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Methyl methacrylate (CAS No. 80-62-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for methyl methacrylate was derived (1997) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1996 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for methyl methacrylate.
Inhalation Reference Concentration (RfC)
The literature published since the oral RfC for methyl methacrylate was derived (1997) does not appear to
contain study data that could potentially produce a change in the RfC. A literature search conducted for
the years 1996 to 2002 identified no new studies that would be directly useful in the derivation of an RfC
for methyl methacrylate.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (E—evidence of non-carcinogenicity for humans)
was derived (1997) does not appear to contain study data that could potentially produce a change in the
WOE
The IRIS WOE for methyl methacrylate was derived based on the results of four chronic inhalation
studies in three animal species. A literature search conducted for the years 1996 to 2002 identified one
negative Ames test conducted with four different Salmonella strains (1996) and one mortality study of
workers that found no clear evidence that employment at polymethyl methacrylate production factories or
exposure to methyl methacrylate had adversely affected the mortalities of workers (2000). One study of
the relation of malignant neoplasm incidence to the dose of methyl methacrylate in workers found a "clear
correlation" between the dose of methyl methacrylate and the risk for cancer of the genital system in
females and of the lung in males (2000). This study, however, was published only in Russian so the
quality of the study cannot be assessed.
An International Agency for Research on Cancer (IARC) Monograph (1994) characterized methyl
methacylate as Group 3—not classifiable as to carcinogemcity in humans.
Unknown Relevance
Ten documents, most of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-142
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Methyl methacrylate (CAS No. 80-62-6)
(continued)
Note: A literature search conducted for the years 1996 to 2002 identified three studies carried out to
develop, apply, and validate a physiologically-based pharmacokinetic (PBPK) model for methyl
methacrylate (1999, 2001). Two of these studies (1999) are referenced in letters from Methacrylate
Producers Association, Inc. to EPA (2001).
F-143
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2-Methyl-4-chlorophenoxyacetic acid (CAS No. 94-74-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2-methyl-4-chlorophenoxyacetic acid was derived (1988)
contains study data that could potentially produce a change in the RfD.
The IRIS RfD for 2-methyl-4-chlorophenoxyacetic acid was derived based on a 1-year dietary study in
dogs (1986) An uncertainty factor was assigned based on the lack of a complete database on chronic
toxicity (chronic rat and mouse study, and teratogenicity in two species). A literature search conducted for
the years 1987 to 2002 identified a 2-year dietary toxicity study in Wistar rats (1999), an 18-month
dietary toxicity study in ICR mice (1990), and a two-generation dietary reproductive toxicity study in rats
(2001).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1986 to 2002 identified a 2-year dietary oncogenicity
study in Wistar rats and an 18-month chronic toxicity study in IRC mice.
Unknown Relevance
Five documents were categorized as being of unknown relevance, two of which were submissions to EPA
Office of Toxic Substances (OTS).
Note: Because of the large number of references found in the literature search (approximately 665),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-144
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2-(2-Methyl-4-chlorophenoxy)propionic acid (MCPP) (CAS No. 93-65-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for MCPP was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1987 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
MCPP.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Nine documents, five of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-145
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Methylmercury (CAS No. 22967-92-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for methylmercury was derived (2001) does not appear to
contain study data that could potentially produce a change in the RfD.
The IRIS RfD for methylmercury was derived based on a benchmark dose analysis of epidemiological
studies of developmental neuropsychological impairment in a Faroe Islands cohort. The literature search
conducted for the years 1998 to 2002 identified a number of epidemiology and developmental toxicity
studies (published between 1998 and 2001), including a study describing a biologically-based dose
response model for developmental toxicity of methylmercury in rats (2000, 2001) and four developmental
toxicity studies in rats and monkeys (2000). Because the IRIS RfD is based on a robust epidemiologic dat
set in a sensitive subpopulation, these studies are not likely to result in changes in the current RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1994) does not appear to contain study data that could produce a change in the WOE. Review of the
ATSDR Toxicological Profile (1999) and a literature search conducted for the years 1998 to 2002
identified no new studies that would be directly useful in establishing a WOE classification.
Unknown Relevance
Seventeen documents were categorized as being of unknown relevance, including studies titled "Effects
of chronic, intrautenne organic and inorganic mercury intoxication on the epileptogenicity of developing
rats" (2000), "Fetal methylmercury syndrome" (2000), "Effect of low-dose developmental methylmercury
intoxication on epileptogenicity in rats" (2000), and "Porphyrinunas induced by mercury and other
metals" (2001).
Note: Because of the large number of references found in the literature search (approximately 370),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and lexicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-146
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
3-Methylphenol (CAS No. 108-39-4)
Oral Reference Dose (RfD)
Studies made available since the oral RfD for 3-methylphenol was derived (1987) appear to contain data
that could potentially produce a change in the RfD. Unpublished developmental toxicity studies (rats and
rabbits) and a two-generation reproductive toxicity study (rat) were documented in the EPA Office of
Pesticide Programs (OPP) Reregistration Eligibility Decision (RED) (1994), the Toxic Substance Control
Act Test Submission (TSCATS) database, submissions by the Chemical Manufacturers' Association
(Cresols Panel) (CMA) to the IRIS Submission Desk, and the ATSDR Toxicological Profile (1992). A
literature search conducted for the years 1993 to 2002 identified no additional published studies that
would be directly useful in the derivation of an RfD for 3-methylphenol.
ATSDR did not derive a chronic or intermediate oral minimal risk level (MRL) in its 1992 Toxicological
Profile. The OPP RED (1994) indicated that a reference dose was not required because significant
toxicological residues of 3-methylphenol are not expected in food or feed products.
Inhalation Reference Concentration (RfC)
An RfC for 3-methylphenol is not available because EPA determined that the data were insufficient to
support development of an RfC (latest assessment 1991). The RfC and supporting information previously
on IRIS were withdrawn. Review of the ATSDR Toxicological Profile (1992) and the OPP RED (1994)
and a literature search conducted for the years 1993 to 2002 identified no new studies that would be
directly useful in the derivation of an RfC for 3-methylphenol.
Oral Slope Factor (CSV)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1989) does not appear to contain study data that could produce a change in the WOE. Review of the
ATSDR Toxicological Profile (1992) and the OPP RED (1994) and a literature search conducted for the
years 1993 to 2002 identified no new studies that would be directly useful in establishing a WOE
classification. In submissions to the IRIS Submission Desk, however, CMA presented (1993, 1994) data
on genetic assays (generated in response to a Toxic Substance Control Act [TSCA] test rule and from the
National Toxicology Program [NTP] [1988, 1989]).
Unknown Relevance
Five documents, two of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including a study titled "Reproductive toxicology, m-/p-
cresol" (1997).
F-147
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
4-Methylphenol (CAS No. 106-44-5)
Oral Reference Dose (RfD)
The oral RfD and supporting information for 4-methylphenol previously on IRIS were withdrawn in
1991. Unpublished developmental toxicity studies (rats and rabbits) and a two-generation reproductive
toxicity study (rat) not previously considered in the IRIS assessment were documented in the Toxic
Substance Control Act Test Submission (TSCATS) database, submissions by the Chemical
Manufacturers' Association (Cresols Panel) (CMA) to the IRIS Submission Desk, and the ATSDR
Toxicological Profile (1992). These studies could potentially support the development of an RfD for 4-
methylphenol. A literature search conducted for the years 1991 to 2002 identified no additional published
studies that would be directly useful in the derivation of an RfD for 4-methylphenol.
Inhalation Reference Concentration (RfC)
An RfC for 4-methylphenol is not available because EPA determined that the health effects data were
inadequate to support development of an RfC (latest assessment 1991). Review of the ATSDR
Toxicological Profile (1992) and a literature search conducted for the years 1991 to 2002 identified no
new studies that would be directly useful in the derivation of an RfC for 4-methylphenol.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1989) does not appear to contain study data that could produce a change in the WOE. Review of the
ATSDR Toxicological Profile (1992) and a literature search conducted for the years 1991 to 2002
identified no new studies that would be directly useful in establishing a WOE classification. In
submissions to the IRIS Submission Desk, CMA presented data (1993,1994) on genetic assays
(generated in response to a Toxic Substances Control Act [TSCA] test rule and from the National
Toxicology Program [NTP] [1988, 1989]).
Unknown Relevance
Nine documents, three of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including studies titled "Initial Submission: Developmental
Toxicity Evaluation with O-Cresol, M-Cresol, and P-Cresol Administered by Gavage to Sprague-Dawley
Rats with Cover Letter Dated 082492" (1992), "Reproductive toxicology, nv/p-cresol" (1997), and "P-
cresol and uric acid: two old uremic toxins revisited" (1997), and a letter from the Department of Health
and Human Services to EPA (2000) regarding Salmonella assays performed on cresols (with
attachments).
F-148
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
4-Methylphenol (CAS No. 106-44-5)
(continued)
Note: Because of the large number of references found in the literature search (approximately 450),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and lexicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-149
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Metribuzin (CAS No. 21087-64-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for metribuzin was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for metribuzin was derived based on a 2-year dietary study in dogs completed in 1974. The
EPA Office of Pesticide Programs (OPP) Reregistration Eligibility Decision (RED) (1998) presented an
RfD based on a two-generation reproductive toxicity study in Crl:CD BR rats (1988; unpublished) and a
2-year dietary study in Fischer 344 rats (1993; unpublished).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1993) does not appear to contain study data that could produce a change in the WOE. A
review of the 1998 RED and a literature search conducted for the years 1997 to 2002 identified three
negative carcinogenicity studies, two in rats and one in mice (1998) and one positive DNA adduct study
(1997). The 1998 RED reports that in 1995 the OPP/Health Effects Division (HED) RfD Peer Review
Committee classified metribuzin as D—not classifiable as to human carcinogenicity—and did not refer it
to the OPP/HED Cancer Peer Review Committee.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-150
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Nitrate (CAS No. 14797-55-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for nitrate was derived (1990) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for nitrate was derived based on two epidemiological studies showing the incidence of
methemoglobinemia (1950, 1951). A literature search conducted for the years 1989 to 2002 identified
four epidemiological studies, including studies that evaluated the effect of well-water nitrates on infant
health (1991), the correlation between Type-1 diabetes and nitrate in drinking water (1992), the effect of
nitrate in drinking water on thyroid function and volume (1994), and the risk factors associated with
neural tube defects (1996). The literature search also identified several chronic toxicity studies (1993,
1998) and short-term reproductive and developmental studies (1993, 1996, 1997) in animals.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A literature search conducted for the years 1989 to 2002 identified several epidemiological studies
investigating cancer incidence, including two cohort studies of male nitrate fertilizer workers (1991,
1993), a study investigating the relationship between the intake of nitrates, nitrites, and N-
mtrosodimethylamine in adult Finnish men and women (1999), four case-control studies (1993, 1995,
1997, 1998), and a study analyzing the relationship between nitrate levels in drinking water and various
cancers (1998). In addition, three studies explored the relationship between nitrate exposure and
endogenous formation of carcinogenic nitrosamines (1991, 1998, 1998).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS
Note: In addition to the epidemiological studies mentioned above, a literature search conducted for the
years 1989 to 2002 identified studies that may be relevant to the establishment of a WOE classification.
One study evaluated the peripheral lymphocyte HPRT variant frequency in humans exposed to nitrate in
drinking water (1996). Other studies investigated DNA strand break studies in Chinese hamster V79 cells
(1990) and human lymphocytes (1993).
F-151
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Nitrate (CAS No. 14797-55-8)
(continued)
Unknown Relevance
Forty-four documents were categorized as being of unknown relevance. Among these studies are
"Correlation Between the Risk of Gastric Cancer in the Province of Soria, Spain and the Nitrate Content
of Drinking Water," "Risk Factors of Gastric Precancerous Lesions in High-Risk Colombian Population,
II. Nitrate and Nitrite," "Nitrate Content in the Diet of Population, Various Foci of Opisthorchiasis,"
"Nitrate Contamination of Drinking Water, Evaluation of Genotoxic Risk in Human Populations,"
"Consumption of Nitrate, Nitrite, and Nitrosodimethylamine and Cancer of the Larynx, Esophagus, and
Oral Cavity," "Transplacental Transfer of Nitrates and Their Influence on the Human Fetus," "Dietary
Factors and the Risk of Glioma in Adults: Results of a Case-Control Study in Melbourne, Australia,"
"Impact of Nitrates in Drinking Water on Cancer Mortality in Valencia, Spain," "Risk of Non-Hodgkin's
Lymphoma and Drinking Water Nitrate," "Spontaneous Abortions Possibly Related to Ingestion of
Nitrate-Contaminated Well Water, Lagrange County, Indiana," "Childhood IDDM is Linked to Nitrate
Levels in Drinking Water," "Nitrate Intake and Gastric Cancer Risk Results from the Netherlands Cohort
Study," and "Non-Hodgkin's Lymphoma and Nitrate in Drinking Water: A Study in Yorkshire, United
Kingdom."
Note: Because of the large number of references found in the literature search (approximately 4,500),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A. A tertiary search was
conducted to eliminate references also containing phytotox*, ecotox*, and aquatic. Any references
containing one of these search terms were also coded as N/A. Because a large number of references
remained (approximately 1,100), search results were limited to the CAS number. Any references not
containing the CAS number were coded "labanimal/noCAS#." The remaining references (approximately
300) were retained for review.
F-152
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Nitrite (CAS No. 14797-65-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for nitrite was derived (1986) does not appear to contain study
data that could potentially produce a change in the RfD. A literature search conducted for the years 1985
to 2002 identified no new studies that would be directly useful in the denvation of an RfD for nitrite.
Note: The IRIS RfD for nitrite is based on an epidemiological study that evaluated exposure to nitrate
(nitrogen) in contaminated drinking water. A screening-level review of the current health effects literature
for nitrate, which was conducted under this Phase II review of the IRIS database, is also available. This
evaluation indicated that the literature published since 1990 contains study data that could potentially
produce a change in the RfD for nitrate.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A literature search conducted for the years 1985 to 2002 identified a follow-up study investigating
the relationship between the intake of nitrates, nitrites, and n-nitrosodimethylamme and the risk of
colorectal and other gastro-intestmal cancers in Finnish men and women (1999).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1985 to 2002 identified a study evaluating the
teratogenic and mutagenic effects of nitrite on mouse fetuses (1989) and a cohort study investigating the
risk of colorectal and other gastro-intestinal cancers after exposure to nitrite (1999).
Unknown Relevance
Twenty-two documents were categorized as being of unknown relevance Among these studies are
"Nitrite-induced Methemoglobinemia" (1987), "Mammalian Synthesis of Nitrite, Nitrate, Nitric Oxide,
and N-Nitrosating Agents" (1992), "Consumption of Nitrate, Nitrite, and Nitrosodimethylamine and the
Risk of Upper Aerodigestive Tract Cancer" (1995), "Nitrites caused DNA Adduct Formation as Measured
by 32p DNA Radiolabeling and Two-dimensional Thin-layer Chromatography" (1995), and "Induction of
Cell Death in the Intestinal Crypt of Mice Following Oral Administration of Nitrate and Nitrite" (1998).
F-153
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Nitrite (CAS No. 14797-65-0)
(continued)
Note: Because of the large number of references found in the literature search (approximately 3,200),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemic!*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A. A tertiary search was
conducted to eliminate references also containing phytotox*, ecotox*, and aquatic. Any references
containing one of these search terms were also coded as N/A. Because a large number of references
remained (approximately 1,200), search results were limited to the CAS number. Any references not
containing the CAS number were coded "labanimal/noCAS#." The remaining references (approximately
430) were retained for review.
F-154
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
N-Nitrosodimethylamine (CAS No. 62-75-9)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A National Center for Environmental Assessment (NCEA) Provisional Assessment (2001) derived
a provisional RfD for N-nitrosodimethylamme based on a developmental drinking water study in CD-I
mice (1978).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the oral CSF for N-nitrosodimethylamine was derived (1986) may contain
study data that could potentially produce a change in the CSF.
The IRIS CSF for N-mtrosodimethylamine was derived based on a drinking water study in Colworth rats
(1984). A Health Canada Assessment (1999) derived a tumorigenic dose OS (TD05) for N-
nitrosodimethylamme based the same study used to derive the IRIS CSF. A literature search conducted
for the years 1998 to 2002 identified a study investigating the relationship between the intake of nitrates,
nitrites, and N-nitrosodimethylamine and the risk of cancer in Finnish men and women (1999) that may
be useful in the derivation of a CSF for N-nitrosodimethylamine. The nature and extent of exposure data
in the human study cannot be fully determined from the abstract.
Inhalation Unit Risk (IUR)
The literature published since the inhalation IUR for N-nitrosodimethylamine was derived (1986) does
not appear to contain study data that could potentially produce a change in the IUR. A review of the
Health Canada Assessment (1999) and a literature search conducted for the years 1998 to 2002 identified
no new studies that would be directly useful in the derivation of an IUR for N-nitrosodimethylamine.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1986) may contain study data that could potentially produce a change in the WOE.
The IRIS WOE for N-nitrosodimethylamine was derived based on the induction of tumors at multiple
sites in both rodents and nonrodent mammals exposed by various routes (1967,1973, 1976, 1984). An
International Agency for Research on Cancer (IARC) Monograph published in 1987 characterized N-
nitrosodimethylamine as Group 2A—probably carcinogenic to humans. A review of the Health Canada
Assessment (1999) and a literature search conducted for the years 1998 to 2002 identified a study that
reported a positive relationship between the intake of N-nitrosodimethylamine and the risk of cancer
(1999) and eleven studies evaluating mechanisms of carcinogenic action for N-nitrosodimethylamine
(1998,1999, 2000, 2001).
F-155
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
N-Nitrosodimethylamine (CAS No. 62-75-9)
(continued)
Other studies found in the literature search that might be relevant to the WOE classification include many
genotoxicity and mutagenicity studies that all reported positive findings. These include microbial
mutagenicity studies (1999, 2000); DNA adduct studies (1999, 2001); a DNA strand break study (1998);
mutational spectrum studies in human lymphoblastoid cells (1998), the lacl transgene in Big Blue
C57BL/6 mice (1998, 1999), and the lacl transgene in B6C3F1 mouse liver (1998); a study of mutagenic
effects on human sperm chromosomes (2001); and a renal tumor induction study (2001) in male albino
non-inbred rats exposed to a single injection of N-nitrosodimethylamine.
Unknown Relevance
Twenty documents were categorized as being of unknown relevance, seven of which were records from
CRISP, a biomedical database of research projects supported by the Department of Health and Human
Services, and one of which was a submission to EPA's Office of Toxic Substances (OTS). Among these
are "Mechanisms in Perinatal Carcinogenesis," "Necrosis Factor Alpha Induced Hepatotoxicity," "N-
nitrosodimethylamine, Toxicologic Significance," and "Mechanisms for Tnf Alpha in Xenobiotic Liver
Injury."
F-156
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
N-Nitrosodi-N-propylamine (CAS No. 621-64-7)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: An ATSDR lexicological Profile (1989) presented an acute oral minimal risk level (MRL) for N-
nitrosodi-N-propylamine but derived no intermediate or chronic MRL.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the oral CSF for N-nitrosodi-N-propylamine was derived (1987) does not
appear to contain study data that could potentially produce a change in the CSF. The IRIS CSF for N-
nitrosodi-N-propylamine was derived based on a lifetime drinking water carcinogenicity study in BD rats
(1967). A literature search conducted for the years 1986 to 2002 identified a 50-week carcinogenicity
study in CS7B1 mice involving twice weekly administration by gastric intubation (1989; published in
Russian).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: A literature search conducted for the years 1986 to 2002 identified a 15-week intratracheal
carcinogenicity study in Syrian golden hamsters (1988).
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (62—probable human carcinogen) was derived
(1987) does not appear to contain study data that could produce a change in the WOE.
An International Agency for Research on Cancer (LARC) Monograph (1987) characterized N-mtrosodi-
N-propylamine as Group 2B—possibly carcinogenic to humans. A literature search conducted for the
years 1986 to 2002 identified a 15-week intratracheal carcinogenicity study in Syrian golden hamsters
(1988) and 50-week oral carcinogenicity study in C57B1 mice (1989; published in Russian) (see above),
as well as several positive genotoxicity and mutagenicity studies, including microbial mutagenicity
studies (1992, 2000), mutagenicity studies using Syrian golden hamster hepatocyte V79 cells (1986) and
lacZ transgenic mice (MutaMouse) (1999), a genotoxicity study using rodent pancreas (1987), and studies
of DNA fragmentation in human and rat hepatocytes (1988) and human and rat kidney cells (1996).
Unknown Relevance
Nineteen documents were categorized as being of unknown relevance. Among these are "Induction of
Hepatocellular Carcinoma in Nonhuman Primates by Chemical Carcinogens," and "Integration of
Laboratory and Epidemiologic Studies to Evaluate Genotoxic Exposure in Tool and Die Workers."
F-157
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
N-Nitrosodiphenylamine (CAS No. 86-30-6)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A National Center for Environmental Assessment (NCEA) Provisional Assessment (2001) derived
a provisional RfD for N-nitrosodiphenylamine based on a chronic dietary study in rats (1979), which was
the same study from which the IRIS CSF was derived.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the oral CSF for N-nitrosodiphenylamine was derived (1987) does not
appear to contain study data that could potentially produce a change in the CSF. Review of the ATSDR
Toxicological Profile (1993) and a literature search conducted for the years 1992 to 2002 identified no
new studies that would be directly useful in the derivation of a CSF for N-nitrosodiphenylamine.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1987) does not appear to contain study data that could produce a change in the WOE. An International
Agency for Research on Cancer (IARC) Monograph (1987) characterized N-nitrosodiphenylamine as
Group 3—not classifiable as to carcinogenicity in humans. Review of the ATSDR Toxicological Profile
(1993) and a literature search conducted for the years 1992 to 2002 identified no new studies that would
be directly useful in the derivation of a WOE for N-nitrosodiphenylamine.
Unknown Relevance
Three documents were categorized as being of unknown relevance. Among these studies are "The Genetic
Toxicology of N-nitrosodiphenylamme."
F-158
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Oxyfluorfen (CAS No. 42874-03-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for oxyfluorfen was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for oxyfluorfen was derived based on a 20-month dietary study in Charles River CD-I
mice (1977). In the 2001 Reregistration Eligibility Decision (RED), EPA Office of Pesticide Programs
(OPP) derived an RfD based on the same study as the IRIS RfD, as well as two 104-week dietary toxicity
studies in dogs (1981, 1990) and a chronic carcinogenicity study in mice (1990) that may be useful in the
derivation of an RfD for oxyfluorfen.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included'in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: In the RED, the EPA OPP Cancer Peer Review Committee classified oxyfluorfen as Group C—
possible human carcinogen—based upon combined hepatocellular adenomas/carcinomas in the mouse
carcinogenicity study used to derive the OPP RfD.
Unknown Relevance
No literature search was necessary.
F-159
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Pentabromodiphenyl ether (CAS No. 32S34-81-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for pentabromodiphenyl ether was derived (1986) does not
appear to contain study data that could potentially produce a change in the RfD. The IRIS RfD for
pentabromodiphenyl ether was derived based on a 90-day gavage bioassay in male Sprague-Dawley rats
(1980). A literature search conducted for the years 1985 to 2002 identified no new studies that would be
directly useful in the derivation of an RfD for pentabromodiphenyl ether.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1990) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1989 to 2002 identified no new studies that would be directly
useful in the derivation of a WOE for pentabromodiphenyl ether.
Unknown Relevance
Thirty-seven documents were categorized as being of unknown relevance, 34 of which were submissions
to EPA Office of Toxic Substances (OTS) Among these studies are "Chromosome Aberrations in Human
Peripheral Blood Lymphocytes with Pentabromodiphenyl Oxide," and "Teratogenic Evaluation of a
Polybromodiphenyl Oxide Mixture in New Zealand White Rabbits Following Oral Exposure."
Note: Abstracts of studies using commercial grade pentabromodiphenyl ether, such as DE-71, were
included for consideration even though this form is a mixture of several polybromodiphenyl ethers. In the
IRIS summary, the primary reference used to derive the RfD is a study that investigated the effects of
commercial grade pentabromodiphenyl ether.
F-160
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Pentachlorocyclopentadiene (CAS No. 25329-35-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1988 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-161
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Pentafluoroethane (CAS No. 354-33-6)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An inhalation RfC for pentafluoroethane is not available because EPA determined that the data were
inadequate for derivation of an RfC (latest assessment 1993). The literature available since 1993 contains
study data that could potentially be used to developed an RfC. A literature search conducted for the years
1992 to 2002 identified a 13-week inhalation study of pentafluoroethane in rats (1993).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: A literature search conducted for the years 1993 to 2002 identified a genotoxicity and
carcinogemcity study (1992) and a series of four studies assessing the clastogenic and mutagenic action of
pentafluoroethane which were completed in 1991 and 1992 and submitted to EPA Office of Toxic
Substances (OTS) in 1993.
Unknown Relevance
Five documents were categorized as being of unknown relevance, two of which were submissions to EPA
OTS.
Note: A literature search conducted for the years 1992 to 2002 found two studies that made use of
physiologically-based pharmacokinetic (PBPK) models for pentafluoroethane. To evaluate cardiac
sensitization potential, one study investigated the relation between air and blood concentrations in
humans (1995) under a variety of exposure concentrations and durations. The other study investigated the
relation between the cardiac endpoint as assessed in dogs and the target arterial concentration in humans
(2000).
F-162
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
m-Phenylenediamine (CAS No. 108-45-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for m-phenylenediamine was derived (1986) contains study
data that could potentially produce a change in the RfD.
The IRIS RfD for m-phenylenediamine was derived based on a 90-day oral toxicity study in rats (1982).
A literature search conducted for the years 198S to 2002 identified a 78-week oral toxicity and
carcinogenicity study in B6C3F1 mice (1988) that may be useful in the derivation of an RfD for m-
phenylenediamine.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: An International Agency for Research on Cancer (LARC) Monograph (1987) characterized m-
phenylenediamine as Group 3—not classifiable as to carcinogenicity in humans. A literature search
conducted for the years 1985 to 2002 identified several studies that may be relevant to establishing a
WOE classification. These included the 78-week oral toxicity and carcinogenicity study in B6C3F1 mice
mentioned above (1988) that found no association between exposure and tumor incidences; microbial
mutagemcity studies (198S, 1989, 1995, 1997) that mostly reported positive findings; and genotoxicity
studies in mice using the bone marrow micronucleus test (1992), in human lymphocytes (1995), and in
human DNA fragments (1998), all of which reported positive findings.
Unknown Relevance
Seventy-one documents were categorized as being of unknown relevance, 42 of which were submissions
to EPA Office of Toxic Substances (OTS). Among these studies are "Lifetime Toxicity/Carcinogenesis
Study in Rats," "Teratological Studies with M-Phenylenediamine on Rats," and "Toxicology of Hairdyes:
an Overview."
F-163
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Phenylmercuric acetate (CAS No. 62-38-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for phenylmercuric acetate was derived (1985) does not
appear to contain study data that could potentially produce a change in the RfD. The IRIS RfD for
phenylmercuric acetate was derived based on a chronic oral study in rats (1950). A literature search
conducted for the years 1984 to 2002 identified no new chronic animal studies, but identified one study
(1986; published in Bulgarian) of the embryotoxic and teratogenic action of phenylmercuric acetate in
albino rats in which the administered doses appear to be higher than those doses from which the IRIS RfD
was derived.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1984 to 2002 identified two genotoxicity studies (1996,
1997) with positive results.
Unknown Relevance
Eleven documents were categorized as being of unknown relevance. Among these studies are
"Comparative studies of 2 organic compounds alone or in combination with ethanol following pre- or
post-natal application in mice," "Nephrotoxicity of phenyl-Hg-acetate in alloxan-diabetic rats," "The
neurotoxicity and mutagenicity of phenylmercury acetate and nitrate in single and combined applications
in animal studies," "A comparative study of the effects of mercury compounds on cell viability and
nucleic acid synthesis in hela cells," and "Computerised analysis of pathological findings in longterm
trials with phenylmercuric acetate in rats."
Note: The literature search identified approximately 1,000 references because one synonym for
phenylmercuric acetate is PMA, and PMA is used as an abbreviation for other chemical substances, such
as phenylmercaptunc acid and phorbol myristic/myristate acetate. Therefore, a secondary search was
conducted in EndNote to identify references containing PMA, but not containing mercur* or the CAS
number for phenylmercuric acetate. These references were coded as N/A. In addition, references
containing aminophenylmercuric acetate or the keywords "phenylmercuric acetate/analogs &
derivatives," but not the CAS number for phenylmercuric acetate were also coded as N/A.
F-164
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Phenylmercuric acetate (CAS No. 62-38-4)
(continued)
The search results were further limited with a secondary search to identify references containing
common laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle,
dog, human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and
mutag*. Any references not containing one of these search terms were coded as N/A.
F-165
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Screening-Level Review of the IRIS Database Phase II September 2002
\Evaluation of the Recent Literature and Determination of Currency for:
Phosmet (CAS No. 732-11-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for phosmet was derived (1986) includes study data that could
potentially produce a change in the RfD.
The IRIS RfD was derived based on a 2-year dietary study in rats (1967). In the 2001 Interim
Reregistration Eligibility Decision (IRED), EPA Office of Pesticide Programs (OPP) derived an RfD
based on a 2-year oral toxicity and carcinogenicity study in rats (1991).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: The 2001 IRED indicates that OPP's Cancer Assessment Review Committee recommended against
completing a quantitative cancer nsk assessment for phosmet. According to the RED document, this
recommendation is "consistent with the previous recommendation to use the reference dose (RfD)
approach, in which chronic risks assessed using the RfD are considered to be protective of any
carcinogenic effect, in addition to systemic or other chronic effects."
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: The 2001 IRED reports the findings of OPP's Cancer Assessment Review Committee (1999),
which concluded that phosmet had "suggestive evidence of carcinogenicity, but not sufficient to assess
human carcinogenic potential."
Unknown Relevance
No literature search was necessary.
F-166
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Phthalic anhydride (CAS No. 85-44-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for phthalic anhydride was derived (1988) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1987 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for phthalic anhydride.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A 1998 study entitled "Chromosome aberrations in vitro related to cytotoxicity of nonmutagenic
and metabolic poisons" describes phthalic anhydride as a noncarcinogen. A 1987 study entitled
"Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells evaluations of
108 chemicals," which has been classified as being of unknown relevance, may include information about
the carcinogenicity of phthalic anhydride.
Unknown Relevance
Ten documents, five of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including a submission titled "Letters regarding adverse
health effects suffered by employees exposed to phthalic anhydride."
F-167
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Picloram (CAS No. 1918-02-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for picloram was derived (1987) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for picloram was derived based on a 6-month dog feeding study completed in 1982.In its
1995 Reregistration Eligibility Decision (RED), EPA Office of Pesticide Programs (OPP) derived an RfD
for picloram based on a 2-year chronic toxicity study in rats (1986) that is cited in the IRIS assessment. A
literature search conducted for the years 1994 to 2002 identified a 2002 Federal Register notice (April 17,
2002) referring to a 1998 OPP updated nsk assessment of picloram identified as part of the Six-year
Review process10. The risk assessment included "relevant studies that had become available on the
toxicity of picloram including its potential developmental and reproductive toxicity," but derived the
same RfD as the 1995 RED.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (LARC) Monograph (1991) classified picloram
asGroup 3—not classifiable as to carcinogenicity in humans. The OPP RED (1995)classified picloram as
Group E—evidence of non-carcmogenicity for humans—based on the assessment of OPP's Cancer
Assessment Review Committee (applies to the picloram acid and potassium salt forms). A 2002 Federal
Register notice (April 17, 2002) refers to a 1998 OPP updated risk assessment of picloram that also
classifies picloram as Group E—evidence of non-carcinogenicity for humans.
Unknown Relevance
Two documents were categorized as being of unknown relevance.
10EPA. 2002. Six-Year Review, Chemical Contaminants, Health Effects Technical Support
Document. Office of Water, Office of Science and Technology. EPA Publication No. 822-R-01-001.
February 2002.
F-168
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Pirimiphos-methyl (CAS No. 29232-93-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for pirimiphos-methyl was denved (1986) includes study data
that could potentially produce a change in the RfD.
The IRIS RfD was derived based on a 28-day and a 56-day human feeding study (1974,1976). In the
Revised Human Health Risk Assessment and supporting documentation for the Reregistration Eligibility
Decision (RED) (1999), EPA Office of Pesticide Programs (OPP) derived an RfD based on a 13-week
oral neurotoxicity study in rats (1995).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No literature search was necessary.
F-169
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Potassium silver cyanide (CAS No. 506-61-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for potassium silver cyanide was derived (198S) contains
study data that could potentially produce a change in the RfD.
The IRIS RfD for potassium silver cyanide was derived based on a conversion of the no-observed-
adverse-effect-level (NOAEL) for dissociated cyanide determined from a chronic oral study and a
subchronic to chronic oral bioassay in rats (19SS, 1979). A literature search conducted for the years 1984
to 2002 identified no new studies that would be directly useful in the derivation of an RfD for potassium
silver cyanide. However, the ATSDR Toxicological Profile for dissociated cyanide (1997) considered
literature published since 1985 that may be useful in the derivation of an RfD for potassium silver
cyanide. The ATSDR Toxicological Profile for dissociated cyanide (1997) provided an intermediate oral
minimal risk level (MRL) for cyanide based on a National Toxicology Program (NTP) 13-week drinking
water study in F344/N rats and B6C3F1 mice exposed to sodium cyanide (1993).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-170
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Prometon (CAS No. 1610-18-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for prometon was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for prometon was derived based on a subchronic dietary study in Sprague Dawley rats
(1982). A literature search conducted for the years 198S to 2002 identified a 2-year dietary study in
Sprague-Dawley rats that noted toxicity-related reduced survival; this abstract does not specify
administered doses, but suggests effects occurred only at "excessive levels" (1994).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS
Note: A literature search conducted for the years 1985 to 2002 identified a 2-year dietary study in
Sprague-Dawley rats that showed an increased incidence of mammary tumors (1994) and a genotoxicity
study (1995)
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-171
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Pronamide (CAS No. 23950-58-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for pronamide was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for pronamide was derived based on a 2-year dietary study in dogs (1970). In the 1994
Reregistration Eligibility Decision (RED), EPA Office of Pesticide Programs (OPP) derived an RfD for
pronamide based on a chronic carcmogenicity feeding study in rats (1990; unpublished ).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In 1992, OPP's Carcinogenicity Peer Review Committee classified pronamide as Group B2—
probable human carcinogen).
Unknown Relevance
No literature search was necessary.
F-172
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Propanil (CAS No. 709-98-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for propanil was derived (1987) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for propanil was derived based on a 2-year rat dietary study (1964). An uncertainty factor
was assigned based on the lack of an adequate toxicity database. A literature search conducted for the
years 1986 to 2002 identified a reproductive toxicity study in rats orally administered propanil during
early pregnancy (1997) and a study that evaluated immune parameters in propanil-exposed farm families
(with a companion study by the same laboratory that may provide appropriate exposure data) (2001).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS
Note: A literature search conducted for the years 1986 to 2002 identified one genotoxicity study that
reported propanil was negative in a Salmonella typhimurium reversion assay; propanil produced a dose-
dependent hepatocyte toxicity in a Chmese-hamster-ovary-hypoxanthine-guamne-phosphoribosyl-
transferase (HGPRT) test (1988).
Unknown Relevance
Thirteen documents were categorized as being of unknown relevance, nine of which were from the
Computer Retrieval of Information on Scientific Projects (CRISP) database, a biomedical database of
research projects supported by the Department of Health and Human Services.
Note: Because of the large number of references found in the literature search (approximately 670),
search results were limited with a secondary search in EndNote to identify references containing the CAS
number or synonyms of propanil. Search results were further limited by a tertiary search to identify
common laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle,
dog, human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and
mutag*. Any references not containing one of these search terms were coded as N/A.
F-173
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Propargyl alcohol (CAS No. 107-19-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for propargyl alcohol was derived (1990) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1989 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for propargyl alcohol.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1989 to 2002 identified a study that reported propargyl
alcohol induced chromosomal aberrations in vitro, was clastogenic in vitro, did not induce reverse
mutations detectable with the Salmonella/mammalian microsome assay, and did not induce micronuclei in
the mouse bone-marrow micronucleus assay (1994).
Unknown Relevance
Four documents were categorized as being of unknown relevance, two of which were submissions to EPA
Office of Toxic Substances (OTS).
F-174
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Propham (CAS No. 122-42-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for propham was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1986 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
propham.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1987) characterized
propham as Group 3—not classifiable as to carcinogenicity in humans.
Unknown Relevance
One documents were categorized as being of unknown relevance.
F-175
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Propylene glycol monomethyl ether (CAS No. 107-98-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
The literature published since the oral RfD for propylene glycol monomethyl ether was derived (1991)
contains study data that could potentially produce a change in the RfC.
The IRIS RfC for propylene glycol monomethyl ether was derived based on a subchronic inhalation study
in rats and rabbits (1983). A literature search conducted for the years 1990 to 2002 identified a 2-year
inhalation study in B6C3Fl-mice and F344-rats (1996) and a 2-generation reproductive study in Sprague-
Dawley rats (1999). The Chemical Manufacturers Association (CMA) March 2000 submission to the
IRIS Submission Desk presented a 2-year inhalation study in Fischer 344 rats (1998) that has been used
by the state of California to derive an inhalation reference exposure level.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Seventeen documents, many of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including studies titled "Initial Submission: Preliminary
P1/F1 Generation Results Only in Two-Generation Reproduction Inhalation Study of Propylene Glycol
Monomethyl Ether" (1995), "Reproductive Toxicology. Propylene Glycol Monomethyl Ether" (1997),
"Propylene Glycol Monomethyl Ether: Two-Generation Inhalation Reproduction Study in Sprague-
Dawley Rats" (1997), "Initial Submission: Inhalation Toxicity Study with Propylene Glycol Monomethyl
Ether in Rats & Mice" (date unknown), and "2-Year Vapor Inhalation Chronic/Oncogemcity Study and
Hepatic and Renal Cellular Proliferation, P4SO Enzyme Induction and Protein Droplet Nephropathy"
(1998) (this appears to be the 1998 study presented by CMA [see above]).
F-176
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Propylene glycol (CAS No. 57-55-6)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An RfC for propylene glycol is not available because EPA determined that the data were inadequate to
support development of an RfC (latest assessment 1991). The literature published since EPA's last review
of the health effects literature for propylene glycol appears to contain study data that could potentially
produce a change in the RfC.
In the 1997 Toxicological Profile, ATSDR derived an inhalation minimal risk level (MRL) based on a 13-
week inhalation toxicity study in Sprague-Dawley rats (1989). This 13-week inhalation study was
published prior to the 1991 deliberations of EPA's RfD/RfC Work Group; however, EPA apparently
based the assessment of propylene glycol health effects literature on a 1987 review that would not have
identified the 13-week inhalation study. A literature search for the years 1996 to 2002 identified no
additional studies that would be directly useful in the derivation of an RfC.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (1UR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Twenty-nine documents, most of which were submissions to EPA Office of Toxic Substances (OTS)
were categorized as being of unknown relevance. Among these studies are "Reproductive toxicology.
Propylene glycol" (1997), "Propylene glycol toxicity related to high-dose lorazepam infusion: case report
and discussion" (1999), "Propylene glycol toxicity in a patient receiving intravenous diazepam" (2000),
"Correction and comment: possible toxicity from propylene glycol in injectable drug preparations"
(1997), and "Etomidate and propylene glycol toxicity" (1998).
F-177
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Propyleneimine (CAS No. 75-55-8)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An RfC for propyleneimine is not available because EPA determined that the data were inadequate to
support development of an RfC (latest assessment 1991). A literature search conducted for the years 1990
to 2002 identified no new studies that would be directly useful in the derivation of an RfC for
propyleneimine.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) characterized
propyleneimine as Group 2B—possibly carcinogenic to humans.
Unknown Relevance
One document, a submission to EPA's Office of Toxic Substances (OTS), titled "Initial Submission:
Mutagenicity Study with 2-Methylaziridine in Salmonella Typhimurium and Saccharomyces Cerevisiae
(Final Report)" (1992), was categorized as being of unknown relevance.
F-178
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Pyridine (CAS No. 110-86-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for pyridine was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD. Review of the ATSDR Toxicological
Profile (1992) and a literature search conducted for the years 1991 to 2002 identified no new studies that
would be directly useful in the derivation of an RfD for pyridine.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (2000) characterized pyridine
as Group 3—not classifiable as to carcinogenicity in humans. A National Toxicology Program (NTP)
Cancer Bioassay (2000) found "clear evidence of carcinogenicity" of pyridine based on a 2-year oral
study in rats.
Unknown Relevance
Eleven documents, five of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including studies titled "2-Year Chronic Dosed Water Study
of Pyridine (C55301b) in Male and Female F344 Rats and Male Wistar Rats" (1997), "Initial Submission:
Mortality Patterns of Workers in the Niagara Plant (Final Report on Mixtures of Chemical Substances)
with Attachments" (1992), and "Genotoxicity of Industrial Solvents" (1992).
Note: Because of the large number of references found in the literature search (approximately 1,465),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A. An additional secondary
search was conducted to identify references that contained neither the word pyridine nor the CAS number
for pyridine (110-86-1). Any references not containing pyridine or its CAS number were coded as N/A.
Finally, 2-amino-l-methyl-6- phenylimidazo[4,5-b]pyridine (Phip) is a carcinogen found in tobacco
smoke, automobile exhaust, and cooked food, and has no direct relevance to the toxicity assessment of
pyridine. A large number of references were identified by a secondary search for the abbreviation Phip.
Any references containing the abbreviation Phip were coded as N/A.
F-179
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Quinalphos (CAS No. 13593-03-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for quinalphos was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for quinalphos was derived based on a 2-year dietary study in canines (1980). A literature
search conducted for the years 1985 to 2002 identified several studies that could potentially produce a
change in the RfD, including a study in which quinalphos was administered orally to pregnant rats and a
no-observed-effect-level (NOEL) of 2 milligrams per kilogram body weight (mg/kg) was established
(1999). The literature search also identified studies evaluating the effects of quinalphos exposure in
neonatal rat pups (1998), the oral toxicity in Wistar rats subchronically gavaged with quinalphos daily for
90 days (1993), the fetotoxicity in pregnant Wistar rats gavaged with quinalphos (1992), and cytogenetic
and fetotoxic effects in pregnant mice injected intrapentoneally with Ekalux (quinalphos) (1989).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1985 to 2002 identified a dermal study evaluating the
rumorigenic potential of quinalphos in Swiss albino mice (2000), a study evaluating mutagemcity in
mouse marrow cells in vivo and Chinese hamster lung cells in vitro (1993), two studies evaluating
cytogenetic effects showing a significant increase in chromosomal aberrations (1990, 1991), and a study
evaluating cytogenetic and fetotoxic effects in pregnant mice injected intraperitoneally with Ekalux
(quinalphos) (1989).
Unknown Relevance
Four documents, one of which was a submission to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. Among these studies are "Cytological Effects of Some
Organophosphorous Pesticides" (1985) and "Cytogenetic and Fetotoxic Effects of Organophosphate
Pesticides on Mice" (1989).
Note: Because of the large number of references found in the literature search (approximately 500),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-180
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Quinoline (CAS No. 91-22-5)
Oral Reference Dose (RfD)
An oral RfD for quinoline is not available because EPA determined that the data were insufficient to
support development of an RfD (latest assessment 2001). A literature search conducted for the years 2000
to 2002 identified no new studies that would be directly useful in the derivation of an RfD for quinoline.
Inhalation Reference Concentration (RfC)
An inhalation RfC for quinoline is not available because EPA determined that the data were insufficient
to support development of an RfC (latest assessment 2001). A literature search conducted for the years
2000 to 2002 identified no new studies that would be directly useful in the derivation of an RfC for
quinoline.
Oral Slope Factor (CSF)
The literature published since the CSF for quinoline was derived (2001) does not appear to contain study
data that could potentially produce a change in the RfD. A literature search conducted for the years 2000
to 2002 identified no new studies that would be directly useful in the derivation of a CSF for quinoline.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(2001) does not appear to contain study data that could produce a change in the WOE. A literature search
conducted for the years 2000 to 2002 identified one study (2000) that found that quinoline is genotoxic in
its target organ, the liver, and identified the G:C to C:G transversion as the molecular signature of
quinoline-mduced mutations.
Unknown Relevance
Two documents were categorized as being of unknown relevance, both of which were records listed in the
Computer Retrieval of Information on Scientific Projects (CRISP) database (a biomedical database of
research projects supported by the Department of Health and Human Services).
F-181
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Quinone (CAS No. 106-51-4)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An inhalation RfC for quinone is not available because EPA determined that the data were insufficient to
support development of an RfC (latest assessment 1990). A literature search conducted for the years 1989
to 2002 does not appear to contain study data that could be used to develop an RfC.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: The International Agency for Research on Cancer (IARC) Monograph (1999) characterized
quinone as Group 3—not classifiable as to carcinogenicity in humans A literature search conducted for
the years 1989 to 2002 identified multiple genotoxicity studies, including studies of DNA adduct
formation, tumor induction, inhibition of DNA synthesis, gene mutations, cell transformation, induction
of micronuclei, and clastogenicity. The literature search also identified many studies that examined the
cytotoxic mechanisms and the mechanisms of tumor induction of quinone and parent compounds (e.g.,
benzene)".
Unknown Relevance
Twenty-three documents were categorized as being of unknown relevance, three of which were
submissions to EPA Office of Toxic Substances (OTS) and three were records from the Computer
Retrieval of Information on Scientific Projects (CRISP) database, a biomedical database of research
projects supported by the Department of Health and Human Services.
1' Quinone is a primary metabolite of benzene and is often discussed in benzene toxicity studies.
Therefore, the literature search included studies related to benzene toxicity that mentioned quinone,
relevant studies were generally coded as 5, "other toxicity studies not directly useful for establishing IRIS
toxicity values."
F-182
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Quinone (CAS No. 106-51-4)
(continued)
Note: Because of the large number of references found in the literature search (approximately 1,700),
search results were limited with a secondary search in EndNote to identify references containing the CAS
number and synonyms other than "quinone." However, since a large number of references resulted
(approximately 750) search results were limited with a tertiary search in EndNote to identify references
containing common laboratory species and toxicological terms, including: rat, mouse/mice, gerbil,
hamster, beagle, dog, human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*,
genotox*, mutat*, and mutag*. Any references not containing one of these search terms and not
containing the CAS number were coded as N/A.
F-183
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Radium 226, 228 (CAS No. 7440-14-4)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The CSF for radium 226, 228 and supporting information previously on IRIS were withdrawn (latest
assessment 1993). Review of the International Agency for Research on Cancer (IARC) Monograph
(2001) and a literature search conducted for the years 2000 to 2002 identified no new studies that would
be directly useful in the derivation of a CSF for radium 226, 228.
Note: The National Center for Environmental Assessment (NCEA) Provisional Assessment (1998)
includes cancer slope factors for radium isotopes based on the carcinogenicity of ionizing radiation. No
studies examining the non-ionizing radiation effects of radium were identified
Inhalation Unit Risk (IUR)
The IUR for radium 226,228 and supporting information previously on IRIS were withdrawn (latest
assessment 1993). Review of the IARC Monograph (2001) and a literature search conducted for the years
2000 to 2002 identified no new studies that would be directly useful in the derivation of an IUR for
radium 226, 228.
Note: The NCEA Provisional Assessment (1998) includes inhalation slope factors for radium isotopes
based on the carcinogenicity of ionizing radiation. No studies examining the non-ionizing radiation
effects of radium were identified.
Cancer \Veight-of-Evidence (WOE) Classification
The WOE for radium 226, 228 and supporting information previously on IRIS were withdrawn (latest
assessment 1993). Review of the IARC Monograph (2001) and a literature search conducted for the years
2000 to 2002 identified no new studies that would be directly useful in the derivation a WOE for radium
226, 228. The literature search identified a study that examined radium-induced eye melanomas in
canines (2000) and a study that examined the effective thresholds for induction of skeletal malignancy in
canines by radionuclides (2000).
Unknown Relevance
Five documents were categorized as being of unknown relevance, one of which was a record from the
Computer Retrieval of Information on Scientific Projects (CRISP) database, a biomedical database of
research projects supported by the Department of Health and Human Services. Also included were studies
titled "Cancer Incidence After Childhood Nasopharyngeal Radium Irradiation" and "A Mortality Follow-
up Study of WWII Submariners Who Received Nasopharyngeal Radium Irradiation Treatment."
F-184
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Radon 222 (CAS No. 14859-67-7)
Note: The International Agency for Research on Cancer (IARC) Monograph for radon 222 lists the CAS
No. for radon as 10043-92-2. A literature search was conducted for the years 2000 to 2002 using the CAS
No. 1004-92-2, as well as the CAS No. 14859-67-7. However, none of the studies identified through the
literature search using CAS No. 1004-92-2 contained information relevant to radon 222 toxicity;
therefore, these studies were coded as N/A.
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The CSF for radon 222 and supporting information previously on IRIS were withdrawn in 1993 pending
further review. Review of the IARC Monograph (2001) and a literature search conducted for the years
2000 to 2002 identified no new studies that would be directly useful in the derivation a CSF for radon
222.
Inhalation Unit Risk (IUR)
The IUR for radon 222 and supporting information previously on IRIS were withdrawn in 1993 pending
further review. Review of the IARC Monograph (2001) and a literature search conducted for the years
2000 to 2002 identified no new studies that would be directly useful in the derivation an IUR for radon
222.
Cancer Weight-of-Evidence (WOE) Classification
The WOE for radon 222 and supporting information previously on IRIS were withdrawn in 1993 pending
further review. Review of the IARC Monograph (2001) and a literature search conducted for the years
2000 to 2002 identified no new studies that would be directly useful in the derivation a WOE for radon
222.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-185
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Resmethrin (CAS No. 10453-86-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for resmethrin was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD. Review of the World Health Organization
(WHO) Environmental Health Criteria on resmethrins (1989) and a literature search conducted for the
years 1988 to 2002, identified no new studies that would be directly useful in the derivation of an RfD for
resmethrin.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: A literature search conducted for the years 1988 to 2002 identified a mutagenicity study using
Salmonella typhimurium that reported negative results (1988).
Unknown Relevance
Seventeen documents were categorized as being of unknown relevance, six of which were included in the
"Index of Cleared Science Reviews" on the EPA Office of Pesticide Programs (OPP) Web site. Among
the studies identified were "Evaluation of New Mouse Dietary Carcinogenicity Study and Reevaluation of
Previously Submitted Mouse Carcinogenicity Study on Resmithrin (SBP 1: 52)," "SBP-1382
(Resmethrin, Technical Manufacturing Use Product). Evaluation of 2-Generation Reproduction Study in
Rat and Reevaluation of the following Previously Submitted Studies: 3-Generation Reproduction Study in
Rat, Six Month Dog, Rat Developmental and Rabbit Developmental Toxicity Studies," "Memorandum:
Resemthrm (SB-13 82). Review of Chronic Rat Feeding/Careinogemcity Study Submitted as 6(a)(2)
Data," and "Household Pesticides and Risk of Pediatric Brain Tumors."
F-186
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Savey (CAS No. 78587-05-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for savey was derived (1988) does not appear to contain study
data that could potentially produce a change in the RfD. A literature search conducted for the years 1987
to 2002 identified no new studies that would be directly useful in the derivation of an RfD for savey.
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
Four documents were categorized as being of unknown relevance, all of which were submissions to EPA
Office of Toxic Substances (OTS).
F-187
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Selenious acid (CAS No. 7783-00-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for selenious acid was derived (1991) does not appear to
contain study data that could potentially produce a change in the RfD. Review of the ATSDR draft
Toxicological Profile for selenium (2001), which includes selenious acid, and a literature search
conducted for the years 2000 to 2002, identified no new studies that would be directly useful in the
derivation of an RfD for selenious acid.
Note: The RfD for selenious acid was derived from a follow-up study of approximately 400 individuals
residing in an area of China with high environmental concentrations of selenium (1989). This study was
also used to derive an RfD for selenium (CAS No 7782-49-2). the ATSDR draft Toxicological Profile for
selenium (2001) presents a minimal risk level (MRL) for selenium derived from a second follow-up study
in the same area of China (1994). This second study may be relevant to the derivation of an RfD for
selenious acid.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1990) does not appear to contain study data that could potentially produce a change in the
WOE. Review of the ATSDR draft Toxicological Profile on selenium (2001), which includes selenious
acid, and a literature search conducted for the years 2000 to 2002 identified no new studies that would be
directly useful in establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-188
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Selenium sulfide (CAS No. 7446-34-6)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A draft ATSDR Toxicological Profile on selenium, which includes selenium sulfide, was published
in 2001.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1990) does not appear to contain study data that could produce a change in the WOE. A review of the
ATSDR draft Toxicological Profile on selenium (2001), which includes selenium sulfide, and a literature
search conducted for the years 2000 to 2002, identified no new studies that would be directly useful in
establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-189
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Selenium and compounds (CAS No. 7782-49-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for selenium and compounds was derived (1991) contains
study data that could potentially produce a change in the RfD.
The IRIS RfD for selenium and compounds was derived based on a follow-up study of approximately 400
individuals residing in an area of China with high environmental concentrations of selenium (1989). The
ATSDR draft Toxicological Profile for selenium (2001) derived a minimal risk level (MRL) based on a
second follow-up study of the same area in China (1994). A literature search conducted for the years 2000
to 2002 identified several epidemiological studies that may be useful in the derivation of an RfD for
selenium and compounds. The first study evaluated toxic and carcinogenic health outcomes (2000) and
the second study evaluated reproductive health outcomes (2000) for a cohort of residents of an Italian
municipality who had been chronically exposed to drinking water with a high content of inorganic
selenium. The literature also identified an epidemiological study evaluating the effects of selenium in
food on semen quality in men (2001). Also, the literature search identified a reproductive and a
developmental toxicity study in rats (dietary exposures for 9 weeks) (2000) and pigs (dietary exposures
through one reproductive cycle) (2001).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1990) does not appear to contain study data that could produce a change in the WOE. A
review of the ATSDR draft Toxicological Profile on selenium and compounds (2001) and a literature
search conducted for the years 2000 to 2002 identified no new studies that would be directly useful in
establishing a WOE classification.
Unknown Relevance
Six documents were categorized as being of unknown relevance.
F-190
-------
Screening-Level Review of the IRIS Database Phase 11 September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Selenourea (CAS No. 630-10-4)
Oral Reference Dose (RfD)
The oral RfD for selenourea and supporting information were withdrawn from IRIS by EPA pending
further review (1991). A literature search conducted for the years 1990 to 2002 identified no new studies
that would be directly useful in the derivation of an RfD for selenourea.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSV)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in ERIS.
Unknown Relevance
Four documents, two of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-191
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Silver cyanide (CAS No. 506-64-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for silver cyanide was derived (198S) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1984 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for silver cyanide.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-192
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Simazine (CAS No. 122-34-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for simazine was derived (1991) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for simazine was derived based on a 2-year dietary study in rats (1988). A literature search
conducted for the years 1990 to 2002 identified a study of immunomorphological effects in rats exposed
to simazine in their diets for 6 months (1991), a developmental toxicity study in Sprague-Dawley rats
(1992), and a reproductive toxicity study in Sprague-Dawley rats exposed orally to simazine (exposure
duration unspecified) (1994).
Note: In April 2002, EPA announced the preliminary determination that three triazine pesticides-
simazine, atrazme, propazine-and three metabolites share a common mechanism of toxicity and could be
grouped together for purposes of a cumulative risk assessment and as part of the tolerance reassessment
process for triazine pesticides.EPA expects the risk assessment to be completed in 2003 or 2004.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A literature search conducted for the years 1990 to 2002 identified a study of mammary
tumorigenesis in Sprague-Dawley rats exposed to simazine in their diets for 2 years (1994).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer \Veight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1999) assigned simazine a
cancer classification of Group 3—not classifiable as to carcmogenicity in humans. A literature search
conducted for the years 1990 to 2002 identified five studies evaluating genotoxic effects (1992, 1994),
chromosomal damage induced by exposure to simazine in drinking water (1995), and clastogenic
potential on Chinese hamster ovary cells (1996, 1999).
F-193
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Simazine (CAS No. 122-34-9)
(continued)
Unknown Relevance
Nineteen documents were categorized as being of unknown relevance. Five of these documents were
submissions to EPA Office of Toxic Substances (OTS), including: "Teratology study of simazine
technical in New Zealand white rabbits," "Reproduction study G 27692 tech. rat seg. ii (test for
teratogenic or embryotoxic effects) (final report)," "Letter from Ciba-Geigy Corporation to USEPA
submitting a summary on simazine 104-week chronic toxicity and carcinogenicity study in rats," and
"Subacute oral 13-week toxicity study of simazine in rats."Three of the documents were referenced in the
EPA report "The grouping of a Series of Triazine Pestcides Based on a Common Mechanism of
Toxicity," including: "Comparison of LH surge in female rats exposed to atrazine, simazine, and
diaminochlorotriazine (DACT) via oral gavage for one month" (2001) and "52-Week toxicity study of
simazine, atrazine, and DACT administered in the diet to female rats" (2002).
The EPA Office of Pesticide Programs (OPP) Web site provides an "Index of Cleared Science Reviews"
for simazine, including "Carcinogenic risk for simazine-registered commodities" (1991), "Review of
simazine 2-generation reproduction study in rats," two data reviews for simazine reregistration (January
and February 1993), "Reference dose for chronic oral exposure (RfD) for simazine" (1993), and
"Atrazine and simazine-reviews of five studies examining: 1) short-term effects on the rat estrus cycle; 2)
antiestrogenicity in rats; 3) in vitro antagonism of estrogen action and in vitro binding with the estrogen
receptor; 4) estrogenic responses in MCF-7 human breast cancer cells; 5) estrogenic responses in vivo
(rat) and in vitro" (1999).
Note: Because of the large number of references found in the literature search (approximately 950),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and lexicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-194
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Sodium diethyldithiocarbamate (CAS No. 148-18-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for sodium diethyldithiocarbamate was derived (1985) does
not appear to contain study data that could potentially produce a change in the RfD. The IRIS RfD for
sodium diethyldithiocarbamate was derived based on 90-day subchronic oral toxicity study in albino rats
(1967) and a 2-year dietary study in F344 rats (1979). A literature search conducted for the years 1984 to
2002 identified a study of the effects of sodium diethyldithiocarbamate on developing mouse embryos
(1994). This study was conducted using histological preparations, rather than by administering sodium
diethyldithiocarbamate to pregnant mice.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: In 1984, EPA Office of Solid Waste reported a human carcinogen potency factor for sodium
diethyldithiocarbamate of 0.25 (milligrams per kilogram body weight per day)'1 ([mg/kg/day]'1).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A 1991 British Industrial Biological Research Association (BIBRA) working group toxicity profile
for sodium diethyldithiocarbamate notes that mutagenic activity has been seen in Ames bacterial tests and
in mammalian cells in culture. A literature search conducted for the years 1984 to 2002 identified seven
studies of the genotoxicity and mutagenicity of sodium diethyldithiocarbamate.
Unknown Relevance
Four documents, including one submission to EPA Office of Toxic Substances (OTS), were categorized
as being of unknown relevance. Among these documents was a study titled, "Diethyldithiocarbamate
inhibits scheduled and unscheduled DNA synthesis of rat thymocytes in vitro and in vivo: Dose-effect
relationships and mechanisms of action."
F-195
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Strychnine (CAS No. 57-24-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for strychnine was derived (1985) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1984 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
strychnine.
Note: A Reregistration Eligibility Decision (RED) for strychnine (1996) stated that "based on the severe
oral toxicity of this chemical and the nonfood use status, a reference dose and carcinogenicity
classification has not been determined at this time."
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS
Unknown Relevance
Thirteen documents were categorized as being of unknown relevance, including "Effect of strychnine on
the reactivity of neurons of the sensorimotor cortex and temporary connection in rabbits" (1988).
Note: Because of the large number of references found in the literature search (approximately 950),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and lexicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.In addition, several hundred
references were identified that either did not address strychnine or did not address the toxicity of
strychnine.Therefore, a secondary search was conducted in EndNote to identify references containing
"strychnine-binding" or the keywords "strychnine/analogs & derivatives," "strychnine/therapeutic use,"
or "strychnine/pharmacology.'These references were coded as N/A.In addition, references containing the
keyword "strychnine/administration & dosage," but not "metabolism" or "toxicity" were also coded as
N/A.
F-196
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Systhane (CAS No. 88671-89-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for systhane was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1987 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
systhane.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Five documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including a study titled "Teratology Study of Ih-1,2,4-
Triazole-1-Propanenitrile, Apha-Butyl-Alpha-(-4-Chlorophenyl)- in Rats" (1992).
F-197
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Tebuthiuron (CAS No. 34014-18-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for tebuthiuron was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1987 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
tebuthiuron.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1987 to 2002 identified one study of genotoxic activities
of pesticides, including tebuthiuron, using a modified SOS microplate assay (1995). The results of the
study were not reported in the abstract.
Unknown Relevance
No documents were categorized as being of unknown relevance
F-198
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Terbutryn (CAS No. 886-50-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for terbutryn was derived (1988) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for terbutryn was derived based on a 2-year dietary study in rats (1980). A literature search
conducted for the years 1987 to 2002 identified one 2-year dietary study in Sprague-Dawley rats that
noted toxicity-related reduced survival (1994).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS
Note: A literature search conducted for the years 1987 to 2002 identified a 2-year dietary study in
Sprague-Dawley rats that found an increased incidence of mammary tumors (1994) and two genotoxicity
studies that found terbutryn induced primary DNA damage (2000 and 2002), but failed to produce any
significant increases in sister-chromatid exchanges or micronucleus in freshly isolated human peripheral
blood leukocytes (2002).
Unknown Relevance
Two documents, both of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance. The studies were titled "Chronic Dietary Toxicity Study of
Terbutryn Technical, 2-(Tert-Butylamino-)-4-)Ethylammo)-6-(Methyltio)-S-Triazine in Dogs" (1994) and
"Toxicological Investigation of: Cp 99386" (1992).
F-199
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Tetrabromodiphenyl ether (CAS No. 40088-47-9)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1990) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1989 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification for tetrabromodiphenyl ether.
Unknown Relevance
One document was categorized as being of unknown relevance.
F-200
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,2,4,5-Tetrachlorobenzene (CAS No. 95-94-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 1,2,4,5-tetrachlorobenzene was derived (1985) contains
study data that could potentially produce a change in the RfD.
The IRIS RfD for 1,2,4,5-tetrachlorobenzene was derived based on an oral subchronic study in rats
(1984). In its 1992 assessment, Health Canada derived a tolerable daily intake (TDI) based on a
subchronic (13-week) dietary study in rats (1991).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer \Veight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In its 1992 assessment, Health Canada classified 1,2,4,5-tetrachlorobenzene as Group
VI—unclassifiable with respect to carcinogenicity in humans.
Unknown Relevance
No literature search was necessary.
F-201
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Tetrachlorocyclopentadiene (CAS No. 695-77-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcmogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1988 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-202
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,1,1,2-Tetrachloroethane (CAS No. 630-20-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 1,1,1,2-tetrachloroethane was derived (1987) does not
appear to contain study data that could potentially produce a change in the RfD. A literature search
conducted for the years 1986 to 2002 identified no new studies that would be directly useful in the
derivation of an RfD for 1,1,1,2-tetrachloroethane.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for 1,1,1,2-tetrachloroethane was derived (1988) does not appear
to contain study data that could potentially produce a change in the CSF. Review of the International
Agency for Research on Cancer (IARC) Monograph (1999) and a literature search conducted for the
years 1998 to 2002 identified no new studies that would be directly useful in the derivation of a CSF for
1,1,1,2-tetrachloroethane.
Inhalation Unit Risk (IUR)
The literature published since the IUR for 1,1,1,2-tetrachloroethane was derived (1988) does not appear to
contain study data that could potentially produce a change in the IUR. Review of the IARC Monograph
(1999) and a literature search conducted for the years 1998 to 2002 identified no new studies that would
be directly useful in the derivation of an IUR for 1,1,1,2-tetrachloroethane.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1988) does not appear to contain study data that could produce a change in the WOE. The IARC
Monograph (1999) characterized 1,1,1,2-tetrachloroethane as Group 3—not classifiable as to
carcinogenicity in humans. A literature search conducted for the years 1998 to 2002 identified no new
studies that would be directly useful in establishing a WOE classification. The literature search identified
three studies of 1,1,1,2-tetrachloroethane genotoxicity, including two in vivo assays (involving
intraperitoneal injection in the rat and mouse) (1989, 1991) and an in vitro chromosomal aberration assay
using Chinese hamster lung fibroblast cells (1996). At least two of the three studies reported positive
evidence of genotoxicity.
Unknown Relevance
Fifteen documents, ten of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including studies titled "Comparison of the Inhalation
Toxicity of 1,1,1,2-Tetrachloroethane and Perchloroethylene in the Rat" (1987), "Mortality among Dow
Chemical Employees of a Texas Operations Per-Tet Manufacturing Plant" (1989), and "Genotoxic and
Biochemical Activities of Some Chlorinated Ethanes" (1989).
F-203
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,1,2,2-TetrachIoroethane (CAS No. 79-34-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: The ATSDR Toxicological Profile (1996) presents a chronic oral minimal risk level (MRL) derived
from a 1978 respiratory study in rats. The National Center for Environmental Assessment (NCEA)
Provisional Assessment (2000) presents an RfD derived from a 1994 subchronic dietary study in rats and
mice.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for 1,1,2,2-tetrachloroethane was derived (1986) does not appear
to contain study data that could potentially produce a change in the CSF. Review of the NCEA "Risk
Assessment Issue Paper for: Evaluation of Deriving a Provisional Carcinogenicity Assessment for
1,1,2,2-TetrachIoroethane" (2000), and a literature search conducted for the years 1999 to 2002 identified
no new studies that would be directly useful in the derivation of a CSF for 1,1,2,2-tetrachloroethane.
Inhalation Unit Risk (IUR)
The literature published since the IUR for 1,1,2,2-tetrachloroethane was derived (1986) does not appear to
contain study data that could potentially produce a change in the IUR. Review of the NCEA "Risk
Assessment Issue Paper for: Evaluation of Deriving a Provisional Carcinogenicity Asssessment for
1,1,2,2-TetrachIoroethane" (2000), and a literature search conducted for the years 1999 to 2002 identified
no new studies that would be directly useful in the derivation of an IUR for 1,1,2,2-tetrachloroethane.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1986) does not appear to contain study data that could produce a change in the WOE. An IARC
Monograph (1999) characterized 1,1,2,2-tetrachloroethane as Group 3—not classifiable as to
Carcinogenicity in humans. A Health Canada Assessment (1992) classified 1,1,2,2-tetrachloroethane as
Group III—possibly carcinogenic to humans. The NCEA Provisional Assessment (2000) recommended
no changes to the WOE classification. A literature search conducted for the years 1999 to 2002 identified
no new studies that would be directly useful in establishing a WOE classification.
Unknown Relevance
Six documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including a study titled "Observations on the Toxicity of
Various Halogenated Hydrocarbons Used or Projected for Use in Ethyl Fluid" (2000).
F-204
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,3,4,6-Tetrachlorophenol (CAS No. 58-90-2)
Note: A number of epidemiological studies of soft cell sarcomas were identified during the literature
search. These studies were coded 8 because they primarily focused on chlorophenol and dioxin
exposures. However, they may contain data regarding 2,3,4,6-tetrachlorophenol because they were
identified during the literature search for 2,3,4,6-tetrachlorophenol.
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,3,4,6-tetrachlorophenol was derived (1987) does not
appear to contain study data that could potentially produce a change in the RfD. A literature search
conducted for the years 1986 to 2002 identified no new studies that would be directly useful in the
derivation of an RfD for 2,3,4,6-tetrachlorophenol.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1986 to 2002 identified studies of 2,3,4,6-
tetrachlorophenol's potential to cause mutations in Salmonella (1990) and hamster cells (1986) and to
cause DNA damage in mouse embryos (1995)
Unknown Relevance
Six documents, one of which was a submission to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including a study titled "Teratological Evaluation of 2,3,4,6-
Tetrachlorophenol (Tcp) in Rats" (1987).
Note: Because of the large number of references found in the literature search (approximately 1,150),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-205
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Tetraethyl lead (CAS No. 78-00-2)
Note: Triethyl lead is a metabolite of tetraethyl lead. A number of references studying the effects of
triethyl lead to determine the toxicity of exposure to tetraethyl lead were identified by the literature search
conducted for the years 1984 to 2002. These studies were coded 8 because the levels of tetraethyl lead
that would lead to the exposure levels of triethyl lead studied were not determined.
Oral Reference Dose (RfD)
The literature published since the oral RfD for tetraethyl lead was derived (1985) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for tetraethyl lead was derived based on a subchronic study in rats (1964). A 1995
submission to the IRIS Submission Desk (by the International Technology Corporation) identified a
subchronic oral toxicity study of organic lead compounds (including tetraethyl lead) in
rats (1987). A literature search conducted for the years 1984 to 2002 identified no additional studies that
would be directly useful in establishing an RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: Two occupational studies evaluating the inhalation toxicity of tetraethyl lead were identified by the
literature search conducted for the years 1985 to 2002. One study found increased tremors and sinus
bradycardia among gasoline workers (1994). The second study found evidence for obstructive and
restrictive lung pathology among tetraethyl lead handlers and petrol tanker fillers (1999).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: A case-control study (1997) investigating cancer risk among workers in a tetraethyl lead
manufacturing area found limited evidence of a link between tetraethyl lead exposure and colorectal
cancer (1997).
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: An International Agency for Research on Cancer (IARC) Monograph (1987) characterized
tetraethyl lead as Group 3—not classifiable as to carcinogenicity in humans. In addition, an investigation
of mortality from cancer in chemical plant workers (1984, 1986) found no statistically significant increase
in site specific mortality from cancer among workers primarily exposed to tetraethyl lead; however, these
exposure levels were not measured.
F-206
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Tetraethyl lead (CAS No. 78-00-2)
(continued)
Unknown Relevance
Twenty-one documents, nine of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including studies titled "Initial Submission: Preliminary
Comparative Toxicity Studies with Tetramethyl Lead and Tetraethyl Lead" (1992), "Initial Submission:
Department of Transportation Inhalation Toxicity Studies of Tetraethyl lead in Rats" (1992), "Initial
Submission: Special Oral Test of Tetraethyl Lead in Rats" (1992), "Initial Submission: An Epidemiologic
Study of Cancer Risk Following Exposure to Organic Lead among the Dupont Company's Chambers
Works Employees" (1991), "Tetraethyl lead" (1993), "Critical Periods of Exposure and Developmental
Effects of Lead" (1984), and "Biomonitormg and Subclmical Effect in Tetraethyl Lead Exposed Persons
in Hubei China" (1993).
F-207
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Thallic oxide (CAS No. 1314-32-5)
Oral Reference Dose (RfD)
In 1989, the oral RfD for thallic oxide and supporting information previously on IRIS were withdrawn
pending further review. In 1993, EPA confirmed the decision to withdraw the IRIS assessment for thallic
oxide. A literature search was conducted for the years 1988 to 2002. The literature published since 1988
does not appear to contain study data that could be used to develop an RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1988 to 2002 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
One submission to EPA Office of Toxic Substances (OTS) was categorized as being of unknown
relevance.
F-208
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Thallium carbonate (CAS No. 6533-73-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for thallium carbonate was derived (1988) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for thallium carbonate was derived based on an EPA 90-day study in rats exposed to
thallium sulfate (1986). Review of the World Health Organization (WHO) Environmental Health Criteria
for thallium (1996) and a literature search conducted for the years 1995 to 2002 identified a 6-month
study in mice exposed to thallium carbonate in their drinking water (1987; published in Chinese). This
study found decreases in male reproductive endpoints.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (Ł>—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE.
Review of the WHO Environmental Health Criteria for thallium (1996) and a literature search conducted
for the years 1995 to 2002 identified a 1988 study that induced sister-chromatid exchange, chromosomal
aberrations, and gene mutations when cell lines were exposed to thallium carbonate.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-209
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Thallium nitrate (CAS No. 10102-45-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for thallium nitrate was derived (1988) does not appear to
contain study data that could potentially produce a change in the RfD. Review of the World Health
Organization (WHO) Environmental Health Criteria for thallium (1996) and a literature search conducted
for the years 1995 to 2002 identified no new studies that would be directly useful in the derivation of an
RfD for thallium nitrate.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE.
Review of the WHO Environmental Health Criteria for thallium (1996)and a literature search conducted
for the years 1995 to 2002 identified no new studies that would be directly useful in establishing a WOE
classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-210
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Thallium sulfate (CAS No. 7446-18-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for thallium sulfate was derived (1988) does not appear to
contain study data that could potentially produce a change in the RfD. Review of the World Health
Organization (WHO) Environmental Health Criteria for thallium (1996) and a literature search conducted
for the years 1995 to 2002 identified no new studies that would be directly useful in the derivation of an
RfD for thallium sulfate.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE.
Review of the WHO Environmental Health Criteria for thallium (1996) and a literature search conducted
for the years 1995 to 2002 identified a cytogenetic study that did not result in a significant modification of
structural chromosome aberrations nor sister chromatid exchanges (1997) and a study investigating
micronuclei induction in human lymphocytes (1999).
Unknown Relevance
One document was categorized as being of unknown relevance.
F-211
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Thiobencarb (CAS No. 28249-77-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for thiobencarb was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD. A review of the EPA Office of Pesticide
Programs Reregistration Eligibility Decision (RED) (1997) and a literature search conducted for the years
1996 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for
thiobencarb.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: The OPP RED (1997) categorizes thiobencarb as Group D—not classifiable as to human
carcinogeniciry.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-212
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Thiophanate-methyl (CAS No. 235644)5-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for thiophanate-methyl was derived (1986) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for thiophanate-methyl was derived based on a 2-year dietary study in Sprague-Dawley
rats (1972). The EPA Office of Pesticide Programs (OPP) Revised Preliminary Risk Assessment for the
Reregistration Eligibility Decision (RED) (2001) presented an RfD for thiophanate-methyl based on a 1-
year oral capsule study in dogs (1992).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: The OPP Revised Preliminary Risk Assessment for the RED (2001) presented a CSF for
thiophanate-methyl based on an 18-month dietary carcinogenicity study in CD-I mice (1992).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: The OPP Revised Preliminary Risk Assessment for the RED (2001)stated that thiophanate-methyl
was classified as "likely to be carcinogenic to humans."
Unknown Relevance
No literature search was necessary.
F-213
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Toxaphene (CAS No. 8001-35-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: In the 1996 Toxicological Profile, ATSDR derived an intermediate oral minimal risk level (MRL)
for toxaphene based on a toxicity study in rats (1986). In addition, a review of the International Agency
for Research on Cancer (IARC) Monograph (2001) and a literature search conducted for the years 2000 to
2002 identified a number of studies demonstrating hepatotoxicity and immunotoxicity in a variety of
animal species (1957,1971,1986, 2000,2001) and three multigeneration studies in rats that showed no
reproductive or developmental effects (1976, 1988, 1990).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the oral CSF for toxaphene was derived (1987) contains study data that
could potentially produce a change in the CSF.
The IRIS CSF for toxaphene was derived based on an 18-month dietary study in B6C3F1 mice (1978). A
review of the IARC Monograph (2001) and a literature search conducted for the years 2000 to 2002
identified a case-control study of non-Hodgkin lymphoma and a case-control study of leukemia that both
showed no significant increase in risk associated with exposure to toxaphene (1992) and a study
demonstrating an increase in hepatocellular adenomas and carcinomas in B6C3F1 mice (2000).
Inhalation Unit Risk (IUR)
The literature published since the inhalation IUR for toxaphene was derived (1987) does not appear to
contain study data that could produce a change in the IUR. A review of the IARC Monograph (2001) and
a literature search conducted for the years 2000 to 2002 identified no new studies that would be directly
useful in the derivation of an IUR for toxaphene.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1987) does not appear to contain study data that could produce a change in the WOE.
The IRIS WOE for toxaphene was derived based on an 18-month dietary study in B6C3F1 mice (1978).
The IARC Monograph (2001) characterized toxaphene as Group 2B—possibly carcinogenic to humans.
A review of the IARC Monograph (2001)and a literature search conducted for the years 2000 to 2002
identified several genotoxicity and mutagenicity studies, including microbial mutagenicity studies (1978,
1979, 1986, 1987, 1998) and sister chromatid induction studies (1983, 1990, 1999). The majority of the
mutagenicity studies reported positive findings.
F-214
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Toxaphene (CAS No. 8001-35-2)
(continued)
Unknown Relevance
One document was categorized as being of unknown relevance.
Note: According to information available through the IRIS Submission Desk, a March 3, 1998 letter from
Hercules Incorporated noted that new studies were available since the most recent IRIS update; however,
the references for these studies were not provided.
Note: A literature search conducted for the years 2000 to 2002 identified a study describing the
development of a pharmacokinetic model for predicting absorption, elimination, and tissue burden of
toxaphene in rats (2000).
F-215
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,2,4-Tribromobenzene (CAS No. 615-54-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 1,2,4-tribromobenzene was derived (1986) does not appear
to contain study data that could produce a change in the RfD. A literature search conducted for the years
1985 to 2002 identified no new studies that would be directly useful in the derivation of an RfD for 1,2,4-
tribromobenzene.
Inhalation Reference Dose (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Unknown Relevance
Three documents were categorized as being of unknown relevance, one of which was a submission to
EPA Office of Toxic Substances (OTS).
F-216
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Tributyltin oxide (CAS No. 56-35-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for tributyltin oxide was derived (1997) contains study data
that could potentially produce a change in the RfD.
The IRIS RfD for tributyltin oxide was denved based on an 18-month immunotoxicity study in Wistar
rats (1990). A literature search conducted for the years 1996 to 2002 identified a short-term
developmental toxicity screen using Han:NMRI mice gavaged with tributyltin oxide (1996 [abstract],
1997) that may be useful in the derivation of an RfD for tributyltin oxide.
Inhalation Reference Concentration (RfC)
An inhalation RfC for tributyltin oxide is not available because EPA determined that the data were
inadequate for derivation of an RfC (latest assessment 1997). A literature search conducted for the years
1996 to 2002 does not appear to contain study data that could be used to develop an RfC.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1997) does not appear to contain study data that could produce a change in the WOE. A
literature search for the years 1996 to 2002 identified no new studies that would be directly useful in
establishing a WOE classification.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-217
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Trichloroacetic acid (CAS No. 76-03-9)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A review of the International Agency for Research on Cancer (IARC) Monograph (199S) and a
literature search conducted for the years 1992 to 2002 identified two chronic toxicity studies in which
male Fischer 344/N rats and both male and female B6C3F1 mice were exposed to trichloroacetic acid in
drinking water for 104 weeks and 52 weeks, respectively (1990, 1993, 1997); a study evaluating the toxic
effects on in vitro fertilization in B6D2F-1 mice exposed via oral gavage (1992); and several
developmental toxicity studies in pregnant rats exposed orally, whole embryo rat cultures, and whole
embryo mouse cultures (1995, 1996, 1998, 2001, 2002).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A review of the IARC Monograph (1995) and a literature search conducted for the years 1992 to
2002 identified one chronic toxicity study in which male Fischer 344/N rats were exposed to
trichloroacetic acid in their drinking water for 104 weeks (1997) and several studies that investigated the
carcinogenic activity and hepatic tumor promotion of trichloroacetic acid administered to female B6C3F1
mice in drinking water (1996, 1997, 1998).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1993) does not appear to contain study data that could produce a change in the WOE. A review of the
IARC Monograph (1995) and a literature search conducted for the years 1992 to 2002 identified several
studies investigating cytotoxicity and genotoxicity of trichloroacetic acid, including the induction of DNA
strand breaks, protein synthesis inhibition, micronuclei induction, mutations, chromosomal damage, cell
replication (1992, 1995,1996, 1997, 1998) and several studies investigating the mechanism of liver tumor
induction (1994,1995, 1997,1999, 2000). The IARC Monograph (1995) characterized tetraethyl lead as
Group 3—not classifiable as to carcinogenicity in humans.
Unknown Relevance
Four documents were categorized as being of unknown relevance.
F-218
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Trichloroacetic acid (CAS No. 76-03-9)
(continued)
Note: A review of the 1995 IARC Monograph and a literature search conducted for the years 1992 to
2002 found five studies carried out to develop, apply, and validate a physiologically-based
pharmacokinetic (PBPK) model for trichloroacetic acid (1993,1997, 1998, 1999).
Note: Because of the large number of references found in the literature search (approximately 700),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A. Because a large number of
references remained (approximately 430), a tertiary search was conducted to identify references
containing chemexfoliation, therapeutic, pharmacology, chemistry, condylomata, genital warts, and dental
in the keywords. References containing one of these search terms were also coded as N/A.
F-219
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Trichlorocyclopentadiene (CAS No. 77323-84-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1989) does not appear to contain study data that could produce a change in the WOE. A
literature search conducted for the years 1988 to 2002 identified no new studies that would be directly
useful in the derivation of a WOE classification for trichlorocyclopentadiene.
Unknown Relevance
No documents were categorized as being of unknown relevance.
F-220
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Trichlorofluoromethane (CAS No. 75-69-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for trichlorofluoromethane was derived (1985) does not
appear to contain study data that could potentially produce a change in the RfD. A literature search
conducted for the years 1984 to 2002 identified no new studies that would be directly useful in the
derivation of an RfD for trichlorofluoromethane.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A World Health Organization (WHO) Environmental Health Criteria on fully halogenated
compounds (1990) includes an assessment of trichlorofluoromethane and identified negative that long-
term carcinogenicity studies of trichlorofluoromethane (by oral and inhalation routes). WHO concluded
that trichlorofluoromethane has "little or no mutagenic or carcinogenic potential "
Unknown Relevance
Eight documents, were categorized as being of unknown relevance. Among these documents were seven
submissions to EPA Office of Toxic Substances (OTS). One of the submissions to OTS was titled
"Inhalation Toxicity of Freon 11 and of Freon 11 + 0.3% Nitromethane in Rats." Four 1992 OTS
submissions pertain to cardiac effects of trichlorofluoromethane (and other chlorofluorocarbons) in dogs.
Note: A literature search conducted for the years 1984 to 2002 found one study carried out to develop,
apply, and validate a physiologically-based pharmacokmetic (PBPK) model for trichlorofluoromethane
(2001).
Note: Because of the large number of references found in the literature search (approximately 350),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, epidemiol*, genotox*, mutat*, and mutag*.
Any references not containing one of these search terms were coded as N/A.
F-221
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,4,5-Trichlorophenol (CAS No. 95-95-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,4,5-trichlorophenol was derived (1985) does not appear
to contain study data that could potentially produce a change in the RfD. Review of the ATSDR
Toxicological Profile for chlorophenols (1999) and a literature search conducted for the years 1998 to
2002 identified no new studies that would be directly useful in the derivation of an RfD for 2,4,5-
trichlorophenol.
Note: The ATSDR Toxicological Profile (1999) included an intermediate oral minimal risk level (MRL)
for chlorophenols, based on a study of 2,4-dichlorophenol. No chronic MRL was derived because the no-
observed-adverse-effect levels (NOAELs) identified in the chronic studies were greater than the lowest-
observed-adverse-effect levels (LOAELs) identified in the intermediate duration studies.
Inhalation Reference Concentration (RfC)
An inhalation RfC for 2,4,5-trichlorophenol is not available because EPA determined that the data were
inadequate for derivation of an RfC (latest assessment 1991). Review of the ATSDR Toxicological
Profile for chlorophenols (1999) and a literature search conducted for the years 1999 to 2002 identified no
new studies that would be directly useful in the derivation of an RfC for 2,4,5-trichlorophenol.
Note: The ATSDR Toxicological Profile for chlorophenols (1999) includes no inhalation MRLs for 2,4,5-
trichlorophenol. The only available study (an acute inhalation study in rats exposed to 2-chlorophenol)
was determined to be inadequate for deriving an inhalation MRL.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS
Note: In the 1999 Toxicological Profile for chlorophenols, ATSDR cited a number of epidemiological
studies published between 1981 and 1991 that assessed the carcinogenic potential of chlorophenol-based
pesticides. Most of the studies evaluated exposures of farm workers or workers involved in chlorophenol-
based pesticide production; these individuals may also have been exposed to other chlorophenols,
dioxins, and chlorophenoxy pesticides. ATSDR determined that the data were not sufficient to support a
causal relationship, but suggested a possible concern.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A International Agency for Research on Cancer (IARC) Monograph (1999) lists
"polychlorophenols and their sodium salts (mixed exposures)" as Group 2B—possibly carcinogenic to
humans. A literature search conducted for the years 1998 to 2002 identified a single study of the
cytogenetic characteristics of peripheral blood lymphocytes of herbicide plant workers (1998). The study
found that 2,4,5-trichlorophenol had mutagenic effects in humans.
F-222
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,4,5-Trichlorophenol (CAS No. 95-95-4)
(continued)
Unknown Relevance
One documents, a submission to EPA Office of Toxic Substances (OTS), was categorized as being of
unknown relevance
F-223
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,4,6-Trichlorophenol (CAS No. 88-06-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: The ATSDR Toxicological Profile for chlorophenols (1999) includes an intermediate oral minimal
risk level (MRL) for chlorophenols, based on a study of 2,4-dichlorophenol. No chronic MRL was
derived because the no-observed-adverse-effect levels (NOAELs) identified in the chronic studies were
greater than the lowest-observed-adverse-effect levels (LOAELs) identified in the intermediate duration
studies.
Inhalation Reference Concentration (RfC)
An RfC for 2,4,6-trichlorophenol is not available because EPA determined that the data were insufficient
to support development of a RfC (1991). Based on a review of the ATSDR Toxicological Profile for
chlorophenols (1999) and a literature search conducted for the years 1998 to 2000, the literature published
since 1991 does not appear to contain study data that could be used to develop a RfC.
Oral Slope Factor (CSF)
The literature published since the CSF for 2,4,6-trichlorophenol was derived (1989) does not appear to
contain study data that could potentially produce a change in the CSF. Review of the ATSDR
Toxicological Profile for chlorophenols (1999) and a literature search conducted for the years 1998 to
2002 identified no new studies that would be directly useful in the derivation of a CSF for 2,4,6-
trichlorophenol.
Inhalation Unit Risk (IUR)
The literature published since the IUR for 2,4,6-trichlorophenol was derived (1989) does not appear to
contain study data that could potentially produce a change in the IUR. Review of the ATSDR
Toxicological Profile for chlorophenols (1999) and a literature search conducted for the years 1998 to
2002 identified no new studies that would be directly useful in the derivation of an IUR for 2,4,6-
trichlorophenol. ATSDR cited a number of epidemiological studies published between 1981 and 1991
that assessed the carcinogenic potential of chlorophenol-based pesticides. Most of the studies evaluated
exposures of farm workers or chlorophenol-based pesticide production worker. These individuals may
also have been exposed to other chlorophenols, dioxins, and chlorophenoxy pesticides. ATSDR
determined that the data were not sufficient to support a causal relationship, but suggested a possible
concern.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (B2—probable human carcinogen) was derived
(1989) does not appear to contain study data that could produce a change in the WOE classification. A
International Agency for Research on Cancer (IARC) Monograph (1999) lists "polychlorophenols and
their sodium salts (mixed exposures)" as Group 2B—possibly carcinogenic to humans. A literature search
conducted for the years 1998 to 2002 identified no new studies that would be directly useful in the
derivation of a WOE classification for 2,4,6-trichlorophenol.
F-224
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2,4,6-Trichlorophenol (CAS No. 88-06-2)
(continued)
Unknown Relevance
One submission to EPA Office of Toxic Substances (OTS) was categorized as being of unknown
relevance.
F-225
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2 (2,4,5-Trichlorophenoxy) propionic acid (2,4,5-TP) (CAS No. 93-72-1)
Note: A number of epidemiological studies of occupational exposure to chlorophenoxy herbicides were
identified during the literature search. These studies were coded 8 because they primarily focused on
exposures to mixtures of chlorophenoxy herbicides, dioxins, and/or trichlorophenols. However, they may
contain data regarding 2 (2,4,5-trichlorophenoxy) propionic acid (2,4,5-TP) because they were identified
during the literature search for 2,4,5-TP.
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,4,5-TP was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD.
The IRIS RfD for 2,4,5-TP was derived based on a 2-year chronic dietary study in dogs (1978) and a 2-
year dietary study in rats (1966) in which both species were fed the same formulation containing the
potassium salt of 2,4,5-TP. A literature search conducted for the years 1987 to 2002 identified no new
studies that would be directly useful in the derivation of an RfD for 2,4,5-TP. A literature review
conducted by the EPA Office of Water (OW) (2002) as part of its 6-year review of the National Primary
Drinking Water Standards concluded that a "literature search did not identify any new studies that warrant
a review of the RfD or the cancer classification".12
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (D—not classifiable as to human carcinogenicity)
was derived (1987) may contain study data that could produce a change in the WOE classification.
A literature search conducted for the years 1986 to 2002 identified two International Agency for Research
on Cancer (IARC) Monographs on chlorophenoxy herbicides (1986, 1987). The 1987 LARC Monograph
classifies them as Group 2B—possibly carcinogenic to humans. A literature review conducted by OW
(2002) as part of its 6-year review of the National Primary Drinking Water Standards concluded that a
"literature search did not identify any new studies that warrant a review of the RfD or the cancer
classification."
12EPA. 2002. Six-Year Review, Chemical Contaminants, Health Effects Technical Support
Document. Office of Water, Office of Science and Technology. EPA Publication No. 822-R-01-001.
February 2002.
F-226
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
2 (2,4,5-Trichlorophenoxy) propionic acid (2,4,5-TP) (CAS No. 93-72-1)
(continued)
The literature search also identified a negative mutagenicity study of 2,4,5-TP (1988, 1989) and a study
titled "Phenoxy Herbicides and Cancer Insufficient Epidemiologic Evidence for a Causal Relationship"
(1989).
Unknown Relevance
Three documents were categorized as being of unknown relevance, including a study titled "Cause
Specific Mortality among Employees Engaged in the Manufacture Formulation or Packaging of 2,4-D
and Related Salts."
F-227
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,2,3-Trichloropropane (CAS No. 96-18-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 1,2,3-trichloropropane was derived (1986) contains study
data that could potentially produce a change in the RfD.
The IRIS RfD for 1,2,3-trichloropropane was derived based on a 120-day gavage study in rats (1983). In
the 1999 Provisional Assessment, the National Center for Environmental Assessment (NCEA) derived an
RfD based on a 17-week subchronic gavage study in rats and mice (1993).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: In its 1999 Provisional Assessment, NCEA derived an RfC based on a 13-week inhalation study in
rats (1988).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: In its 1999 Provisional Assessment, NCEA derived a CSF based on a 17-week subchronic gavage
study in mice (1993).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In the 1999 Provisional Assessment, NCEA classified 1,2,3-trichloropropane as Group
B2—probable human carcinogen. In addition, the International Agency for Research on Cancer (IARC)
classified 1,2,3-trichloropropane as Group 2B—possibly carcinogenic to humans—in its 1995
Monograph. Also, the National Toxicology Program (NTP) classified 1,2,3-trichloropropane as exhibiting
clear evidence of carcinogenic!ty in a 1993 cancer bioassay. In its Eighth Report on Carcinogens, NTP
classified 1,2,3-trichloropropane as reasonably anticipated to be a human carcinogen.
Unknown Relevance
No literature search was necessary.
Note: An NCEA Superfund Technical Support Center (STSC) memo dated 1/4/02 included as
attachments "Draft Risk Assessment Issue Papers for: Derivation of the Systemic Toxicity of 1,2,3-
trichloropropane (CAS No. 96-18-4)" and "Evaluation of Carcinogenicity of 1,2,3-trichloropropane (CAS
No. 96-18-4) (99-014/8-13-99)."
F-228
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,2,3-Trichloropropane (CAS No. 96-18-4)
(continued)
Note: Letters dated April 17, 1992 and February 4,1994 from Ciba-Geigy Corporation (Ciba) to the IRIS
Submission Desk noted that new studies were available since the most recent IRIS update. In its 1992
letter, Ciba referenced an issue paper addressing the relevance of gavage-induced response to responses in
humans, citing NTP 1991 and Merrick et al. 1991. In its 1994 submission, Ciba cited work by Swenberg
et al. (1993) on DNA adduct formation from exposure to 1,2,3-trichloropropane in rats.
F-229
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
1,1,2-Trichloropropane (CAS No. 598-77-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 1,1,2-trichloropropane was derived (1987) does not appear
to contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1986 to 2002 identified no new studies that would be directly useful in the derivation of an RfD
for 1,1,2-trichloropropane.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
One document, a submission to EPA Office of Toxic Substances (OTS), was categorized as being of
unknown relevance.
F-230
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
l,l,2-Trichloro-l,2,2-trifluoroethane (CAS No. 76-13-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for l,l,2-trichloro-l,2,2-trifluoroethane was derived (1985)
does not appear to contain study data that could potentially produce a change in the RfD. A literature
search conducted for the years 1984 to 2002 identified no new studies that would be directly useful in the
derivation of an RfD for l,l,2-trichloro-l,2,2-trifluoroethane.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1984 to 2002 identified one submission to EPA Office
of Toxic Substances (OTS) that contained inhalation toxicity study information: a two 2-year inhalation
toxicity/carcinogenicity study in rats (1985; unpublished). Results from this study were published in
1988
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: A literature search conducted for the years 1984 to 2002 identified a 2-year inhalation
carcinogenicity study in rats (1988).
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1984 to 2002 identified a negative 2-year inhalation
carcinogenicity study (1988). One study also reported no evidence of mutagenicity in a Salmonella-
typhimurium assay, but evidence for enhancement of the mutagenic response of aromatic hydrocarbons
(1988).
Unknown Relevance
Twenty-five documents, most of which were submissions to EPA OTS, were categorized as being of
unknown relevance.
Note: A literature search conducted for the years 1984 to 2002 found one study carried out to develop,
apply, and validate a physiologically-based pharmacokinetic (PBPK) model for 1,1,2-trichloro-1,2,2-
trifluoroethane(1991).
F-231
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Tridiphane (CAS No. 58138-08-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for tridiphane was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for tridiphane was derived based on a dietary 2-generation reproduction study in rats
conducted by Dow Chemical (1984). A literature search conducted for the years 198S to 2002 identified a
dietary 2-generation reproduction study in Fischer 344 rats (1987) and a oral administration
embryotoxiciry and fetotoxicity study in CF-1 mice and Sprague-Dawley rats (1987).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A literature search conducted for the years 198S to 2002 identified a dietary 2-generation
reproduction study in Fischer 344 rats (1987) that included examinations for hepatic lesions.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
One document was categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (approximately 860),
search results were limited with a secondary search in EndNote to identify references containing
tridiphane's CAS number (58138-08-2) or a synonym. Any references not containing one of these search
terms were coded as N/A.
F-232
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Triethylene glycol monobutyl ether (CAS No. 143-22-6)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An RfC for triethylene glycol monobutyl ether is not available because EPA determined that the data
were inadequate for derivation of an inhalation RfC (1992). The literature published since the inhalation
RfC for triethylene glycol-monobutyl ether was reviewed (1992) does not appear to contain study data
that could potentially produce a change in the RfC. A literature search conducted for the years 1991 to
2002 identified no new studies that would be directly useful in the derivation of an RfC for triethylene
glycol monobutyl ether.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Four documents, three of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-233
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Triethylene glycol monoethyl ether (CAS No. 112-50-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
An RfC for triethylene glycol monoethyl ether is not available because EPA determined that the data were
inadequate for derivation of an inhalation RfC (1992). The literature published since the inhalation RfC
for triethylene glycol monoethyl ether was reviewed (1992) does not appear to contain study data that
could potentially produce a change in the RfC. A literature search conducted for the years 1991 to 2002
identified no new studies that would be directly useful in the derivation of an RfC for triethylene glycol
monoethyl ether.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Five documents, all of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance, including a study titled "Triethylene Glycol Ether: An
Evaluation of Teratogenic Potential and Developmental Toxicity Using an in vivo Screen in Rats."
F-234
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Trifluralin (CAS No. 1582-09-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for trifluralin was derived (1989) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for trifluralin was derived based on a 12-month dietary study in dogs (1984). Review of the
EPA Office of Pesticide Programs Reregistration Eligibility Decision (RED) (1996) and a literature
search conducted for the years 1991 to 2002 identified a 2-year dietary toxicity study in B6C3F1 mice
(1991) and two developmental toxicity studies, with administration by gavage, in rats and rabbits (1990,
1995). In the 1996 RED, OPP derived an RfD based on a chronic (1-year) toxicity feeding study in dogs
(1992).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for trifluralin was derived (1987) does not appear to contain study
data that could potentially produce a change in the CSF.
The IRIS CSF for trifluralin was derived based on a rat study that showed an increased incidence of renal
pelvis carcinomas, urinary papillomas, and thyroid adenomas and carcinomas (1980). Review of the
International Agency for Research on Cancer (IARC) Monograph (1991), the OPP RED (1996), and a
literature search conducted for the years 1991 to 2002 identified a 2-year dietary oncogenicity study in
B6C3F1 mice (1991). This study found no treatment-related increase in the incidence of benign or
malignant neoplasms.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (C—possible human carcinogen) was derived
(1987) does not appear to contain study data that could potentially produce a change in the WOE.
The IRIS WOE for trifluralin was derived based on a rat study that showed an increased incidence of
renal pelvis carcinomas, urinary papillomas, and thyroid adenomas and carcinomas (1980). Review of the
IARC monograph (1991), the OPP RED (1996), and a literature search conducted for the years 1991 to
2002 suggests that studies in the more recent literature are not likely to produce a change in the WOE
classification.
The IARC Monograph (1991) characterized trifluralin as Group 3—not classifiable as to carcinogenicity
in humans. The OPP RED (1996) stated that the Carcinogenicity Peer Review Committee classified
trifluralin as Group C—possible human carcinogen—based on limited evidence of carcinogenicity in
male and female rats (long-term rodent carcinogenicity studies, rat and mouse bioassays, and genotoxicity
tests).
F-235
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Trifluralin (CAS No. 1582-09-8)
(continued)
Also, A literature search conducted for the years 1991 to 2002 identified a negative carcinogenicity
bioassay in the mouse (1991), mouse bone-marrow micronucleus test (1997) in which trifluralin caused a
significant increase in the number of micronuclei in female mice only, and a bioassay in human peripheral
blood lymphocytes (1996) where trifluralin exhibited a weak cytotoxic effect. For example, in this study
trifluralin caused a reduction in the proliferative rate index and cytokinesis block proliferation index and
induced a slight increase in the frequency of sister chromatid exchanges. However, there were no
genotoxic effects observed in the chromosomal aberration and micronuclei tests. In addition, a
genotoxicity study (1991) reported trifluralin-induced cytotoxicity in the mouse lymphoma assay, without
forward mutations. This study also showed no reverse mutation in Salmonella-typhimurium, no increase
in the frequency of sister chromatid exchanges in Chinese hamster cells, and a negative result in a
dominant lethal assay in male Wistar-rats. An additional study (1998) showed that the effect of trifluralin
on microtubules in a Chinese hamster fibroblast cell bioassay was negligible and few spindles were
disrupted in association with aberrant mitotic figures.
Unknown Relevance
Three documents, two of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (approximately 710),
search results were limited with a secondary search in EndNote to identify references containing common
laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog,
human, rabbit, pig, monkey, primate, worker, subject, patient, inhalation, epidemiol*, genotox*, mutat*,
and mutag*. Any references not containing one of these search terms were coded as N/A.
F-236
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Uranium, soluble salts (CAS No. not available)
Oral Reference Dose (RfD)
The literature published since the oral RfD for soluble uranium salts was derived (1989) contains study
data that could potentially produce a change in the RfD.
The IRIS RfD for soluble uranium salts was derived based on a 30-day dietary bioassay in rabbits (1949).
In the 1999 Toxicological Profile, ATSDR derived an intermediate oral minimal risk level (MRL) for
soluble uranium salts based on renal effects exhibited in rabbits (1998). However, ATSDR did not derive
a chronic oral MRL because of lack of sufficient data. ATSDR noted that the intermediate MRL for
soluble uranium salts would likely be protective for chronic duration exposure.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: In the 1999 Toxicological Profile, ATSDR derived a chronic MRL for non-cancer inhalation
exposure for soluble uranium salts based on kidney effects exhibited in dogs in 2-year inhalation study
(1953).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
No literature search was necessary.
F-237
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Vanadium pentoxide (CAS No. 1314-62-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for vanadium pentoxide was derived (1986) contains study
data that could potentially produce a change in the RfD.
The IRIS RfD for vanadium pentoxide was derived based on a chronic dietary study in rats (1953). A
literature search conducted for the years 198S to 2002 identified a reproductive/developmental toxicity
study in male mice (1996), a 6-month immunotoxicity drinking water study in Wistar rats (1993), two
teratogenicity/developmental toxicity studies in pregnant Wistar rats (1993; published in Chinese), a
fetotoxiciry study in pregnant Wistar rats (1993; published in Chinese), and a developmental toxicity
study in NIH mice (1991; published in Chinese).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1985 to 2002 identified a 26-week inhalation study of
pulmonary reactivity in male cynomolgus monkeys (1992).
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search conducted for the years 1991 to 2002 identified a study in which
histopathological lung lesions developed following an intratracheal administration of vanadium pentoxide
powder (2001); a single cell gel electrophoresis assay that found an increased number of cells with
damage in the liver, kidney, lung, spleen, and heart, but not bone marrow following vanadium pentoxide
exposure (1999); a single cell gel electrophoresis assay that found clear dose-response DNA migration in
whole blood leukocytes and a significant positive effect with the highest tested concentration in human
lymphocyte cultures (1996); and a genotoxicity study that found no significant increases in the frequency
of sister chromatid exchanges or gene mutations, but reported dose-related increases of micronucleated
cells in culture and decreases in the number of binucleated cells in the presence of cytochalasin B (1994).
Unknown Relevance
Eight documents, five of which were submissions to EPA Office of Toxic Substances (OTS), were
categorized as being of unknown relevance.
F-238
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Screening-Level Review of the IRIS Database Phase II September 2002
Evaluation of the Recent Literature and Determination of Currency for:
Vinclozolin (CAS No. 50471-44-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for vinclozolin was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for vinclozolin was derived based on a 6-month dietary study in dogs (1982). In the 2000
Reregistration Eligibility Decision (RED), EPA Office of Pesticide Programs (OPP) derived an RfD for
vinclozolin based on a chronic (2-year) dietary toxicity study in rats (1994).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: In the 2000 RED, OPP derived a CSF for vinclozolin based on a 1994 study that repored an
increased incidence of spleen sarcomas in rats. The CSF is based on a low-dose linear extrapolation of
3,5-dichloroaniline resulting solely from the use of vinclozolin. OPP assumed that the carcinogenic
potential of 3,5-dichloroaniline represented the carcinogenicity of all chloroanilines, unless sufficient
evidence is otherwise available.
Note: The chronic population adjusted dose provided in the OPP RED (2000) was considered protective
of possible cancer effects because this dose was protective of the precursor anti-androgen effects that lead
to tumors. OPP also determined that a nonlinear (margin-of-exposure) approach was appropriate for
vinclozolin. .
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: In the 2000 RED, OPP classified vinclozolin as Group C—possible human carcinogen—based on
Leydig (interstitial testicular) cell tumors in rats in chronic and carcinogenicity studies.
Unknown Relevance
No literature search was necessary.
F-239
-------
Screening-Level Review of the IRIS Database Phase II September 2002
Appendix G: Summary of Findings
-------
Screening-Level Review of the IRIS Database Phase II
September 2002
Appendix G: Summary of Findings
Chemical
Acetonitnle
Acrylonitrile
Adiponitnle
Aldicarb
Aldnn
Ally
Allyl alcohol
Ametryn
4-Aminopyndme
Amitraz
Ammonium acetate
Ammonium sulfamate
Aniline
Antimony
Antimony tnoxide
Apollo
Arsenic (inorganic )
Arsme
Assure
Azobenzene
Barium cyanide
Baythroid
Benefin
Benomyl
Bidnn
Biphenthnn
1 , 1 -Biphenyl
Bis(2-chloroethoxy)methane
Bis(2-chloroisopropyl) ether
Bisphenol A
Bromodichloromethane
p-Bromodiphenyl ether
Bromoform
Bromoxynil octanoate
Cacodylic acid
Captafol
CAS Number
75-05-8
107-13-1
111-69-3
116-06-3
309-00-2
74223-64-6
107-18-6
834-12-8
504-24-5
33089-61-1
631-61-8
7773-06-0
62-53-3
7440-36-0
1309-64-4
74115-24-5
7440-38-2
7784-42-1
76578-14-8
103-33-3
542-62-1
68359-37-5
1861-40-1
17804-35-2
141-66-2
82657-04-3
92-52-4
111-91-1
39638-32-9
80-05-7
75-27-4
101-55-3
75-25-2
1689-99-2
75-60-5
2425-06-1
RfD
C
O
N
C
C
N
C
C
C
0
N
O
C
N
C
O
C
C
C
N
N
C
C
0
C
N
N
N
N
O
N
RfC
C
C
O
C
0
C
N
C
O
0
C
--
CSF
N
C
—
C
N
C
O
N
C
0
O
O
IUR WOE
C
N N
C
C
N N
. .
O
C
O
C
- -
C
0 0
O
C
N C
O
C
C C
- -
O
- -
C
C
0
O
O C
C
C N
N
0
UR
3
8
24
7
1
5
11
5
4
4
4
0
4
5
2
1
0
3
7
1
0
11
0
N/A
0
3
8
3
4
20
25
1
23
6
12
8
G-l
-------
Screening-Level Review of the IRIS Database Phase II
September 2002
Chemical
Carbaryl
Carbofuran
Carbon disulfide
Carbonyl sulfide
Carbosulfan
Carboxin
Chlorimuron-ethyl
Chlorine
1-Chlorobutane
2-Chlorobutane
2-Chlorophenol
p-Chlorophenyl methyl sulfide
Coke oven emissions
Cumene
Cyanazme
Cyanogen
Cyclohexanone
Cyclohexylamme
Dalapon (sodium salt)
Damtol
2,4-Diammotoluene
Dibenzofuran
Dibromochloromethane
Dibromodichloromethane
p,p'-Dibromodiphenyl ether
Dicamba
p,p'-Dichlorodiphenyltnchloroethane
1 , 1 -Dichloroethane
cis- 1 ,2-Dichloroethylene
trans- 1 ,2-Dichloroethylene
Dichloromethane
4-(2,4-Dichlorophenoxy)butync acid
1 ,2-Dichloropropane
2,3-Dichloropropanol
Dicofol
Diethyl phthalate
Diethyl-p-mtrophenyl phosphate
Dimethipm
CAS Number
63-25-2
1563-66-2
75-15-0
463-58-1
55285-14-8
5234-68-4
90982-32-4
7782-50-5
109-69-3
78-86-4
95-57-8
123-09-1
8007-45-2
98-82-8
21725-46-2
460-19-5
108-94-1
108-91-8
75-99-0
39515-41-8
95-80-7
132-64-9
124-48-1
594-18-3
2050-47-7
1918-00-9
50-29-3
75-34-3
156-59-2
156-60-5
75-09-2
94-82-6
78-87-5
616-23-9
115-32-2
84-66-2
311-45-5
55290-64-7
RfD
N
C
C
-
C
C
C
C
C
C
C
N
C
C
C
C
C
o
N
N
N
O
0
C
C
N
O
C
0
N
C
JRfC CSF J1DR_
C
N
C
_ .
O O O
- -
- .
N
C
0
o
o
- -
C
C
. -
_ -
C C
o
- -
0
0 C C
o
C
-- C C
. -
. .
wop
0
o
o
0
o
C
C
o
C
C
C
0
o
o
0
0
C
N
C
C
0
N
C
C
C
o
o
C
C
C
C
UR
7
15
11
9
4
2
7
11
9
0
2
0
34
6
3
0
18
8
0
9
20
0
15
2
0
20
3
5
2
1
13
0
12
3
1
9
3
7
G-2
-------
Screening-Level Review of the IRIS Database Phase II
September 2002
Chemical
N,N-Dimethylformamide
2,4-DimethylphenoI
3,4-Dimethylphenol
2,4-Dmitrotoluene
Diphenamid
1 ,2-Diphenylhydrazine
Disulfoton
Endosulfan
Endothall
Epichlorohydrin
1 ,2-Epoxybutane
Ethephon
S-Ethyl dipropylthiocarbamate
Ethyl p-nitrophenyl phenylphosphorothioate
Ethylene glycol monobutyl ether (EGBE)
Ethylphthalyl ethylglycolate
Flundone
Flurpnmidol
Fluvalmate
Fomesafen
Formic acid
Furmecyclox
Glycidaldehyde
n-Heptane
alpha-Hexachlorocyclohexane
beta-Hexachlorocyclohexane
Hexachlorophene
1 ,6-Hexamethylene dusocyanate
Hexazinone
Hydrazine/Hydrazme sulfate
Hydroquinone
Isobutyl alcohol
Lead and compounds (inorganic)
d-Limonene
Malathion
Maleic anhydnde
Maleic hydrazide
Manganese
CAS Number
68-12-2
105-67-9
95-65-8
121-14-2
957-51-7
122-66-7
298-04-4
115-29-7
145-73-3
106-89-8
106-88-7
16672-87-0
759.94-4
2104-64-5
1 1 1-76-2
84-72-0
59756-60-4
56425-91-3
69409-94-5
72178-02-0
64-18-6
60568-05-0
765-34-4
142-82-5
319-84-6
319-85-7
70-30-4
822-06-0
51235-04-2
302-01-2
123-31-9
78-83-1
7439-92-1
5989-27-5
121-75-5
108-31-6
123-33-1
7439-96-5
RfD
O
N
C
C
C
N
C
N
N
C
C
C
C
C
C
C
C
C
C
0
0
N
N
O
N
N
N
N
N
C
JRfC CSE^
N
. .
C
C C
O
. .
N C
C
. .
C
- -
. -
. .
C
O
C
- -
C
C
C
O N
C O
O
. .
C
O
N
IUR WOE
O
. .
O
C C
- -
N N
0
O
O
C
- -
- -
N
O
C
C
C
C C
C N
O O
0
O
N C
O O
C
O
0
0
C
UR
N/A
0
1
3
2
2
N/A
8
9
78
13
3
0
7
22
0
5
15
10
2
5
0
1
14
4
5
8
23
N/A
N/A
43
34
N/A
6
N/A
13
N/A
6
G-3
-------
Screening-Level Review of the IRIS Database Phase II
September 2002
Chemical
Mepiquat chloride
Mercuric chloride
Mercury, elemental
Merphos oxide
Methamidophos
Methyl isocyanate
Methyl methacrylate
2-Methyl-4-chlorophenoxyaceticacid
2-(2-Methyl-4-chlorophenoxy)propionic
acid
Methylmercury
3-Methylphenol
4-Methylphenol
Metribuzin
Nitrate
Nitrite
N-Nitrosodimethylamine
N-Nitrosodi-N-propylamine
N-Nitrosodiphenylamine
Oxyfhiorfen
Pentabromodiphenyl ether
Pentachlorocyclopentadiene
Pentafluoroethane
m-Phenylenediamine
Phenylmercuric acetate
Phosmet
Phthalic anhydride
Picloram
Pirimiphos-methyl
Potassium silver cyanide
Prometon
Pronamide
Propanil
Propargyl alcohol
Propham
Propylene glycol monomethyl ether
Propylene glycol
Propyleneimine
CAS Number
24307-26-4
7487-94-7
7439-97-6
78-48-8
10265-92-6
624-83-9
80-62-6
94-74-6
93-65-2
22967-92-6
108-39-4
106-44-5
21087-64-9
14797-55-8
14797-65-0
62-75-9
621-64-7
86-30-6
42874-03-3
32534-81-9
25329-35-5
354-33-6
108-45-2
62-38-4
732-11-6
85-44-9
1918-02-1
29232-93-7
506-61-6
1610-18-0
23950-58-5
709-98-8
107-19-7
122-42-9
107-98-2
57-55-6
75-55-8
RfD
N
C
N
N
C
N
C
C
N
N
N
N
C
O
o
0
N
C
N
C
N
C
N
N
N
N
N
N
C
C
--
JR1C CSE IUR WOE
o
-- C -- C
N -- -- C
C -- -- 0
o
C -- -- O
C -- -- C
o
C
C -- -- C
C -- -- C
c
-- 0 -- O
O -- O
N C N
C O C
-- c -- c
o
- c
c
N -- -- O
o
o
o -- o
- o
o
- -
--
- o
o
o
o
- o
N
N
C -- -- O
UR
N/A
11
33
1
N/A
27
10
5
9
17
5
9
0
44
22
20
19
3
N/A
37
0
5
71
11
N/A
10
2
N/A
0
0
N/A
13
4
1
32
29
1
G-4
-------
Screening-Level Review of the IRIS Database Phase II
September 2002
Chemical
Pyndme
Quinalphos
Quinoline
Quinone
Radium 226,228
Radon 222
Resmethnn
Savey
Selenious acid
Selenium sulfide
Selenium and Compounds
Selenourea
Silver cyanide
Simazme
Sodium diethyldithiocarbamate
Strychnine
Systhane
Tebuthiuron
Terbutryn
Tetrabromodiphenyl ether
1 ,2,4,5-Tetrachlorobenzene
Tetrachlorocyclopentadiene
1,1,1 ,2-TetrachIoroethane
1 , 1 ,2,2-Tetrachloroethane
2,3,4,6-Tetrachlorophenol
Tetraethyl lead
Thallic oxide
Thallium carbonate
Thallium nitrate
Thallium sulfate
Thiobencarb
Thiophanate-methyl
Toxaphene
1 ,2,4-Tribromobenzene
Tnbutyltin oxide
Tnchloroacetic acid
Tnchlorocyclopentadiene
Tnchlorofluoromethane
CAS Number
110-86-1
13593-03-8
91-22-5
106-51-4
7440-14-4
14859-67-7
10453-86-8
78587-05-0
7783-00-8
7446-34-6
7782-49-2
630-10-4
506-64-9
122-34-9
148-18-5
57-24-9
88671-89-0
34014-18-1
886-50-0
40088-47-9
95-94-3
695-77-2
630-20-6
79-34-5
58-90-2
78-00-2
1314-32-5
6533-73-9
10102-45-1
7446-18-6
28249-77-6
23564-05-8
8001-35-2
615-54-3
56-35-9
76-03-9
77323-84-3
75-69-4
RfD
C
N
C
C
C
C
0
N
C
C
N
C
C
C
C
N
N
C
o
C
N
C
N
C
C
C
N
O
C
N
O
C
JSfC CSJL
_ .
C C
C
C
C
_-
- -
_ .
- -
o
o
- -
. .
- -
- -
C
C
o
_ -
_ -
--
o
N
_ -
C
0
- -
.-
J1IR WOE
0
o
C
o
C C
C C
o
C
C
C
. -
o
o
- -
o
o
C
o
C
C C
C C
0
0 0
C
C
C
C
o
o
C C
C
C
C
o
UR
11
4
2
23
5
0
17
4
0
0
6
4
0
19
4
13
5
0
2
1
N/A
0
15
6
6
21
1
0
0
1
0
N/A
1
3
0
4
0
8
G-5
-------
Screening-Level Review of the IRIS Database Phase II
September 2002
Chemical
2,4,5-Tnchlorophenol
2,4,6-Tnchlorophenol
2 (2,4,5-Tnchlorophenoxy) propiomc acid
1 ,2,3-Tnchloropropane
1 , 1 ,2-Trichloropropane
1 , 1 ,2-Tnchloro- 1 ,2,2-tnfluoroethane
Tridiphane
Tnethylene glycol monobutyl ether
Tnethylene glycol monoethyl ether
Tnfluralm
Uranium, soluble salts
Vanadium pentoxide
Vinclozolm
CAS Number
95-95-4
88-06-2
93-72-1
96-18-4
598-77-6
76-13-1
58138-08-2
143-22-6
112-50-5
1582-09-8
NA
1314-62-1
50471-44-8
RfD
C
O
C
N
C
C
N
--
N
N
N
N
RfC
C
C
O
0
C
C
O
O
--
CSF
C
O
O
C
O
ItIR
O
C
0
--
WOE
0
C
N
O
0
--
C
O
O
UR
1
1
3
N/A
1
31
1
4
5
3
N/A
8
N/A
Summary of Assessments:
Available in the existing IRIS summary 141 40 30 21 80
Not available in the existing IRIS summary 59 160 170 179 120
No literature likely to produce a significant change in the IRIS
summary was identified
80
31
24
15
69
New literature was identified that could potentially produce a
significant change in the IRIS summary1
61
11
Not available in IRIS, but potentially relevant information was
identified
23
20
18
75
Notes-
1 The screening-level review of the IRIS summaries for 79 chemicals (40%) identified new health effects information
that, if evaluated in detail, could possibly result in a change to at least one existing value
- - No value is available in the existing IRIS file
C The literature published since the IRIS consensus review does not appear to contain study data that could
potentially produce a change in the IRIS summary The existing IRIS summary is considered current.
N New health effects information that could potentially affect the IRIS summary was identified.
O No value is available in the existing IRIS file Potentially relevant information was identified during
evaluation of the literature compilations or literature search results. This information may or may not
support the derivation of an IRIS toxicity value or WOE designation. The narratives for individual
chemicals provide further discussions about the nature of this information
G-6
-------
Screening-Level Review of the IRIS Database Phase II September 2002
CAS chemical abstracts registry service
CSF oral cancer slope factor
IRIS Integrated Risk Information System
IUR inhalation unit nsk
N/A not applicable, no literature search was deemed necessary
RfD oral reference dose
RfC inhalation reference concentration
UR unknown relevance, number of studies identified as being of unknown relevance during literature
sorting
WOE cancer weight-of-evidence
G-7
------- |