United States
Environmental Protection
Summary Report for the
Screening-Level Review of
Toxicity Information
Contained in the Integrated
Risk Information System
(IRIS) Database - Phase I
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NCEA-S-1391
November 2001
Summary Report for the Screening-level Review of
Toxicity Information Contained in the
Integrated Risk Information System (IRIS) Database
Phase I
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 I November 2001
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.
11
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Screening-Level Review of the IRIS Database Phase I November 2001
CONTENTS
1.0 INTRODUCTION AND PURPOSE 1
2.0 METHODS 2
2.1 Task 1: Selecting 100 IRIS Chemicals 2
2.2 Task 2: Identifying Existing Literature Compilations 2
2.3 Task 3: Conducting Literature Searches 6
2.4 Task 4: Sorting Literature Search Results 7
2.5 Task 5: Evaluating Health Effects Information 8
3.0 RESULTS AND CONCLUSIONS 10
APPENDICES
Appendix A: List of 100 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 Screening-Level
Review 3
Table 2: Literature Search Terms 7
Table 3: Laboratory Species and Toxicological Terms 8
Table 4: Results of Screening-Level Review of IRIS 11
in
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Screening-Level Review of the IRIS Database Phase 1 November 2001
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. 42. Susan Rieth served as the Work Assignment Manager.
IV
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Screening-Level Review of the IRIS Database Phase I November 2001
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 the EPA's National Center for Environmental Assessment (NCEA).
IRIS assessments contain chemical-specific summaries of 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 (lURs) 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 been published in the literature, but
has not been 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 lexicological 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, in fact, the majority of
effort required in fully assessing a chemical. The screening-level methodology was designed to
quickly identify and characterize the majority of new health effects literature and may not
provide an accurate or comprehensive evaluation of the literature for all IRIS chemicals.
The size of the IRIS database precluded screening-level reviews of all of the chemicals included
in IRIS at one time. Therefore, screening-level reviews were conducted for 100 chemicals
randomly selected from the IRIS database of more than 500 chemicals. These 100 chemicals
were randomly selected so that conclusions could be extended to the entire IRIS database.
Additional chemicals from the IRIS database will likely undergo screening-level reviews in the
future.
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Screening-Level Review of the IRIS Database Phase I November 2001
2.0 METHODS
The screening-level review of the IRIS summaries was conducted in five steps: 1) selecting the
100 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 prepared, 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 summaries.
2.1 Task 1: Selecting 100 IRIS Chemicals
EPA prepared a list of all chemicals contained in the IRIS database, excluding those chemicals
currently being reassessed under the IRIS program. The complete list of chemicals was imported
into Microsoft Excel to randomly select 100 chemicals for the 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 IRIS chemicals was then reorganized using the Sort tool to sort the
chemicals in ascending order by the randomly assigned number. This process created a randomly
reshuffled list of all chemicals contained in the IRIS database. The first 100 chemicals identified
in this sort were selected for the literature-screening reviews and are listed in Appendix A.
2.2 Task 2: Identifying Existing Literature Compilations
EPA programs (e.g., Office of Pesticide Programs [OPP]) and other authoritative scientific
organizations (e.g., the International Agency for Research on Cancer [IARC] and the Agency for
Toxic Substances and Disease Registry [ATSDR]) periodically review and summarize the
toxicology literature for chemicals that are included in the IRIS database. As a first step in
conducting the screening-level reviews, toxicity information contained in the IRIS summaries
and available toxicology literature compilations was identified. This information was then
assessed to most efficiently target literature searches to be conducted under Task 3.
Literature compilations were identified by searching Web-based databases or EPA files, as listed
in Table 1. Key toxicity information contained in the IRIS summaries, information about the
availability of toxicology literature compilations, and toxicity values developed by other
authoritative scientific bodies were organized in a Lotus Notes database. The specific toxicity
information tracked in the Lotus Notes database from each source is also listed in Table 1. 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, 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.
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Screening-Level Review of the IRIS Database Phase I
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The information contained in this database was used to develop the literature search strategies
implemented for each chemical under Task 3; therefore, ensuring the accuracy of the toxicity
information presented in the Lotus Notes database was key to ensuring accurate screening-level
reviews. 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.
Table 1: Literature Compilations and Toxicity Information Considered in
the Screening-Level Review
Source
IRIS
IRIS Submission
Desk
ATSDR
Toxicological
Profiles
ATSDR
Supplemental
Documents
Health Canada1
IARC Monographs
WHO/IPCS
NTP Cancer
Bioassay
Information Extracted
Toxicity values and
WOE designation
Principal study
descriptions
Date values placed online
Publication date
Relevant information
Publication date
Minimal risk levels
Principal study
descriptions
Date of last update
Publication date
Toxicity values and
cancer classification
Principal study
descriptions
Publication date
IARC classification
Publication date
Publication date
Results
Location of Source
httpV/www.epa.gov/iris/subst/index.html
Available through EPA
TERA's on-line ITER database
http-//147.160 131 23/pubhcurl/pub_search_hst.cfm
http://www.atsdr cdc gov/toxpro2 html
Available through ATSDR
TERA's on-line ITER database
http.// 1 47. 1 60. 1 3 1 23/publicurl/pub_search_hst cfm
http://19351 164 Ml
httpV/www who int/pcs/pubs/pub_ehc htm
httpV/ntp-server.niehs nih.gov/
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Table 1: Literature Compilations and Toxicity Information Considered in
the Screening-Level Review
Source
Information Extracted
Location of Source
NTP Report on
Carcinogens
Publication date
Cancer classification
httpV/ntp-server.niehs nih.gov/NewHomeRoc/
AboutRoC html
OPPRED
documents
Publication date
Toxicity values
Principal study
descriptions
http://www epa gov/REDs/
NCEA Provisional
Assessments2
Date of assessment
Toxicity values and
cancer classification
Principal study
descriptions
Available through EPA
Notes:
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.
2 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 Disease Registry
EPA U.S. Environmental Protection Agency
IARC International Agency for Research on Cancer
IPCS International Programme on Chemical Safety
IRIS Integrated Risk Information System
NCEA National Center for Environmental Assessment
NTP National Toxicity Program
OPP Office of Pesticide Programs
RED Reregistration Eligibility Decision
WHO World Health Organization
Information contained in the Lotus Notes database was 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 IRJS toxicity values and/or WOE designation. A determination
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Screening-Level Review of the IRIS Database Phase I November 2001
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. The literature
compilation was considered a credible source of toxicology information. A determination
was made to conduct a literature search beginning with the year before the compilation
was published to the present.
Example: The consensus date was June 4, 1990. ATSDR published a toxicological
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 a study or information available after the
IRIS consensus date, suggesting that significant new health effects literature exists that
may result in a revised IRIS toxicity value. The literature compilation was considered a
credible source of toxicology information. 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 199S study was identified as health effects information that
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
available in the IRIS summary, including the RfO, RfC, and cancer endpoints (CSF, IUR, and
WOE designation) and were documented in the Lotus Notes database for each chemical, as
shown in the sample report provided in Appendix B.
If a toxicity value or WOE designation was not available in an IRIS summary, then a screening-
level review to determine whether the value reflected the current health effects literature could
not be performed. Nonetheless, if information relevant to an absent toxicity value was identified
when screening the literature compilations, this information was noted in the Lotus Notes
database.
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Screening-Level Review of the IRIS Database Phase I November 2001
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 databases 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.
• MEDLINE (available through PUBMED at http://www. ncbi. nlm. nih.gov/PubMed/): This
databases contains bibliographic citations and author abstracts from more than 4,000
biomedical journals.
• CANCERLIT (http://cancernet.nci.nih.gov/cancerlit shtml): 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.
Additional information about each of the databases searched is provided at the listed Web sites.
For chemicals with IRIS summaries containing toxicity values and WOE designations, each of
the four databases were searched. For chemicals with IRIS summaries containing only a RfD
and/or a RfC, only TOXLINE and MEDLINE were searched because CANCERLIT and CCRIS
contain information specific to cancer endpoints only.
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 SO 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.
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Screening-Level Review of the IRIS Database Phase I November 2001
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 atone identified all relevant entries. If the CAS number was listed in
CCRIS, the search results were saved. If the CAS number was not listed in CCRIS, then no
cancer-related data were available.
EndNote, a reference managing software program, was used to manage and organize results
obtained from the literature search. For each chemical, results were 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. 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
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
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Each of these categones and the criteria used to assign categories are described in more detail in
Appendix D.
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 in 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 100 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), however, 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 "Express" identified over 3,500 references. References not
relevant to an IRIS assessment for Express were identified through a search of EndNote and
were coded N/A in the EndNote file. Other chemicals, such as 2,4-D, 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, but were not assigned a code. The use of the
additional search terms 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.
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 the
more recent health effects information not considered in the IRIS summaries 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
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Screening-Level Review of the IRIS Database Phase I November 2001
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 RfOs and
RfCs, CSFs and lURs, and WOE designations. Decision trees are provided in Appendix E. Each
IRIS toxicity value (i.e., RfD, RfC, oral slope factor, or inhalation unit risk) and WOE
designation currently contained in IRIS was evaluated separately. Such evaluations were not
performed if 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 lURs 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 100 chemicals were summarized in 1-
page narratives. 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 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. Where a toxicity value or WOE
designation was absent from an IRIS summary for an individual chemical, similar conclusions
could not be drawn. Nonetheless, if information relevant to an absent toxicity value was
identified when screening the available literature compilations and literature search results, this
information 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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Screening-Level Review of the IRIS Database Phase I November 2001
3.0 RESULTS AND CONCLUSIONS
A screening-level review of 100 chemicals randomly selected from the IRIS database was
conducted to address questions about whether or not the existing IRIS summaries for each
chemical captured the current health effects literature. The results of this review are summarized
in the following text and Table 4. Results for individual chemicals are provided in Appendix G.
For 57 (57%) of the 100 chemicals reviewed, no significant new health effects information that
would likely produce a significant change in existing toxicity values was identified. For 43
chemicals (43%) new health effects information was identified that, if evaluated in detail, could
possibly result in a change to an existing value.
Results relevant to the specific toxicity values and WOE designations are as follows:
• RfDs were available for 70 of the chemicals reviewed. New health effects information
that could potentially result in a significant change in the RfD was identified for 32 of the
70 chemicals.
• RfCs were available for 25 of the chemicals reviewed. New health effects information
that could potentially result in a significant change in the RfC was identified for 5 of the
25 chemicals.
• CSFs were available for 18 of the chemicals reviewed. New health effects information
that could potentially result in a significant change in the CSF was identified for 3 of the
18 chemicals.
• lURs were available for 10 of the chemicals reviewed. New health effects information
that could potentially result in a significant change in the IUR was identified for 4 of the
10 chemicals.
• WOE designations were available for 39 of the chemicals reviewed. New health effects
information that could potentially result in a significant change in the WOE designations
was identified for 2 of the 39 chemicals.
For most chemicals in IRIS, one or more toxicity values are not available in IRIS (e.g., for
dibutyl phthalate, an RfD, RfC and WOE are available in IRIS, but not a CSF or IUR). During
the screening-level review, significant health effects information that may apply to a value
absent from an IRIS summary was noted when identified. Of the 100 chemicals evaluated,
information relevant to a toxicity value absent from an existing IRIS summary was identified for
38 chemicals (38%). 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
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Screening-Level Review of the IRIS Database Phase I November 2001
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
RfD RfC CSF IUR WOE
Number of each value:
Available in the existing IRIS summary 70 25 18 10 39
Not available in the existing ERIS summary 30 75 82 90 61
No literature likely to produce a significant change in the IRIS 38 20 15 6 37
summary was identified
New literature was identified that could potentially produce a 32 5 3 4 2
significant change in the IRIS summary
Not available in IRIS, but potentially relevant information was 4 9 10 1 30
identified
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
in the literature compilations based on available study summaries and 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 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.
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Screening-Level Review of the IRIS Database Phase I November 2001
• 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's Office of Pesticide Programs (OPP) and are considered confidential business
information. Although OPP Reregistration Eligibility Decision (RED) documents, 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.
• 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.
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APPENDICES
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Appendix A: 100 Randomly Selected IRIS Chemicals
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Appendix A: 100 Randomly Selected IRIS Chemicals
Number Chemical CAS 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
37
38
Acetochlor
Acetyl chloride
Acifluorfen (sodium)
Ammonium met hacry late
Asulam
Atrazine
Bayleton
Benzidine
Benzotnchlonde
Beryllium and Compounds
beta-Chloronaphthalene
Bis(chloroethyl)ether
Bis(chloromethyl)ether
Bromomethane
Calcium cyanide
Caprolactam
Chloral hydrate
Chlordane
1 -Chloro- 1 , 1 -difluoroethane
Chlorocyclopentadiene
Chlorsulfuron
Chromium(III), insoluble salts
Copper Cyanide
Creosote
Crotonaldehyde
Cypermethnn
Cyromazme
Dacthal
Demeton
Diazomethane
Dibutyl phthalate
3,3'-Dichlorobenzidine
Dichlorodifluoromethane
p,p'-Dichlorodiphenyldichloroethane
2,4-Dichlorophenol
2,4-Dichlorophenoxyacetic acid
Dichlorvos
Diethylene glycol dmitrate
34256-82-1
75-36-5
62476-59-9
16325-47-6
3337-71-1
1912-24-9
43121-43-3
92-87-5
98-07-7
7440-41-7
91-58-7
111-44-4
542-88-1
74-83-9
592-01-8
105-60-2
302-17-0
12789-03-6
75-68-3
41851-50-7
64902-72-3
16065-83-1
544-92-3
8001-58-9
123-73-9
52315-07-8
66215-27-8
1861-32-1
8065-48-3
334-88-3
84-74-2
91-94-1
75-71-8
72-54-8
120-83-2
94-75-7
62-73-7
693-21-0
A-l
-------
Screening-Level Review of the IRIS Database Phase 1
November 2001
Number
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
75
76
77
78
Chemical
Dnsopropyl methylphosphonate
Dimethyl terephthalate
Dimethylamine
N-N-Dimethylamline
Diquat
Dodine
Endnn
2-Ethoxyethanol
Ethyl acetate
Ethyl carbamate
Ethyl ether
Express
Fenamiphos
Fluorine (soluble fluoride)
Folpet
Fonofos
Furfural
Glufosinate-ammomum
Heptachlor
Hexabromobenzene
Hexabromodiphenyl ether
Hexachlorodibenzo-p-dioxin, mixture
n-Hexane
Imazahl
Iprodione
Isopropalm
Isoxaben
Lactofen
Maneb
Methomyl
Methyl iodide
4-(2-Methyl-4-chlorophenoxy) butync acid
4,4'-Methylene bis(N,N'-dimethyl)aniline
Methylene Diphenyl Dnsocyanate (monomenc and polymeric)
2-Methylphenol
Molmate
Naled
Napropamide
Nickel carbonyl
Nickel subsulfide
CAS Number
1445-75-6
120-61-6
124-40-3
121-69-7
85-00-7
2439-10-3
72-20-8
110-80-5
141-78-6
51-79-6
60-29-7
101200-48-0
22224-92-6
7782-41-4
133-07-3
944-22-9
98-01-1
77182-82-2
76-44-8
87-82-1
36483-60-0
19408-74-3
1 10-54-3
35554-44-0
36734-19-7
33820-53-0
82558-50-7
77501-63-4
12427-38-2
16752-77-5
74-88-4
94-81-5
101-61-1
101-68-8/9016-87-9
95-48-7
2212-67-1
300-76-5
15299-99-7
13463-39-3
12035-72-2
A-2
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Screening-Level Review of the IRIS Database Phase I
November 2001
Number
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
Chemical
Nitroguanidine
p-Nitrophenol
2-Nitropropane
N-Nitrosopyrrolidme
Norflurazon
Oryzalin
Paclobutrazol
Phosalone
Phosphoric acid
Prochloraz
Propazine
Propylene glycol monoethyl ether
Rotenone
Strontium
Thallium chlonde
Triasulfuron
1 ,2,4-Tnchlorobenzene
1,1,1 -Trichloroethane
2,2,4-Tnmethylpentane
2,4,6-Tnnitrotoluene
Zinc phosphide
Zmeb
CAS Number
556-88-7
100-02-7
79-46-9
930-55-2
27314-13-2
19044-88-3
76738-62-0
2310-17-0
7664-38-2
67747-09-5
139-40-2
52125-53-8
83-79-4
7440-24-6
7791-12-0
82097-50-5
120-82-1
71-55-6
540-84-1
1 18-96-7
1314-84-7
12122-67-7
Notes-
CAS Number chemical abstracts registry service number
A-3
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Screening-Level Review of the IRIS Database Phase I November 2001
Appendix B: Sample Lotus Notes Report
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Appendix B: Sample Lotus Notes Report
Summary of Toxicity Information for Chemicals Listed in IRIS
Chemical Name: Acetochlor CASRN: 34256-82-1
IRIS
RfD (mg/kg/day): 0.02
Date of Last Significant Revision: 3/24/92
Availability:
Critical Effect: Salivation, increased ALT and ornithine carbamyl transferase; significant
increases in triglyceride and decreased blood glucose levels; histopathological changes in kidneys
and testes of males
UF: 100
MF:1
Was an UF assigned based on lack of supporting data? No
What was the data gap?
Study Animal/Species: Dog
Principal Study Description: 1-yr dog feeding study
Principal Study Reference: ICI, Inc., 1988a
RfC (mg/m3):
Date of Last Significant Revision:
Availability: Not available
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:
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: Not available
Date of Last Significant Revision:
B-l
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Screening-Level Review of the IRIS Database Phase I November 2001
Information Available through the IRIS Submission Desk
Comments: Not available
ATSDR
Toxicological Profile (date of most recent update): Not available
Oral MRL (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:
B-2
-------
Screening-Level Review of the IRIS Database Phase I November 2001
(ARC
Date of Most Recent Monograph: Not available
Classification:
WHO
Publication Date: Not available
Publishing Organization:
NTP Cancer Bioassay (published since 1986)
Publication Date: Not available
Route of exposure:
Result:
NTP Report on Carcinogens
Date Listed: Not available
Classification:
Reregistration Eligibility Decisions (RED)
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:
B-3
-------
Screening-Level Review of the IRIS Database Phase I November 2001
IUR(ug/m3)-1:
Tumor Type:
Study Animal/Species:
Principal Study Reference:
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 1991 to present
B-4
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Appendix C: Electronic Files
-------
Screening-Level Review of the IRJS Database Phase I November 2001
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 100 chemicals
C-l
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Screening-Level Review of the IRIS Database Phase I November 2001
Appendix D: Reference Sorting Criteria
-------
Screening-Level Review of the IRIS Database Phase I
November 2001
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 epidemiotogical studies) Studies
in this category would include:
• genotoxicity studies
• DNA adduct studies
• other short-term m 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 pharmacokmetic (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
pharmacokinetics in an animal species and humans.
D-l
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Screening-Level Review of the IRIS Database Phase I
November 2001
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 (RiD, 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 pharmacokmetic 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,
I ARC, 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 I
November 2001
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
mutagenicity 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 I November 2001
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 toxiaty 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)
'f yes.
if yes
Human
epidemiologic
study
if yes
Are new subchronic or chronic animal studies or
epidemiologies! 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 available?
[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
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?
yes
What is the identfied data gap? Do new study data appear
to fill that gap (including "Other data)?
n°
If no, then further review of "Other" data is
not necessary.
I no ^
ArePBPK
modeling data
available?
yes
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
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
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
(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
humans7
no
ves _
no
Potential for new data to change the human
equivalent dose and thereby chanoe the
CCA ID
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. IARC monographs.
NTP Report on Carcinogens
No WOE designation identified that significantly
HiffpmH 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 carcmogeniaty in
humans)
if yes
B1orB2
Probable Human Carcinogen
(BV limited evidence of carcmogeniaty in
humans,
B2. Sufficient evidence of carcmogeniaty 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
carcmogeniaty in humans, or determination that
carcinogenic action in experimental models is not relevant
to humans ]
Are new positive animal or epidemiological data or
extensive mechanistic data available?
[Note The evidence for carcmogeniaty 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 "0" or "E."]
Not Classifiable as to Human
Carcmogeniaty
(inadequate or no evidence)
if yes
Are new animal or epidemiological data available?
[Note Eosilivfi evidence could potentially change the WOE
classification to "C," "B," or even "A" Sufficient negative
evidence could potentially change the designation to "E"]
Evidence for Noncarcmogenicity for
Humans
if yes
Because sufficent positive evidence of human
carcmogeniaty is required to classify a
chemcial as an "A" carcinogen, new
carcmogeniaty 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
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.
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
carcmogeniaty 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 I November 2001
Appendix F: Chemical Summaries
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Acetochlor (CAS No. 34256-82-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for acetochlor was derived (1992) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for acetochlor was derived based on a 52-week dietary study in beagles published in 1988.
A literature search conducted for the years 1991 to 2001 identified a 1992 Bulgarian study of
cardiovascular system effects in white rats after 6 months of oral exposure to acetochlor [only the abstract
is available in English]. A 2000 study compared the metabolism of acetochlor in rats and humans.
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 Office of Pesticide Programs (OPP) has classified acetochlor as a Group B2
carcinogen—probable human carcinogen.
Unknown Relevance
Four documents were categorized as being of unknown relevance.
F-l
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Acetyl Chloride (CAS No. 75-36-5)
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 (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)
for acetyl chloride was derived (1990) does not appear to include study data that could potentially
produce a change in the WOE designation. A literature search conducted for the years 1989 to 2001
identified no new studies that would be directly useful in the derivation of a WOE classification for acetyl
chloride.
Unknown Relevance
No studies were categorized as being of unknown relevance.
F-2
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Acifluorfen (Sodium) (CAS No. 62476-59-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for acifluorfen (sodium) 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 2001 identified no new studies that would be directly useful in the derivation of an RfD
for acifluorfen (sodium).
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 study was categorized as being of unknown relevance.
F-3
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Ammonium Methacrylate (CAS No. 16325-47-6)
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 search results (from 1989 to 2001) indicate that no new health effects studies have been
published since the WOE classification (D—not classifiable as to human carcinogenicity) for ammonium
methacrylate was derived (1990).
Unknown Relevance
No studies were categorized as being of unknown relevance.
F-4
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Asulam (CAS No. 3337-71-1)
Oral Reference Dose (RID)
The Office of Pesticide Programs (OPP) published an oral RfD for asulam in their 1995 Reregistration
Eligibility Decision (RED). Both the RED RfD and IRIS RfD (1987) are based on a 1981 chronic dietary
feeding study in rats.
The literature published since the RED oral RfD for asulam was derived (1995) does not appear to
contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1994 to 2001 identified no new studies that would be directly useful in the derivation of an RfD
for asulam. >
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 studies were categorized as being of unknown relevance.
F-5
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Atrazine (CAS No. 1912-24-9)
Oral Reference Dose (RfD)
A preliminary risk assessment for atrazine prepared by EPA's Office of Pesticide Programs (OPP 2001)
as part of the Registration Eligibility Decision (RED) for the pesticide identified new information not
considered in the IRIS assessment for atrazine. The IRIS RfD was derived based on a 2-year rat feeding
study (1986) and a 1-year dog feeding study (1987). OPP derived an RfD based on a 6-month LH surge
study in rats (1996).
Because the OPP risk assessment was so recently conducted, a literature search was not deemed
necessary.
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 was published in 1999.
Atrazine was classified as a Group 3 carcinogen—unclassifiable as to carcinogenicity in humans. The
OPP preliminary risk assessment (2001) classified atrazine as "not likely to be carcinogenic to humans."
Unknown Relevance
A literature search was not performed.
F-6
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Bayleton (CAS No. 43121-43-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for bayleton was derived (1986) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for bayleton was derived based on a 1978 2-year dietary study in rats. A literature search
conducted for the years 198S to 2001 identified a 24-week dietary study in pregnant rats fed bayleton and
treated with a single injection of nitrosomethylurea (1994) and a 1986 review of dietary studies in mice,
rats, and dogs. It cannot be determined whether or not the study data summarized in the 1986 review were
considered in the IRIS assessment for bayleton.
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 more recent literature includes three medium-term liver bioassay studies in rats (1992, 1992,
and 1993), an evaluation of the mutagenic potential of acute exposures in rats (1994), a study of the
genotoxicity in mouse bone marrow and the sister-chromatid exchange test with human lymphocytes
(1996), and a study of the mode of carcinogenic action inducing follicular cell tumors in the thyroids of
rodents.
Unknown Relevance
Three studies were categorized as being of unknown relevance.
F-7
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Benzidine (CAS No. 98-07-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for benzidine was derived (1987) does not appear to contain
study data that could potentially produce a change in the RfD. In 1999, the Agency for Toxic Substances
and Disease Registry (ATSDR) published a toxicological profile for benzidine and determined that data
were inadequate to derive an oral minimal risk level. A literature search conducted for the years 1998 to
2001 identified no new studies that would be directly useful in deriving an oral RfD for benzidine.
Inhalation Reference Concentration (RfC)
The health effects data for benzidine were reviewed by the RfD/RfC Work Group in 1991 and were
determined to be inadequate for derivation of an inhalation RfC. The literature published since the Work
Group conducted their review does not appear to contain study data that would support development of an
inhalation RfC for benzidine. ATSDR, in their 1999 toxicological profile for benzidine, concluded that
data were inadequate to derive an inhalation MRL. A literature search conducted for the years 1998 to
2001 identified no new studies that would be directly useful in deriving an inhalation RfC for benzidine.
Oral Slope Factor (CSF)
The literature published since the oral CSF for benzidine was derived (1986) contains study data that
could potentially produce a change in the CSF.
Benzidine's CSF was derived based on a 1973 study of bladder cancer in a worker population
occupationally exposed to benzidine by inhalation. A cohort study of Chinese workers exposed to
benzidine was published in 2001. (See the IUR discussion for study details.)
Inhalation Unit Risk (IUR)
The literature published since the IUR for benzidine was derived (1986) contains study data that could
potentially produce a change in the IUR.
Benzidine's IUR was derived based on a 1973 study of bladder cancer in a worker population
occupationally exposed to benzidine by inhalation. A cohort study of Chinese workers exposed to
benzidine was published in 2001. The cohort consisted of 1,788 exposed and 373 nonexposed workers
followed from 1991 to 1997. Results for this benzidine-exposed cohort were published by the same
investigators in two earlier abstracts (1998).
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (A—human carcinogen) for benzidine was denved
(1986) does not appear to contain study data that would produce a change in the WOE. Study data
published since the IRIS assessment was prepared support the finding that benzidine is a carcinogen
(including positive evidence of mutagenicity and DNA adduct formation).
Unknown Relevance
Four studies were characterized as being of unknown relevance.
F-8
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Benzotrichloride (CAS No. 98-07-7)
Oral Reference Dose (RfD)
No assessment of the oral 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 benzotrichloride was derived (1989) does not appear to include
study data that could potentially produce a change in the CSF. A review of the I ARC monograph
published in 1999 and a literature search conducted for the years 1998 to 2001 identified no new studies
that would be directly useful in the derivation of a CSF for benzotrichloride.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
In 1986, EPA designated benzotrichloride as a Class B2 carcinogen—probable human carcinogen. The
literature published since the WOE was established is not likely to include studies that could potentially
produce a change in the WOE classification. In the 1999 International Agency for Research on Cancer
(IARC) monograph, combined exposure to benzotrichloride and benzoyl chloride was classified as
probably carcinogenic to humans (Group 2A), consistent with the current EPA carcinogen classification.
Benzotrichloride was also classified as having sufficient evidence of carcinogenicity in experimental
animals.
Unknown Relevance
No studies were characterized as being of unknown relevance.
F-9
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Beryllium and Compounds (CAS No. 7440-41-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for beryllium and compounds was derived (1998) does not
appear to include study data that could potentially produce a change in the RfD.
The IRIS RfD was derived based on a dietary study in dogs (1976). The Agency for Toxic Substances
and Disease Registry (ATSDR) published a lexicological profile in 2000. ATSDR derived an oral
minimal risk level (0.001 mg/kg/day) based on a 1976 dietary study in dogs, which is the same study used
to derive the IRIS RfD. A literature search conducted for the years 1999 to 2001 identified no new studies
that would be directly useful in deriving an oral RfD for beryllium and compounds.
Inhalation Reference Concentration (RfC)
The literature published since the RfC for beryllium and compounds was derived (1998) does not appear
to include study data that could potentially produce a change in the inhalation RfC.
The IRIS RfC was derived based on an occupational study of humans (1996) and a community exposure
study (1949). In the 2000 toxicological profile, ATSDR determined that insufficient data were available
to derive an inhalation RfC. A literature search conducted for the years 1999 to 2001 identified no new
studies that would be directly useful in deriving an inhalation RfC for beryllium and compounds.
Oral Slope Factor (CSF)
At the time of the last IRIS assessment for beryllium and compounds (1998), the oral database was
considered inadequate for the assessment of carcinogenicity. Review of ATSDR's 2000 toxicological
profile and a literature search conducted for the years 1999 to 2001 identified no new studies that would
be directly useful in deriving a CSF.
Inhalation Unit Risk (IUR)
The literature published since the cancer dose-response assessment for beryllium was conducted appears
to include study data that could potentially produce a change in the IUR.
The beryllium cancer dose-response assessment in IRIS was derived in 1987 based on a 1980
occupational study. The National Institute of Occupational Safety and Health (NIOSH) completed a lung
cancer case-control study nested within a cohort mortality study of beryllium manufacturing workers at
the Reading Beryllium Processing Facility. At the time of the IRIS assessment, this study was under peer
review. Rather than calculate an interim quantitative estimate based on data available at the time of the
assessment, EPA retained the IUR denved in 1987 until the NIOSH assessment could be evaluated as the
basis for a quantitative estimate. A literature search conducted for the years 1999 to 2001 revealed that the
NIOSH study appears to have been published (Sanderson et al. 2001).
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE classification (Bl—probable human carcinogen) was derived
(1998) does not appear to include study data that could potentially produce a change in the WOE
designation. The recent literature appears to contain study data that further support the current WOE. In
addition to the lung cancer case-control study listed above, a study of the effects of metal salts (including
beryllium) on the fidelity of DNA synthesis in vitro was published in 1999.
F-10
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Screening-Level Review of the IRIS Database Phase I November 2001
Unknown Relevance
Three studies were characterized as being of unknown relevance.
F-ll
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Beta-Chloronaphthalene (CAS No. 91-58-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for beta-chloronaphthalene was derived (1990) does not
appear to include study data that could potentially produce a change in the RfD. A literature search
conducted for the years 1989 to 2001 identified no new studies that would be directly useful in deriving
an oral RfD for beta-chloronaphthalene.
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 study was characterized as being of unknown relevance.
F-12
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Bis(chloroethyl)ether (BCEE) (CAS No. 111-44-4)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
The literature published since 1991, when EPA concluded that the available information was insufficient
to derive an inhalation RfC, does not appear to contain study data that would support development of an
inhalation RfC for BCEE. A literature search conducted for the years 1990 to 2001 identified no new
studies that would be directly useful in the derivation of an inhalation RfC.
Oral Slope Factor (CSF)
The literature published since the CSF for BCEE was derived (1986) does not appear to include study
data that could potentially produce a change in the CSF. A review of the International Agency for
Research on Cancer (IARC) monograph (1999), World Health Organization (WHO) Environmental
Health Criteria document for selected chloroalkyl ethers (1998), and a literature search conducted for the
years 1998 to 2001 identified no new studies that would be directly useful in the derivation of a CSF.
Inhalation Unit Risk (1UR)
The literature published since the IUR for BCEE was derived (1986) does not appear to include study
data that could potentially produce a change in the IUR. A review of the IARC monograph (1999), WHO
Environmental Health Criteria document for selected chloroalkyl ethers (1998), and a literature search
conducted for the years 1998 to 2001 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
(1986) does not appear to include study data that could produce a change in the WOE. An IARC
Monograph was published (1999). IARC, however, characterized BCEE as not classifiable as to its
carcinogenicity to humans (Group 3). Two studies (1993 and 1997) examined the risk of cancer among
workers exposed to a number of chemicals, including BCEE, during the production of chlorohydrin. A
literature search conducted for the years 1998 to 2001 identified no new studies that would be directly
useful in establishing a WOE classification.
Unknown Relevance
One study was characterized as being of unknown relevance.
F-13
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Bis(chloromethyl)ether (CAS No. 542-88-1)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
The literature published since 1991, when EPA concluded that the available information was insufficient
to derive an inhalation RfC, does not appear to include study data that could potentially produce a change
in the RfC. A review of the Health Canada assessment (1992) and a literature search conducted for the
years 1991 to 2001 identified no new studies that would be directly useful in the derivation of an RfC for
bis(chloromethyl)ether.
Oral Slope Factor (CSF)
The literature published since the CSF was derived (1988) does not appear to include study data that
could potentially produce a change in the CSF for bis(chloromethyl)ether. A review of the Health Canada
assessment (1992) and a literature search conducted for the years 1991 to 2001 identified no new studies
that would be directly useful in the derivation of a CSF for bis(chloromethyl)ether.
Note: The IRIS CSF was derived based on a 1975 study of respiratory tract tumors in rats, whereas the
Health Canada TDOS was derived based on a 1981 study of nose tumors in rats.
Inhalation Unit Risk (IUR)
The literature published since the IUR was derived (1988) appears to include study data that could
potentially produce a change in the IUR for bis(chloromethyl)ether. A review of the Health Canada
assessment (1992) and a literature search conducted for the years 1991 to 2001 identified a cohort study
of chemical workers exposed to chloromethyl ethers with an observation period of 30 years. Whether
exposures to bis(chloromethyl)ether were specifically measured in the study could not be determined
from the abstract.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE was derived (1988) does not appear to include study data that
could potentially produce a change in the cancer WOE. This new literature, however, does include study
data that would further support the WOE.
The IRIS WOE of A (human carcinogen) was derived in 1988 based on results from six studies of
exposed workers and bioassay data from rats and mice. The studies of exposed workers found increases in
lung tumors. The literature search identified an additional five studies of the carcinogenicity of
bis(chloromethyl)ether.
Unknown Relevance
Eleven studies were categorized as being of unknown relevance. Among these studies are "Long-Term
Carcinogenicity Bioassays on Industrial Chemicals and Man-Made Mineral Fibers" and "A Lifetime
Study of Rats and Mice Exposed to Vapors of Bis(chloromethyl)ether."
F-14
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Bromomethane (CAS No. 74-83-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD was derived (1988) includes study data that could potentially
produce a change in the WOE.
The IRIS RfD was derived based on a 1984 subchronic study where rats were exposed to bromomethane
via gavage. The National Center for Environmental Assessment (NCEA) released a provisional oral RfD
in 1998 based on the same 1984 rat study used to derive the IRIS RfD in 1988. A literature search
conducted for the years 1997 to 2001, however, identified a 1-year feeding study in beagle dogs, which
NCEA does not appear to have considered when developing the provisional value. The results of this
study were published in 1998 and 2000. The literature search also identified a developmental toxicity
study in rats and rabbits (oral administration), published in 1998.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for bromomethane was derived (1991) includes study
data that could potentially produce a change in the RfC.
The IRIS RfC was derived using data from a 29-month inhalation study in rats reported in 1987 and 1991.
In 1998, NCEA released a provisional inhalation RfC based on a 13-week inhalation study of rats
published in 1992. A literature search conducted for the years 1997 to 2001 identified no other studies
that could potentially produce a change in the inhalation RfC for bromomethane.
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
In 1989, EPA designated bromomethane as a Class D carcinogen—not classifiable as to human
carcinogenicity. In 1998, NCEA reviewed available study data and determined that insufficient evidence
was available to determine carcinogenicity in humans. The literature published since the NCEA review
does not appear to contain study data that could potentially produce a change in the WOE classification.
A literature search conducted for the years 1997 to 2001 identified four studies, including an investigation
of DNA methylation in rats and mice (1999), a genotoxicity study in exposed workers (1998), an
evaluation of DNA adducts (1997), and a population-based case-control study of brain rumors in children
(1997). None of these studies were referenced in the NCEA provisional assessment of carcinogenicity. A
limited review of the available abstracts suggests that the studies do not support a finding of
bromomethane carcinogenicity.
Unknown Relevance
Sixteen studies were categorized as being of unknown relevance. These studies included a 1997 study
entitled "Chronic (29-Month) Inhalation Toxicity and Carcinogenicity Study of Methyl Bromide in Rats,
Reexamination of Nasal Cavity" (this may be the same study used as the basis for the current RfC), a
F-15
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Screening-Level Review of the IRIS Database Phase I November 2001
2000 study entitled "Methylene Bromide: A Ninety-Day Repeated Inhalation Toxicity Study in Rats and
Dogs With a Subsequent Two-Year Holding Period for Rats," and a 2000 study entitled "Teratologic
Assessment of Butylene Oxide and Methyl Bromide NIOSH Technical Report #81-124." Insufficient
information is provided to determine if these studies were considered when NCEA developed provisional
values in 1998 or if study results could potentially change the IRIS assessment.
F-16
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Calcium Cyanide (CAS No. 592-01-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for calcium cyanide was derived (1985) does not appear to
include study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1984 to 2001 identified no new studies that would be directly useful in the derivation of a RfD
for calcium cyanide.
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 is included in IRIS.
Unknown Relevance
One study was categorized as being of unknown relevance.
F-17
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Caprolactam (CAS Mo. 105-60-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for caprolactam was derived (1988) contains study data that
could potentially produce a change in the RfD.
Caprolactam's RfD (1988) was derived based on a three-generation reproduction study published in 1984.
In this study, rats were orally exposed to caprolactam. A literature search conducted for the years 1987 to
2001 identified a number of studies addressing the toxicity of caprolactam, many of which were
submitted to EPA's Office of Toxic Substances (OTS). The results of another three-generation
reproduction study in which rats were exposed to caprolactam in their diets were published in 1988. This
study appears to have been considered in the IRIS assessment. In 1992, 1995, and 2000, results of
subchronic (13-week) and chronic studies of dietary exposures to caprolactam in rats were published.
Other subchronic toxicity studies in rats and dogs were published in 1987 and 199S. Reproductive
toxicity studies in rats and rabbits were published in 1987, 1995, and 2000.
Inhalation Reference Concentration (RfC)
EPA conducted an IRIS assessment for caprolactam in 1994 and found insufficient data to derive an
inhalation RfC. The literature published since 1994 contains study data that could potentially produce a
change in the RfC.
A literature search conducted for the years 1993 to 2001 identified a 13-week inhalation toxicity study of
caprolactam administered to rats as an aqueous aerosol via whole body exposures. The results of this
study were published in 1997 and 1998. The literature search also identified a 1990 study of lung function
in caprolactam workers.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Note: A carcinogenesis bioassay of caprolactam in the rat was submitted to EPA's OTS in 1995.
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) published a monograph (1999) in which
caprolactam was classified as Group 4—probably not carcinogenic to humans. A carcinogenesis bioassay
of caprolactam in the rat was submitted to EPA's OTS in 1995.
Unknown Relevance
Thirty-six studies were characterized as being of unknown relevance.
F-18
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Chloral Hydrate (CAS No. 302-17-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for chloral hydrate was derived (2000) does not appear to
contain study data that could potentially produce a change in the RfD. In 2000, researchers published
results of a study in which male mice and rats were exposed to chloral hydrate in their drinking water for
2 years. They reported no alterations of water consumption, survival, body weight, and organ weights
between the test animals and the control animals. This study, which was in press at the time of the 2000
IRIS assessment, was considered in the derivation of the current RfD.
Inhalation Reference Concentration (RfC)
EPA conducted an IRIS assessment for chloral hydrate in 2000 and determined that insufficient data were
available to include an assessment of the inhalation RfC for chloral hydrate in IRIS. A literature search
conducted for the years 1999 to 2001 identified no new studies that would be directly useful in deriving
an RfC for chloral hydrate.
Oral Slope Factor (CSF)
EPA conducted an IRIS assessment for chloral hydrate in 2000 and determined that insufficient data were
available to calculate a CSF for chloral hydrate. A literature search conducted for the years 1999 to 2001
does not appear to contain study data that could potentially support the development of a CSF. In 2000,
researchers published the results of a study in which male mice and rats were exposed to chloral hydrate
in their drinking water for 2 years. They concluded that chloral hydrate was carcinogenic (causing
hepatocellular neoplasia) in male mice, but not in male rats. This study, which was in press at the time of
the 2000 IRIS assessment, was considered in the evaluation of chloral hydrate carcmogenicity.
Inhalation Unit Risk (IUR)
EPA conducted an IRIS assessment for chloral hydrate in 2000 and determined that no data were
available to calculate a IUR for chloral hydrate. A literature search conducted for the years 1999 to 2001
identified no new studies that would be directly useful in deriving an IUR for chloral hydrate.
Cancer Weight-of-Evidence (WOE) Classification
In 2000, EPA designated chloral hydrate as a Class C carcinogen—possible human carcinogen. In 2000,
the International Agency for Research on Cancer (IARC) released a monograph evaluating the
carcinogenicity of disinfectants and disinfectant byproducts, including chloral hydrate. IARC classified
chloral hydrate as a group 3 carcinogen—unclassifiable as to carcinogenicity in humans. The literature
search (1999 to 2001) identified one study of mutagenicity, which is unlikely to produce a change in the
WOE classification. In 1999, researchers induced micronuclei with chloral hydrate in CYP2E1 competent
cells and in rat hepatocytes
Unknown Relevance
Two studies were categorized as being of unknown relevance.
F-19
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Technical Chlordane (CAS No. 12789-03-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for technical chlordane was derived (1997) does not appear to
include study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1996 to 2001 identified no new studies that would be directly useful in the derivation of an RfD
for technical chlordane.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for technical chlordane was derived (1997) does not
appear to include study data that could potentially produce a change in the RfC. A literature search
conducted for the years 1996 to 2001 identified no new studies that would be directly useful in the
derivation of an RfC for technical chlordane.
Oral Slope Factor (CSF)
The literature published since the CSF for technical chlordane was derived (1997) does not appear to
include study data that could potentially produce a change in the CSF. A literature search conducted for
the years 1996 to 2001 identified no new studies that would be directly useful in the derivation of a CSF
for technical chlordane.
Inhalation Unit Risk (IUR)
The literature published since the IUR for technical chlordane was derived (1997) does not appear to
include study data that could potentially produce a change in the IUR. A literature search conducted for
the years 1996 to 2001 identified no new studies that would be directly useful in the derivation of an IUR
for technical chlordane.
Cancer Weight-of-Evidence (WOE) Classification
In 1997, EPA designated technical chlordane as a Class B2 carcinogen—probable human carcinogen. The
literature published since the WOE was established does not appear to include studies that could
potentially produce a change in the WOE classification. In 1996, papers were published that evaluated
whether exposure to organochlorines, including chlordane, is associated with breast cancer risk among
Long Island women, and that compared concentrations of chlordane in adipose tissue from non-
Hodgkin's lymphoma patients to surgical controls without a malignant disease. In 1998, researchers
reported that chlordane increases liver tumor incidences in rodents and is a tumor promoter.
Unknown Relevance
Seventeen studies were categorized as being of unknown relevance.
Note: The literature search also found studies relevant to chlordane (CAS No. 57-74-9), but not technical
chlordane. These studies were identified by a secondary search of EndNote and were determined to be not
useful to the IRIS assessments.
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
l-Chloro-l,l-Difluoroethane (CAS No. 75-68-3)
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 l-chloro-l,l-difluoroethane was derived (1992) does
not appear to include study data that could potentially produce a change in the RfC. A literature search
conducted for the years 1991 to 2001 identified no new studies that would be directly useful in the
derivation of an RfC for l-chloro-l,l-difluoroethane.
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 studies were categorized as being of unknown relevance. One of these studies is titled "A Two Year
Inhalation Toxicity Study of Fluorocarbon 142b [l-chloro-l,l-difluoroethane] in the Rat." Insufficient
information is provided to determine if this study is the same as the 2-year rat inhalation study used to
derive the RfC.
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Chlorocyclopentadiene (CAS No. 41851-50-7)
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 (D—not classifiable as to human carcinogenicity) was denved
(1989) does not appear to include study data that could potentially produce a change in the WOE. A
literature search conducted for the years 1988 to 2001 identified no new studies that would be directly
useful in the derivation of a WOE classification for Chlorocyclopentadiene.
Unknown Relevance
No studies were categonzed as being of unknown relevance.
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Chlorsulfuron (CAS No. 64902-72-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for chlorsulfuron 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 2001 identified no new studies that would be directly useful in the derivation of an RfD
for chlorsulfuron.
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
Three studies were categorized as being of unknown relevance.
F-23
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Chromium (III), Insoluble Salts (CAS No. 16065-83-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for chromium (III) was derived (1998) does not appear to
contain study data that could potentially produce a change in the RfD.
The Agency for Toxic Substances and Disease Registry (ATSDR) completed a toxicological profile for
chromium (III) in 2000 but did not derive an oral Minimal Risk Level (MRL). A literature search
conducted for the years 1997 to 2001 identified no new studies that would be directly useful in the
derivation of an RfD for chromium (III).
Inhalation Reference Concentration (RfC)
In 1998, EPA determined that there were insufficient data for the derivation of an inhalation RfC for
chromium (III). A literature search conducted for the years 1997 to 2001 identified no new studies that
would be directly useful in the derivation of an RfC for chromium (III).
ATSDR completed a toxicological profile for chromium (III) in 2000 but did not derive an inhalation
MRL. A literature search conducted for the years 1997 to 2001 identified no new studies that would be
directly useful in the derivation of an RfC for chromium (III).
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 was derived (1998) does not appear to contain study data that
could potentially produce a change in the WOE.
The IRIS WOE of D (not classifiable as to human carcinogenicity) was derived because insufficient data
were available. More recent research includes studies of the mutagenicity of chromium (III) (1998 [two
studies], 1997 [two studies]) in human cells and human fibroblasts (two of the study abstracts did not
mention the study animal/species); a DNA adduct study (1998) using human lung cells; and a study of
DNA repair inhibition (1998) (the study abstract did not mention the study animal/species).
Unknown Relevance
Four studies were categorized as being of unknown relevance.
F-24
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Copper Cyanide (CAS No. 544-92-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for copper cyanide 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 2001 identified no new studies that would be directly useful in the derivation of an RfD
for copper 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 is included in IRIS.
Unknown Relevance
No studies were categorized as being of unknown relevance.
F-25
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Creosote (CAS No. 8001-58-9)
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
In 1987, EPA designated creosote as a Class Bl carcinogen—a probable human carcinogen. The literature
published since the WOE classification for creosote was derived does not appear to include study data
that could potentially produce a change in the WOE designation.
In 2000, the Agency for Toxic Substances and Disease Registry (ATSDR) published a draft toxicological
profile for creosote that included an assessment of its carcinogemcity. ATSDR identified approximately
20 studies published since 1987 that examined the association between cancer effects and human
exposure to coal tar creosote and other coal tar products. The majority of these studies suggested that
prolonged human exposure to coal tar creosote and other coal tar products may cause skin cancer or
cancer of other organs. ATSDR identified more than a dozen studies published since 1987 that evaluate
the genotoxic potential of creosote. ATSDR concluded that no definitive data on the genotoxicity of
creosote to humans are available.
A literature search conducted for the years 1999 to 2001 identified no new studies that would be directly
useful in modifying the WOE classification for creosote.
Unknown Relevance
One study was categorized as being of unknown relevance.
F-26
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Crotonaldehyde (CAS No. 123-73-9)
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
In 1991, EPA designated crotonaldehyde as a Class C carcinogen—a possible human carcinogen. The
literature published since the WOE was derived does not appear to include study data that could
potentially produce a change in the WOE.
The literature relevant to a WOE determination published between 1990 and 2001 was limited to seven
studies (1992 [six studies] and 199S) that investigated the mutagenicity, genotoxicity, and DNA impacts
of crotonaldehyde.
Unknown Relevance
One study was categorized as being of unknown relevance.
F-27
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Cypermethrin (CAS No. 52315-07-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for cypermethrin was derived (1989) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for cypermethrin was derived based on a 1-year dog feeding study (1982). The World
Health Organization (WHO) published an Environmental Health Criteria document for cypermethrin in
1989, the same year the IRIS oral RfD was derived. A literature search conducted for the years 1988 to
2001 identified two subchronic toxicity studies in rats (1992, 1988), a cumulative toxicity study in mice,
rats, and rabbits (1990), and a one-generation reproductive toxicity study in rats (1988).
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 (1988 to 2001) identified study data that could be relevant to the development of
a WOE classification. Recent research includes genotoxicity studies (2000,1999, 1995,1992, 1989, 1988
[two studies]), short-term tests of carcinogenic potential (1998, 1992), a study of sister chromatid
exchange (1997), and a study of both chromosomal aberrations and sister chromatid exchange (1993).
Unknown Relevance
A total of 42 studies were categorized as being of unknown relevance.
F-28
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Cyromazine (CAS No. 66215-27-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for cyromazine 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 2001 identified no new studies that would be directly useful in the derivation of an RfD for
cyromazine.
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 studies were categorized as being of unknown relevance.
F-29
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Dacthal (CAS No. 1861-32-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dacthal was derived (1994) does not appear to include
study data that could potentially produce a change in the RfD. The Reregistration Eligibility Decision
(RED) for dacthal was published in 1998. The RfD derived in the RED appears to be based on the same
study as the current IRIS RfD. A literature search conducted for the years 1997 to 2001 identified no new
studies that would be directly useful in the derivation of an oral RfD for dacthal.
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
No studies were identified as being of unknown relevance.
F-30
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Demeton (CAS No. 8065-48-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for demeton was derived (1986) does not appear to include
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1985 to 2001 identified no new studies that would be directly useful in the derivation of an RfD for
demeton.
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 identified three studies potentially relevant to the development of a WOE
classification. Research includes studies of the induction of chromosomal aberrations in hamsters (1986),
clastogenicity in hamsters (1989), and genotoxic and carcinogenic potential (1992).
Unknown Relevance
Eleven studies were categorized as being of unknown relevance.
F-31
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Diazomethane (CAS No. 334-88-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
EPA conducted an IRIS assessment for diazomethane in 1991 and determined that insufficient data were
available to include an assessment of the inhalation RfC in IRIS. A literature search conducted for the
years 1990 to 2001 identified no new studies that would be directly useful in deriving a 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: An International Agency for Research on Cancer (IARC) monograph was published in 1987.
Diazomethane was classified as a group 3 carcinogen—unclassifiable as to carcmogenicity in humans.
Unknown Relevance
One study was categorized as being of unknown relevance.
F-32
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Dibutyl Phthalate (CAS No. 84-74-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dibutyl phthalate was derived (1986) contains study data
that could potentially produce a change in the RfD.
The oral RfD for dibutyl phthalate was derived based on a 1953 subchronic to chronic oral bioassay in
rats. In 1999, the Agency for Toxic Substances and Disease Registry (ATSDR) updated the toxicological
profile for dibutyl phthalate and concluded that there were insufficient data to establish a chronic Minimal
Risk Level (MRL) for dibutyl phthalate.
Review of the draft 1999 ATSDR toxicological profile for dibutyl phthalate and a literature search
conducted for the years 1998 to 2001 identified several new studies that could be directly useful in the
derivation of an RfD for dibutyl phthalate. The results of a 3-month oral toxicity study in rats were
published in 1992. The results of a 13-week National Toxicity Program (NTP) toxicity (feed) study in rats
and mice with an additional perinatal exposure phase were published in 1995. Two NTP continuous
breeding studies in the rat were identified, one published in 1992 and one with its report in preparation.
The results of three reproductive and developmental toxicity studies in rats were published in 1998 and
1999.
Inhalation Reference Concentration (RfC)
EPA conducted an IRIS assessment for dibutyl phthalate in 1990 and determined that insufficient data
were available to include an assessment of the inhalation RfC for dibutyl phthalate in IRIS.
In 1999, ATSDR updated the toxicological profile for dibutyl phthalate and concluded that insufficient
data were available to establish an inhalation MRL. A literature search conducted for the years 1998 to
2001 identified no new studies that would be directly useful in the derivation of an inhalation RfC for
dibutyl phthalate.
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 dibutyl phthalate was derived (1987) does not appear to contain study data that could potentially
produce a change in the WOE classification.
In 1999, ATSDR updated the toxicological profile and did not identify any new studies that contain study
data that could potentially produce a change in the WOE classification. The World Health Organization
(WHO) concluded in a 1997 review that the weight of evidence suggests that dibutyl phthalate is not
mutagemc. A literature search conducted for the years 1998 to 2001 identified three genotoxicity studies
(2000) conducted on human mucosal cells.
F-33
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Screening-Level Review of the IRIS Database Phase I November 2001
Unknown Relevance
Two studies were categorized as being of unknown relevance.
F-34
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
33'-Dichlorobenzidine (CAS No. 91-94-1)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
In 1991, the RfC for 3,3'-dichlorobenzidine was withdrawn because data were determined to be
inadequate to derive an RfC. In 1998, the Agency for Toxic Substances and Disease Registry (ATSDR)
published a toxicological profile for 3,3'-dichlorobenzidine and similarly determined that data were
inadequate to derive an inhalation minimal risk level.
The literature published since the ATSDR toxicological profile for 3,3'-dichlorobenzidine was released
(1998) does not appear to include study data that could potentially produce a change in the RfC. A
literature search conducted for the years 1997 to 2001 identified no new studies that would be directly
useful in the derivation of an RfC for 3,3'-dichlorobenzidine.
Oral Slope Factor (CSV)
The literature published since the CSF for 3,3'-dichlorobenzidine was derived (1988) does not appear to
include study data that could potentially produce a change in the CSF. A review of ATSDR's
toxicological profile and a literature search conducted for the years 1997 to 2001 identified no new
studies that would be directly useful in the derivation of a CSF for 3,3'-dichlorobenzidine.
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) for 3,3'-
dichlorobenzidine was derived (1988) does not appear to include study data that could potentially produce
a change in the WOE designation. A literature search conducted for the years 1997 to 2001 identified no
new studies that would be directly useful in the derivation of a WOE classification for 3,3'-
dichlorobenzidine.
Unknown Relevance
Two documents were categorized as being of unknown relevance.
F-35
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Dichlorodifluoromethane (CAS No. 75-71-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dichlorodifluoromethane was derived (1985) does not
appear to include study data that could potentially produce a change in the RfD. A literature search
conducted for the years 1984 to 2001 identified no new studies that would be directly useful in the
derivation of an RfD for dichlorodifluoromethane.
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 (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
A total of 16 studies were categorized as being of unknown relevance.
F-36
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
p,p'-Dichlorodiphenyldichloroethane (DDD) (CAS No. 72-54-8)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: The Agency for Toxic Substances and Disease Registry (ATSDR) completed an updated
toxicological profile for DDT/DDD/DDE in 2000. ATSDR did not derive any oral Minimal Risk Levels
(MRLs)forDDD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: ATSDR did not derive any inhalation MRLs for DDD in their 2000 update.
Oral Slope Factor (CSF)
The literature published since the CSF for DDD was derived (1987) does not appear to include study data
that could potentially produce a change in the CSF. A review of the 2000 ATSDR toxicological profile
and a literature search conducted for the years 1999 to 2001 identified no new studies that would be
directly useful in the derivation of a CSF for DDD.
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 for DDD (Class B2—probable human carcinogen)
was derived (1987) does not appear to include study data that could potentially produce a change in the
WOE classification. A review of ATSDR's toxicological profile (2000) and a literature search conducted
for the years 1999 to 2001 identified no new studies that would be directly useful in the derivation of a
WOE classification for DDD.
Note: In its 2000 toxicological profile for DDT/DDD/DDE, ATSDR reviewed studies of genotoxicity and
carcinogenicity and presented the cancer classes assigned by EPA, the Department of Health and Human
Services (reasonably anticipated to be a human carcinogen), and the International Agency for Research on
Cancer (IARC). I ARC evaluated technical-grade DDT in its 1991 monograph and classified technical-
grade DDT (a mixture of DDT, its isomers, and related compounds, such as DDD and DDE) as a Group
2B carcinogen—possibly carcinogenic to humans. The Fourth Annual Report on Carcinogens (1985)
produced by the National Toxicology Program (NTP) reported that "the results of oral administration of
TDE [DDD]..., structurally related to DDT and present as contaminants of technical-grade DDT, were
conclusive. In male rats, TDE induced follicular cell carcinomas and adenomas of the thyroid."
Unknown Relevance
No studies were categorized as being of unknown relevance.
F-37
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
2,4-Dichlorophenol (CAS No. 120-83-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,4-dichlorophenol was derived (1986) does not appear to
contain study data that could potentially produce a change in the RfD.
ATSDR completed a toxicological profile for 2,4-dichlorophenol in 1999 and derived an oral minimal
risk level (0.003 mg/kg/day) based on the same study from which the IRIS RfD was derived. This was an
intermediate-term study of immune system effects in rats conducted in 1985. A literature search
conducted for the years 1998 to 2001 identified no new studies that would be directly useful in the
derivation of an RfD for 2,4-dichlorophenol.
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: An NTP Cancer Bioassay published in 1989, however, categorized 2,4-dichlorophenol as NE—no
evidence of carcinogenicity.
Unknown Relevance
Three studies were categorized as unknown relevance.
F-38
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
2,4-Dichlorophenoxyacetic Acid (CAS No. 94-75-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,4-dichlorophenoxyacetic acid (2,4-D) was denved
(1986) contains study data that could potentially produce a change in the RfD.
The IRIS RfD for 2,4-D was derived based on a 90-day oral bioassay using rats (1983) and a 1-year
interim report from a 2-year oral bioassay using rats (1983). A literature search identified subchronic and
chronic toxicity studies in rats, mice, and dogs (1996 [four studies], 1997, 1999); human epidemiologic
studies (1988,1993); and a determination of the maximum food residue levels of 2,4-D that do not cause
toxic effects in a variety of test animals (1997).
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search identified two human epidemiologic studies (1988, 1993) that contain study data
that could be relevant to the development of a RfC.
Oral Slope Factor (CSV)
No assessment of the CSF is included in IRIS.
Note: A literature search identified study data that could be relevant to the development of a CSF. Recent
research includes a chronic dietary oncogenicity studies in mice (1992), rats (1990), and rats and mice
(1996); human epidemiologic studies (1988, 1990, 1993,2001); a case-control study of companion dogs
(1991); and a determination of the maximum food residue levels of 2,4-D that do not cause carcinogenic
effects in mice and rats (1997).
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Note: A literature search identified four human epidemiologic studies (1988, 1990, 1993,2001) and a
case-control study of companion dogs (1991) that contain study data that could be relevant to the
development of a IUR.
Cancer Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Note: A literature search identified study data that could be relevant to the development of a WOE
classification. Recent research includes genotoxic studies (1988, 1990, 1993, 1996, 1998, 1999 [three
studies], 2000); mutagenicity studies (1988,1989,1991, 1993); a follow-up study to the 1991 case-
control study of companion dogs (1995); a study of non-genotoxic effects on gap junctional intercellular
communication (1997); and studies of the association between 2,4-D exposure and activation of c-N-ras
alleles in dogs (1993), Leydig cell function in vitro using rat cells (1996), and urethan-induced lung
adenoma formation in mice (2000).
Unknown Relevance
F-39
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Screening-Level Review of the IRIS Database Phase I November 2001
Eighteen studies were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (2,238), 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, epidemiol*, genotox*, mutat*, and mutag* Any references not containing one
of these search terms were coded as N/A.
F-40
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Dichlorvos (CAS No. 62-73-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dichlorvos was derived (1992) may contain study data that
could potentially produce a change in the RfD.
The IRIS RfD for dichlorvos was derived based on a 1-year dietary study in rats (1990). The Agency for
Toxic Substance and Disease Registry (ATSDR) updated the toxicological profile for dichlorvos in 1997
and a Reregistration Eligibility Decision (RED) Preliminary Risk Assessment was published in 2000.
ATSDR derived an oral Minimal Risk Level (MRL) based on the same 1990 study used to derive the
IRIS oral RfD. The RfD derived for the RED was the same as the IRIS RfD. A literature search conducted
for the years 1999 to 2001, however, identified one three-part oral gavage study in rats (1999) that be
potentially relevant to the derivation of an oral RfD for dichlorvos.
Inhalation Reference Concentration (RfC)
The literature published since the RfC for dichlorvos was derived (1992) does not appear to contain study
data that could potentially produce a change in the RfC.
The IRIS RfC for dichlorvos was derived based on a chronic inhalation study in rats (1976). ATSDR
updated the toxicological profile for dichlorvos in 1997 and an RED Preliminary Risk Assessment was
published in 2000. ATSDR derived an inhalation MRL based on the same 1976 study used to derive the
IRIS inhalation RfC. The RfC derived for the RED was the same as the IRIS RfC. A literature search
conducted for the years 1999 to 2001 identified no new studies that would be directly useful in the
derivation of an inhalation RfC for dichlorvos.
Oral Slope Factor (CSF)
The literature published since the CSF for dichlorvos was derived (1988) does not appear to contain study
data that could potentially produce a change in the CSF. The CSF for dichlorvos was derived based on
National Toxicology Program (NTP) studies of carcinogenicity in mice and rats (1986). The RED
Preliminary Risk Assessment (2000) identified no new information useful for the derivation of a CSF. A
literature search conducted for the years 1999 to 2001 identified no new studies that would be directly
useful in the derivation of an CSF for dichlorvos.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
In 1988, EPA classified dichlorvos as a Class B2 carcinogen—probable human carcinogen. The literature
published since the WOE classification does not appear to contain study data that could potentially
produce a change in the WOE classification.
In 1991, consistent with the EPA's WOE designation, the International Agency for Research on Cancer
(IARC) classified dichlorvos as a Group 2B carcinogen—possibly carcinogenic to humans. The RED
Preliminary Risk Assessment (2000) identified no new information that could potentially produce a
change in the WOE classification. A literature search conducted for the years 1999 to 2001 did not
identify any studies that could potentially produce a change in the WOE classification.
F-41
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Screening-Level Review of the IRIS Database Phase I November 2001
Unknown Relevance
Four studies were categorized as being of unknown relevance.
Note: A synonym for the chemical dichlorvos is "TASK." Because both chemical name and word
variants were used as search parameters for the literature search, a number of studies unrelated to
dichlorvos were found (due to the common use of the word "task"). These studies were identified by a
secondary search in EndNote and coded as N/A.
F-42
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Diethylene Glycol Dinitrate (CAS No. 693-21-0)
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)
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 (1992) does not appear to include study data that could produce a change in the WOE. A
literature search conducted for the years 1991 to 2001 identified no new studies that would potentially
produce a change of the WOE classification for diethylene glycol dinitrate
Unknown Relevance
Two studies were categorized as being of unknown relevance.
F-43
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Diisopropyl Methylphosphonate (CAS No. 1445-75-6)
Oral Reference Dose (RfD)
The literature published since the RfD for diisopropyl methylphosphonate was derived (1988) includes
study data that could potentially produce a change in the RfD.
The IRIS oral RfD was derived based on a 1980 study in dogs. Dogs were exposed to diisopropyl
methylphosphonate in their feed for 90 days. The Agency for Toxic Substances and Disease Registry
(ATSDR) published a toxicological profile for diisopropyl methylphosphonate in 1998 and derived an
oral Minimal Risk Level (0.6 mg/kg/day) based on a 1997 two-generation reproductive study in mink fed
diisopropyl methylphosphonate. A literature search conducted for the years 1997 to 2001 found no
additional studies that would be directly useful in the derivation of an RfD for diisopropyl
methylphosphonate.
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 include study data that could produce a change in the WOE.
In 1998, ATSDR published a toxicological profile for diisopropyl methylphosphonate. ATSDR identified
a series of eight studies published in 1991 that evaluate the genotoxic potential of diisopropyl
methylphosphonate in rats, mice, and hamsters; the studies generally provided negative evidence of
genotoxic potential. A literature search conducted for the years 1997 to 2001 identified a study of the
Tokyo sarin disaster. In 1998, scientists published analyses of the elevated frequency of sister chromatid
exchanges in lymphocytes of individuals exposed to sarin and sarin by-products (including diisopropyl
methylphosphonate) and in experiments exposing lymphocytes to byproducts of sarin synthesis.
Unknown Relevance
No studies were categorized as being of unknown relevance.
F-44
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Dimethyl Terephthalate (CAS No. 120-61-6)
Oral Reference Dose (RfD)
The literature published since the RfD for dimethyl terephthalate was derived (1985) includes study data
that could potentially produce a change in the RfD.
The IRIS RfD for dimethyl terephthalate was derived based on a chronic dietary study in rats (1979). A
more recent study analyzed the induction of bladder stones in rats exposed to dimethyl terephthalate
(198S). Rats were exposed to dimethyl terephthalate in the diet. The abstract indicated that a dose-
response curve was generated, but the exposure duration was not given.
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 identified study data that could be relevant to the development of a WOE
classification. Recent research includes genotoxic studies (1996, 1991); mutagenicity studies on mouse
somatic cells (1988 [three studies]); and a study on chromosome aberration and sister chromatid exchange
in Chinese hamster ovary cells (1990).
Unknown Relevance
A total of 12 studies were categorized as being of unknown relevance.
F-45
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Dimethylamine (CAS No. 124-40-3)
Oral Reference Dose (RID)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
In December 1990, the RfD/RfC Work Group agreed to adopt an RfC for dimethylamine based on the
final results of a 2-year study of dimethylamine conducted by CUT. The previous RfC was withdrawn,
but the new RfC was never added to IRIS. Thus, data from a chronic inhalation bioassay in mice and rats
conducted by CUT are available, but are not reflected in the current IRIS assessment for dimethylamine.
A literature search conducted for the years 1990 to 2001 found no additional studies that would be
directly useful in deriving an inhalation 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.
Unknown Relevance
A total of 16 studies were categorized as being of unknown relevance.
F-46
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
N,N-Dimethylaniline (CAS No. 121-69-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for N,N-dimethylaniline was derived (1987) may contain
study data that could potentially produce a change in the RfD.
The IRIS RfD was derived based on a subchronic gavage bioassay in mice (1984). A literature search
conducted for the years 1986 to 2001 identified two studies—a 2-year National Toxicology Program
(NTP) toxicology and carcinogenesis (gavage) study in rats and mice (1989) and a 13-week gavage study
in rats and mice (1990).
Inhalation Reference Concentration (RfC)
No assessment of the inhalation 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 1986 to 2001 identified a 2-year NTP toxicology and
carcinogenesis (gavage) study in rats and mice reporting some evidence of carcinogenicity in male rats
and equivocal evidence of carcinogenicity in female mice (1989).
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 2001 identified a 2-year NTP toxicology and
carcinogenesis (gavage) study in rats and mice reporting some evidence of carcinogenicity in male rats
and equivocal evidence of carcinogenicity in female mice (1989). In 1993, IARC designated N,N-
dimethylaniline as a group 3 carcinogen.
Unknown Relevance
Twelve studies were categorized as being of unknown relevance. Two EPA/OTS submissions (1992 and
1995) entitled "Basic Toxicity of N,N-Dimethylamline" and a 1995 study entitled "Addendum to Basic
Toxicity of N,N-Dimethylaniline" were identified.
F-47
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Diquat (CAS No. 85-00-7)
Oral Reference Dose (RfD)
The literature published since the RfD for diquat was derived (1986) may include study data that could
potentially produce a change in the RfD.
The IRIS RfD for diquat (0.0022 mg/kg/day) was derived based on a chronic dietary study in the rat
(1985). EPA completed a pesticide Reregistration Eligibility Decision (RED) for diquat in 1995 and
derived an oral RfD (0.005 mg/kg/day) based on a chronic dog study. Because the citation for the dog
study in the RED was incomplete, it cannot be determined whether the chronic dog study was available at
the time of the 1986 IRIS assessment or whether it represents a new study not considered in the IRIS
assessment. A literature search conducted for the years 1994 (the year prior to the RED release) to 2001
identified no new studies that would be directly useful in the derivation of an RfD for diquat.
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 identified study data that could be relevant to the development of a WOE
classification. Recent research includes a genotoxic study (1997) and a DNA adduct study (1997).
Unknown Relevance
Ten studies were categorized as being of unknown relevance.
F-48
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Dodine (CAS No. 2439-10-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for dodine was derived (1987) contains study data that could
potentially produce a change in the RfD.
The IRIS oral RfD was derived based on a 1-year feeding study in dogs (1958). A literature search
conducted for the years 1986 to 2001 identified a study (1998) in which rats were exposed to dodine
through oral administration 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 Weight-of-Evidence (WOE) Classification
No assessment of the WOE classification is included in IRIS.
Unknown Relevance
Six studies were categorized as being of unknown relevance.
F-49
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Endrin (CAS No. 72-20-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD was derived (1988) does not appear to contain study data that
could potentially produce a change in the RfD. A review of the toxicological profile published by the
Agency for Toxic Substances and Disease Registry (ATSDR) in 1996 and a literature search conducted
for the years 1995 to 2001 identified no new studies that would be directly useful in the derivation of an
oral RfD for endrin.
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
In 1989, EPA designated endrin as a Class D carcinogen—not classifiable as to human carcinogenicity.
The literature published since the WOE was derived (1988) does not appear to contain study data that
could potentially produce a change in the WOE classification.
In its 1996 toxicological profile, ATSDR concluded that insufficient human or animal data were available
to assess the potential carcinogenicity of endrin. A literature search conducted for the years 1995 to 2001
identified an epidemiologic study of exposures to organochlorines, including endrin, and breast cancer in
women (1998) and a study of endrin-induced DNA damaged in the livers and brains of rats (1995)
Unknown Relevance
A total of 17 studies were characterized as being of unknown relevance.
F-50
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
2-Ethoxyethanol (Cellosolve or Ethylene Glycol Monoethyl Ether) (CAS No. 110-80-5)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: In 1993, a 13-week drinking water study in rats and mice was released by the National Toxicology
Program (NTP).
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for 2-ethoxyethanol was derived (1990) does not appear
to contain study data that could potentially produce a change in the RfC. A literature search conducted for
the years 1989 to 2001 identified no new studies that would be directly useful in the derivation of an RfC
for 2-ethoxyethanol.
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
Thirty-eight studies were categorized as being of unknown relevance. From a review of the titles, these
publications include teratogenicity studies, mutagenicity studies, reproductive toxicity studies, and oral
and inhalation exposure studies. Many of these studies, however, were ones submitted to EPA/OTS and
the available records contained insufficient information regarding test chemical, study type, or date of
conduct to permit a determination of whether or not the studies could potentially affect the IRIS
assessments.
F-51
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Ethyl Acetate (CAS No. 141-78-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ethyl acetate was derived (1986) does not appear to include
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1985 to 2001 identified no new studies that would be directly useful in the derivation of an RfD for ethyl
acetate.
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
A total of 15 studies were categorized as being of unknown relevance.
Note: Because the literature search identified over 1,100 references, only the results of secondary searches
conducted within EndNote were reviewed.
A synonym search identified approximately 1,000 references. The search results were further limited with
another 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, epidemiol*, genotox*, mutat*, and mutag*. Any studies not containing one of these
search terms were coded as N/A.
Because over 450 references remained, references were further limited by searching for "solvent,"
"solvents," "chromatograph," or "chromatographic," but not "exposed" or "exposure." The results of this
search were coded as N/A. The approximately 280 remaining references were reviewed
F-52
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Ethyl Carbamate (Urethane) (CAS No. 51-79-6)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: A 90-day toxicity study (1996) was found when searching the National Toxicology Program (NTP)
Management Status Report. A literature search conducted for the years 1990 to 2001 identified one study
in which researchers observed morphological changes and proliferative activity of alveolar epithelium in
mouse lungs after oral administration of 0.1% ethyl carbamate solution over 250 days (199S).
Inhalation Reference Concentration (RfC)
EPA conducted an IRIS assessment for ethyl carbamate in 1991 and determined that insufficient data
were available to include an assessment of the inhalation RfC in IRIS. A literature search conducted for
the years 1990 to 2001 identified no new studies that would be directly useful in deriving a 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: An International Agency for Research on Cancer mongraph was published in 1987. Ethyl
carbamate was classified as a Group 2B carcinogen—possibly carcinogenic to humans. A review of the
NTP Management Status Report identified a two-year cancer bioassay scheduled for peer review in June
2002. A literature search conducted for the years 1990 to 2001 identified 26 studies (including, but not
limited to: micronuclei induction, genotoxicity, sister chromatid exchange, carcinogenicity, and
tumorigenesis) that could potentially be useful in the derivation of a WOE classification.
Unknown Relevance
A total of 11 studies were categorized as being of unknown relevance.
Note: Ethyl carbamate (urethane) is commonly used as an anesthetic and a promoter for tumor growth and
appeared in a number of references not relevant to an IRIS assessment. References pertaining to ethanol
(ethyl alcohol CAS No. 64-17-5) and vinyl carbamate (CAS No. 15805-73-9) appeared to be included
due to the use of the word variants option. Because the literature search identified over 950 references
containing the CAS No., ethyl carbamate, urethane, or another synonym, only the results of the following
secondary searches within EndNote were reviewed.
References were first searched for "ethanol," but not "51-79-6," not "ethyl carbamate," and not
"urethane." References were then searched for "carbamate" but not "ethyl." All search results were coded
as N/A. References were then searched for "anesthetized," "anesthetic," "anaesthetized," "anaesthetic,"
"dental," or "amalgam." All results were coded as N/A.
F-53
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Screening-Level Review of the IRIS Database Phase I November 2001
The search results were further limited with another 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, epidemiol*, genotox*, mutat*, and
mutag*. Any references not containing one of these search terms were coded as N/A.
Because over 500 references remained, references were again limited by searching for studies that did not
contain "dose*" or "treat*" or "expos*" (i.e., studies not related to dosage and/or treatment and/or
exposure) and coded the resulting studies as N/A.
F-54
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Ethyl Ether (CAS No. 60-29-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for ethyl 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 2001 identified no new studies that would be directly useful in deriving an RfD for ethyl ether.
Inhalation Reference Concentration (RfC)
No assessment of the inhalation 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
Six studies were categorized as being of unknown relevance.
Note: Because both "ethyl" and "ether" are part of many different chemical names and chemical name
and word variants were used as search parameters for the literature search, over 3,500 references were
found in the literature search. A majority of these references did not pertain to ethyl ether, so a secondary
search was conducted within EndNote to identify those studies that contained "ethyl ether," the CAS No.
(60-29-7), or synonyms (diethyl ether, 1,1'oxybisethane, ethyl oxide, diethyl oxide, ethoxyethane, and
pronarcol).
The search results were further limited with another 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, epidemiol*, genotox*, mutat*, and
mutag*. References not containing one of these search terms were coded as N/A.
F-55
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Express (CAS No. 101200-48-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for express was derived (1988) does not appear to contain
study data that could potentially produce a change in the RfD.
The IRIS RfD was derived based on a 1-year feeding study in dogs (1986). A literature search conducted
for the years 1987 to 2001 identified a 90-day feeding and one-generation reproduction study in male and
female rats. This study, submitted to EPA/OTS in 1992, appears to have been produced by Haskell Labs
in 198S and considered in the IRIS assessment.
Inhalation Reference Concentration (RfC)
No assessment of the inhalation 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 studies were categorized as being of unknown relevance.
Note: Because both chemical name and word variants were used as search parameters for the literature
search, a number of references unrelated to the chemical (express) were found due to the common use of
the word. Over 3,500 references were found in the literature search, so secondary searches within
EndNote were conducted. The first search identified all references containing "expression" and
"expressed," but not the CAS No. (101200-48-0) or synonyms (tribenuron and INL-5300). A number of
studies were identified by the literature search because they contained the words "matrix," "mating,"
"mated," or "material." Therefore, a second search was conducted to identify all references that contained
these words but not the CAS No. or synonyms. References identified with these searches were coded
N/A.
The search results were further limited with another secondary EndNote 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, epidemiol*, genotox*, mutat*, and
mutag*. Codes were assigned to the resulting studies.
After assigning codes, most references identified did not pertain to the chemical. Therefore, an additional
match words search in EndNote for "express," the CAS No., or synonyms (tribenuron methyl, tribenuron,
tribenuron methyl ester, DPX-LS300, benzoic acid, INL-5300, and tribenuron-Me) was conducted. Codes
were also assigned to these references.
F-56
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Fenamiphos (CAS No. 22224-92-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for fenamiphos was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD for fenamiphos was derived based on a 2-year feeding study in dogs (1972). EPA's Office
of Pesticide Programs (OPP), however, released an assessment in 1999 and derived an oral RfD based on
a 1-year feeding study in dogs and a subsequent follow-up study. The date of these studies is unknown;
however, based on reported dosing levels, the principal study used by OPP does not appear to be the same
study upon which the IRIS RfD was based. A literature search conducted for the years 1985 to 2001
identified no additional studies that would be directly useful in the derivation of an oral RfD for
fenamiphos.
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.
Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Note: EPA's OPP, however, released an assessment in 1999 and classified fenamiphos as a Group E
carcinogen—evidence of non-carcinogemcity for humans.
Uncertain Relevance
Nine studies were characterized as being of uncertain relevance.
Note: Studies investigating the efficacy of fenamiphos as a nematicide were identified in a secondary
search in EndNote and coded as N/A
F-57
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Fluorine (CAS No. 7782-41-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for fluorine was derived (1985) may contain study data that
could potentially produce a change in the RfD.
The IRIS RfD for fluorine was derived based on two epidemiologic studies in children (1950, 1977). In
1993, the Agency for Toxic Substance and Disease Registry (ATSDR) updated the toxicological profile
for fluorine and Health Canada updated its assessment of fluorine. ATSDR derived an oral Minimal Risk
Level based on a 1990 chronic study of musculoskeletal effects in humans. Health Canada developed a
TDI based on several studies (1993, 1992 [5 studies], 1991 [3 studies], 1990, 1987, and 1983) of skeletal
effects in humans.
A literature search conducted for the years 1992 to 2001 identified six epidemiologic studies and one
animal toxicity study assessing health effects of fluorine exposures. The epidemiologic studies evaluated
exposure to children drinking fluorinated water (three studies), children drinking brick tea with high
levels of fluorine, elderly people drinking fluorinated water, and people undergoing fluoride treatments.
The results of these studies were published in 1994 (two studies), 1995, 1996 (two studies), 1997, 1998,
and 2000 (several of the studies were published in multiple journals). An animal study, published in 1997,
examined the effects of rats exposed to fluorine in their drinking water over 3 to 7 months.
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.
Weight-of-Evidence (WOE) Classification
No assessment of the WOE is included in IRIS.
Uncertain Relevance
A total of 13 studies were characterized as being of uncertain relevance.
Note: The literature search identified over 1,400 references because both chemical name and word
variants were used as search parameters for the literature search. To limit the search results, secondary
searches were conducted within EndNote. First, a synonym search for references containing "fluorine,"
"fluoride," or the CAS No. (7782-41-4) was conducted.
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*.
References identified in the synonym search and laboratory animal search were reviewed and coded.
F-58
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Screening-Level Review of the IRTS Database Phase I November 2001
In reviewing the references, fluorine was commonly used in magnetic resonance spectroscopy studies,
which were unrelated to fluorine's toxicity. Another secondary search for "magnetic resonance" was
conducted and identified studies were coded as N/A.
F-59
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Folpet (CAS No. 133-07-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for folpet was derived (1987) does not appear to contain study
data that could potentially produce a change in the RfD.
The IRIS RfD for folpet was derived based on a 1986 chronic oral toxicity study in dogs. A
Reregistration Eligibility Decision (RED) was published in 1999 and included an oral RfD based on a
198S chronic dietary toxicity study in rats. The 1985 rat study was cited in the 1987 IRIS assessment, but
was not selected at the time as the basis for the IRIS RfD. A literature search conducted for the years
1998 to 2001 identified no new studies that would be directly useful in the derivation of an oral RfD for
folpet.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for folpet was derived (1987) may contain study data that could
potentially produce a change in the CSF.
The IRIS CSF for folpet was derived based on a 1982 carcinogenicity study in mice. A RED was
published in 1999 that derived a CSF based on a 1982 study and a 1985 study. The RED also summarizes
the results of a 2-year bioassay in the rat completed in 1989. The complete references for the studies
considered in the RED were not available. Therefore, it is unclear if the 1982 study used to derive the
IRIS CSF is the same study used to derive the RED CSF. A literature search conducted for the years 1998
to 2001 identified no additional studies that would be directly useful in the derivation of a CSF for folpet.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Weight-of-Evidence (WOE) Classification
The literature published since the WOE for folpet was derived (1987) does not appear to contain study
data that could potentially produce a change in the WOE. Folpet was classified as a Class B2 carcinogen
(probable human carcinogen) in the IRIS assessment and again in the 1999 RED. A review of the RED
and a literature search conducted for the years 1998 to 2001 identified one mutagenicity study published
in 1998 and a series of mechanistic studies, published in 1994 and 1995, that assessed the carcinogenic ~
action of folpet.
Uncertain Relevance
Four studies were characterized as being of uncertain relevance.
F-60
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Fonofos (CAS No. 944-22-9)
Oral Reference Dose (RfD)
The literature published since the oral RfD for fonofos 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 2001 identified no new studies that would be directly useful in the derivation of an oral RfD for
fonofos.
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
A total of 19 studies were categorized as being of unknown relevance.
F-61
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Furfural (CAS No. 98-01-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for furfural was derived (1987) contains study data that could
potentially produce a change in the RfD.
The RfD was derived based a National Toxicology Program (NTP) oral subchronic study in rats (1981).
A literature search conducted for the years 1986 to 2001 identified three new studies that could be directly
useful in the derivation of an RfD for furfural. The first, an NTP study (published in 1990), describes the
results of a 2-year oral gavage study in rats and mice. Another study examined the effect of furfural on
the liver after administration for 90 or 120 days in the basal diet of rats (1986). The third study reported
liver cirrhosis in rats fed furfural in their diet for IS to ISO days (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: In 1997, the International Agency for Research on Cancer monograph classified furfural as a Group
3 carcinogen—not classifiable as to carcinogenicity in humans. A literature search conducted for the
years 1986 to 2001 identified five studies that could be directly useful in the derivation of a WOE
classification. These included four mutagenicity studies (1988, 1992, 1993, and 1995) and a 2-year NTP
oral gavage study in rats and mice (published in 1990, and also found in the NTP Management Status
Report). The rats and mice study indicated clear evidence of carcinogenic activity for male mice, but only
some evidence for female mice and male rats, and no evidence for female rats.
Unknown Relevance
A total of 17 studies were categorized as being of unknown relevance.
Note: Because the literature search identified over 3SO references, only the results of the secondary
searches conducted within EndNote were reviewed.
First, any references that might focus on a similar chemical, 5-hydroxymethyIfurfural (CAS No. 67-47-0)
and its synonyms, but not furfural (CAS No. 98-01-1) or synonyms of furfural, were identified. The
search results were further limited with another secondary search in EndNote for references containing
common laboratory species and toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle,
dog, human, rabbit, pig, monkey, primate, worker, epidemiol*, genotox*, mutat*, and mutag*. Any
studies not containing one of these search terms were coded as N/A.
F-62
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Glufosinate-Ammonium (CAS No. 77182-82-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for glufosinate-ammonium was derived (1987) may include
study data that could potentially produce a change in the RfD.
The IRIS RfD was derived based on a 13-week feeding study in rats (1982). A literature search conducted
for the years 1986 to 2001 identified one study (submitted to EPA/OTS in 1992) that analyzed the
developmental toxicity of glufosinate-ammonium administered by gavage to Himalayan rabbits Two
reviews of the toxicity of glufosinate-ammonium, including a 1990 journal article and a 2000 FAO/WHO
document, identified chronic toxicity studies in the rat, dog, rabbit, and mouse that were not referenced in
the IRIS assessment.
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 identified a 1990 review paper on glufosinate-ammonium toxicity that
indicated that available oncogenicity studies in rats and mice were negative, and an in vivo genotoxicity
assessment of glufosinate-ammonium (1997).
Unknown Relevance
Twelve studies were categorized as being of unknown relevance, including one titled "Chronotoxicity of
glufosinate ammonium in mice" and eight initial submissions to EPA/OTS alluding to acute toxicity
studies performed with mammals.
Note: Because both chemical name and word variants were used as search parameters for the literature
search, a number of references unrelated to glufosinate-ammonium were found. Many of these references
were found because synonyms for the chemical glufosinate-ammonium include "basta" and "ignite" or
because components of the synonyms (such as butanoic and ammonium) appear in other chemical names.
Therefore, a secondary search was conducted in EndNote to identify references containing "glufosinate
ammonium," "glufosinate-ammonium," or its CAS No. (77182-82-2). The remaining references were
coded as N/A.
F-63
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Heptachlor (CAS No. 76-44-8)
Oral Reference Dose (RfD)
The literature published since the oral RfD for heptachlor was derived (1987) does not appear to include
study data that could potentially produce a change in the RfD.
The IRIS RfD was derived based on a 2-year feeding study in rats (1955). The Reregistration Eligibility
Decision (RED) for heptachlor was published in 1992. The RED oral RfD is the same as the IRIS RfD
and was based on studies from 1955 and 1966. The full references for these studies were not available in
the RED. In 1993, the Agency for Toxic Substances and Disease Registry (ATSDR) published a
toxicological profile for heptachlor and determined that insufficient information was available to derive a
chronic Minimal Risk Level. A literature search conducted for the years 1991 to 2001 identified no new
studies that appear to contain study data that could potentially produce a change in the RfD for
heptachlor.
Note: A review of the National Toxicity Program Management Status Report identified two short-term
toxicity studies (dose-fed)—a 14-day study and a 13-week study. The publication dates for these studies
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 heptachlor was derived (1987) does not appear to include study
data that could potentially produce a change in the CSF. A review of the 1992 RED, ATSDR's 1993
toxicological profile, and a literature search conducted for the years 1991 to 2001 identified no new
studies that would be directly useful in the derivation of a CSF for heptachlor.
Inhalation Unit Risk (IUR)
The literature published since the IUR for heptachlor was derived (1987) does not appear to include study
data that could potentially produce a change in the IUR. A review of the 1992 RED, ATSDR's 1993
toxicological profile, and a literature search conducted for the years 1991 to 2001 identified no new
studies that would be directly useful in the derivation of an IUR.
Cancer Weight-of-Evidence (WOE) Classification
In 1987, EPA designated heptachlor as a Class B2 carcinogen—a probable human carcinogen. The
literature published since the WOE was derived includes study data that potentially support the WOE
classification. In 1991, the International Agency for Research on Cancer published a monograph in which
heptachlor was categorized as Group 2B carcinogen—possibly carcinogenic to humans. The 1992 RED
refers to long-term carcinogenicity studies (dietary), but no quantitative estimates of cancer potency were
derived. The literature search (1991 to 2001) identified 15 studies that investigated the carcinogenic
potential of heptachlor.
Unknown Relevance
Eleven studies were categorized as being of unknown relevance.
F-64
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Screening-Level Review of the IRIS Database Phase I November 2001
Note: Because the literature search identified over 1,100 references, secondary searches were conducted
in EndNote to identify relevant references.
Because the literature search found many references that relate to heptachlor epoxide (CAS No. 1024-57-
3) and not heptachlor (CAS No. 76-44-8), the first search identified references that contained 1024-57-3
but not 76-44-8. These references were coded N/A.
The search results were further limited with another 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 studies not containing one of these search terms were coded as N/A.
F-65
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Hexabromobenzene (CAS No. 87-82-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for hexabromobenzene was derived (1985) does not appear to
include study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1984 to 2001 identified one 1984 study of the teratogenic potential of hexachlorobenzene in
mice; no fetal or maternal toxicity was observed. No other new studies that would be directly useful in the
derivation of an oral RfD for hexabromobenzene were identified.
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 studies were categorized as being of unknown relevance.
F-66
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Hexabromodiphenyl Ether (CAS No. 36483-60-0)
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)
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
In 1990, EPA designated hexabromodiphenyl ether as a Class D carcinogen—not classifiable as to human
carcinogenicity. The literature published since the WOE classification for hexabromodiphenyl ether was
derived does not appear to include study data that would be directly useful in the derivation of a WOE
classification. A literature search conducted for the years 1989 to 2001 identified no new studies that
would be directly useful in the derivation of a WOE classification for hexabromodiphenyl ether.
Unknown Relevance
No studies were categorized as being of unknown relevance.
F-67
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Hexachlorodibenzo-p-Dioxin, Mixture (HxCDD) (CAS No. 1904-74-3)
Oral Reference Dose (RfD)
No assessment of the RiD 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 hexachlorodibenzo-p-dioxin, mixture (HxCDD) was derived
(1987) does not appear to include study data that could potentially produce a change in the CSF. A review
of the International Agency for Research on Cancer (IARC) monograph published in 1997 and a literature
search conducted for the years 1996 to 2001 identified no new studies that would be directly useful in the
derivation of a CSF.
Inhalation Unit Risk (IUR)
The literature published since the IUR for HxCDD was derived (1987) does not appear to include study
data that could potentially produce a change in the IUR. A review of the IARC monograph published in
1997 and a literature search conducted for the years 1996 to 2001 identified no new studies that would be
directly useful in the derivation of an IUR.
Cancer Weight-of-Evidence (WOE) Classification
In 1987, EPA classified HxCDD as a Class B2 carcinogen—probable human carcinogen. The WOE
classification was based upon two NTP oral administration studies of mice and rats (1980).
In 1997, IARC classified HxCDD as a Group 3 carcinogen—not classifiable as to carcinogenicity in
humans. A review of the IARC monograph and a literature search conducted for the years 1996 to 2001
identified no new studies that would be directly useful in the derivation of a WOE classification.
However, the extensive literature discussing chlorinated dibenzodioxins published since the WOE
classification was derived, as well as EPA's ongoing dioxin reassessment, could potentially produce a
change in the WOE classification. The September 2000 draft dioxin reassessment characterized individual
dioxin-like compounds, other than TCDD, as likely human carcinogens (EPA publication number
EPA/600/P-00/001Bg).
Unknown Relevance
One study was categorized as being of unknown relevance.
F-68
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
n-Hexane (CAS No. 110-54-3)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: Although no assessment of the RfD for n-hexane is included in IRIS, an RfD is presented in the
National Center for Environmental Assessment (NCEA) Provisional Assessment for n-hexane (1999).
The NCEA provisional RfD (11 mg/kg/day) is based on a multi-generational reproductive toxicity study
in rats (1994). In their 1999 toxicological profile, ATSDR did not derive a chronic oral Minimal Risk
Level (MRL) for n-hexane.
Inhalation Reference Concentration (RFC)
The literature published since the oral RfC for n-hexane was derived (1990) includes study data that could
potentially produce a change in the RfC.
The IRIS RfC was derived based on an epidemiological inhalation study (1980) and a 90-day inhalation
study in rats (1989). A provisional RfC was derived in the NCEA Provisional Assessment (1999) for n-
hexane based on a multi-generational reproductive toxicity study in rats (1994).
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-69
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Imazalil (CAS No. 35554-44-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for imazahl was derived (1986) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for imazalil was derived based on a 2-year feeding study in dogs (1977). A literature search
conducted for the years 1985 to 2001 identified a reproductive and neurobehavioral toxicity study of
imazalil (1995) potentially relevant to the derivation of an oral RfD. During the study, two generations of
rats were administered imazalil in their diets
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 studies were categorized as being of unknown relevance.
F-70
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Iprodione (CAS No. 36734-19-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for iprodione was derived (1987) contains study data that
could potentially produce a change in the RfD.
The IRIS RfD was based on the results of a 1-year feeding study in dogs (1984). A Reregistration
Eligibility Decision (RED) was published in 1998. An oral RfD was derived based on combined
toxicity/carcinogenicity studies in rats (1992 and 1993). A literature search conducted for the years 1998
to 2001 identified no additional studies that would be directly useful in the derivation of an RfD for
iprodione.
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 RED (1998) established a CSF based on carcinogenicty studies in rats (1992 and 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: The RED (1998) includes an assessment of carcinogenicity. The RED classified iprodione as a
Group B2 carcinogen (probable human carcinogen) based on evidence of rumors in both mice and rats.
Unknown Relevance
One study was categorized as being of unknown relevance.
F-71
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Isopropalin (CAS No. 33820-53-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for isopropalin was derived (1986) does not appear to include
study data that could potentially produce a change in the RfD. A literature search conducted for the years
198S to 2001 identified no new studies that would be directly useful in the derivation of an RfD for
isopropalin.
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
No studies were categorized as being of unknown relevance.
F-72
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Isoxaben (CAS No. 82558-50-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for isoxaben was derived (1987) includes study data that could
potentially produce a change in the RfD.
The IRIS RfD was derived based on a 2-year feeding study in rats (1985). A literature search conducted
for the years 1986 to 2001 identified two reproductive toxicity studies of isoxaben submitted to EPA in
1992, a three generation dietary study of isoxaben in rats and a one generation study in rabbits
administered isoxaben by gavage. Although the former study was apparently conducted in 1984, it is not
cited in the current IRIS assessment.
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
In 1989, EPA classified isoxaben as a Class C carcinogen—possible human carcinogen. The literature
published since the WOE classification was derived does not appear to contain study data that could
potentially produce a change in the WOE classification. A literature search conducted for the years 1988
to 2001 did not identify any studies that would be useful in the derivation of a WOE classification.
Unknown Relevance
A total of 17 studies were categorized as being of unknown relevance. These studies include acute, sub-
chronic, and chronic toxicity studies of isoxaben submitted to EPA/OTS.
Note: A synonym for the chemical isoxaben is "Gallery." Because both chemical name and word variants
were used as search parameters, a number of references unrelated to isoxaben were found due to the
common use of the word "gallery." Because of the large number of references found in the literature
search (1,556), these references were identified by a secondary search within EndNote and coded as N/A.
The search identified all references containing "gal," but not the CAS No. (82558-50-7) or chemical
names (isoxaben, flexidor, EL-107, and benzamizole).
The search results were further limited with another 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, 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 I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Lactofen (CAS No. 77501-63-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for lactofen was derived (1987) does not appear to include
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1986 to 2001 identified no new studies that would be directly useful in the derivation of an oral RfD for
lactofen.
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 studies were categorized as being of unknown relevance.
Note: A synonym for the chemical lactofen is "cobra." Because both chemical name and word variants
were used as search parameters for the literature search, a number of studies unrelated to lactofen were
found due to the common use of the word "cobra." Because of the large number of studies found in the
literature search (477), studies unrelated to lactofen were identified by a secondary search within EndNote
and coded as N/A. The search identified all references containing "cobra" but not the CAS No. (77501-
63-4) or chemical name (lactofen).
F-74
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Maneb (CAS No. 12427-38-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for maneb was derived (1987) includes study data that could
potentially produce a change in the RfD.
The IRIS RfD was derived based on a 6-month feeding study in monkeys (1977, 1986). A literature
search conducted for the years 1986 to 2001 identified study data that may be directly useful in the
derivation of an RfD for maneb. A cohort study analyzed neurological symptoms in Brazilian workers
exposed to maneb (1988). Neurological function and blood chemistry of agricultural workers who had
been exposed to maneb for at least 6 months were compared to data from workers who had not been
exposed. In addition, two studies (1992 and 1993) analyzed the developmental toxicity of maneb in rats.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: A literature search conducted for the years 1986 to 2001 identified a 4.5-month study of rats
exposed to maneb via inhalation (1989).
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) published a monograph in 1998 in which
maneb was classified as a group 3 carcinogen—unclassifiable as to carcinogenicity in humans.
Unknown Relevance
Twenty studies were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (462), ERG limited the
search results 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, epidemiol*, genotox*, mutat*, and mutag*. Any references not containing
one of these search terms were coded as N/A.
F-75
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Methomyl (CAS No. 16752-77-5)
Oral Reference Dose (RfD)
The literature published since the RfD for methomyl was derived (1986) does not appear to include study
data that could potentially produce a change in the RfD.
The IRIS oral RfD was derived based on a 2-year feeding study in dogs (1968). EPA completed a
pesticide Reregistration Eligibility Decision (RED) for methomyl in 1998 and derived an oral RfD based
on the same study cited in IRIS. A literature search conducted for the years 1997 to 2001 identified no
new studies that would be directly useful in the derivation of an RfD for methomyl.
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 RED completed in 1998 included an assessment of the carcinogenicity of methomyl. Based on
available information, methomyl was classified as a Class E carcinogen—not likely to be carcinogenic in
humans. A literature search (1997 to 2001) identified a 1997 in vitro genotoxicity study (assessing
methomyl's ability to induce micronuclei) that could be relevant to the development of a WOE
classification.
Unknown Relevance
Eight studies were categorized as being of unknown relevance.
F-76
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Methyl Iodide (CAS No. 74-88-4)
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.
Note: Under section VII of the IRIS summary, Revision History, the RfC is noted as under review in
1992. A literature search conducted for the years 1991 to 2001 identified no new studies that would be
directly useful in the derivation of an RfC for methyl iodide.
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: Under section VII of the IRIS summary, Revision History, carcinogenicity is noted as under review
in 1994. An International Agency for Research on Cancer monograph was published in 1999 and
assigned methyl iodide as a Group 3 carcinogen—not classifiable as to its carcinogenicity to humans. The
literature search conducted for the years 1991 to 2001 identified four studies that evaluated methyl iodide
DNA adduct formation (1991, 1993) and mutatgenicity (1993, 1994).
Unknown Relevance
Thirteen studies were categorized as being of unknown relevance.
F-77
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
4-(2-Methyl-4-Chlorophenoxy) Butyric Acid (CAS No. 94-81-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 4-(2-methyl-4-chlorophenoxy) butyric acid was derived
(1987) does not appear to include study data that could potentially produce a change in the RfD. A
literature search conducted for the years 1986 to 2001 identified no new studies that would be directly
useful in the derivation of an RfD for 4-(2-methyl-4-chlorophenoxy) butyric 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 (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
One study was categorized as being of unknown relevance.
F-78
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
4,4'-Methylene Bis(N,N'-dimethyl)aniline (CAS No. 101-61-1)
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 4,4'-methylene bis(N,N'-dimethyl)aniline was derived (1989)
does not appear to include study data that could potentially produce a change in the CSF. A literature
search conducted for the years 1988 to 2001 identified no new studies that would likely be directly useful
in the derivation of a CSF for 4,4'-methylene bis(N,N'-dimethyl)amline.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
In 1989, EPA designated 4,4'-methylene bis(N,N'-dimethyl)amline as a Class B2 carcinogen—a probable
human carcinogen. The literature published since the WOE classification was derived does not appear to
include study data that could potentially produce a change in the WOE designation. A literature search
conducted for the years 1988 to 2001 identified two studies of the mutagenicity of the chemical (1988 and
1992) and a study of the chemical's effects as a tumor promoter (1988).
Unknown Relevance
Five documents were categorized as being of unknown relevance, including an initial submission to
EPA/OTS entitled "Ninety-Day Subacute Oral Toxicity Study With
N,N,N',N'-Tetramethyl-(4,4'-Diaminodiphenyl Methane) in Beagle Dogs."
F-79
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Methylene Diphenyl Diisocyanate (Monomeric and Polymeric)
(CAS No. 101-68-8 and 9016-87-9)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
The literature published since the RfC for methylene diphenyl diisocyanate was derived (1997) includes
study data that could potentially produce a change in the RfC.
The IRIS inhalation RfC was derived based on a chronic inhalation and carcinogenicity study (1990,
1994) in rats. A literature search conducted for the years 1996 to 2001 identified two reproductive
toxicity studies in rats exposed to methylene diphenyl diisocyanate by inhalation (1996,2000). A study of
respiratory health in workers who use methylene diphenyl diisocyanate was also identified (2000). Health
surveys and follow-up surveys were available from workers who were exposed for up to 2 years.
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 potentially produce a change in the
WOE.
An International Agency for Research on Cancer monograph was published in 1999 and assigned
methylene diphenyl diisocyanate as a Group 3 carcinogen—not classifiable as to its carcinogenicity to
humans In conducting the literature search for the years 1996 to 2001, three studies were identified that
assessed the genotoxic potential of methylene diphenyl diisocyanate (1996, 1997, 2000).
Unknown Relevance
A total of 22 studies were categorized as being of unknown relevance.
F-80
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
2-Methylphenol (o-Cresol) (CAS No. 95-48-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2-methylphenol (o-cresol) was derived (1987) contains
study data that could potentially produce a change in the RfD.
The IRIS RfD for 2-methylphenol (o-cresol) was derived based on a 90-day oral subchronic neurotoxicity
study in rats (1986, 1987). A review of the World Health Organization (WHO) 1995 Environmental
Health Criteria identified three repeat-dose toxicity studies published after the derivation of the RfD for 2-
methylphenol (o-cresol). In 1988 and 1989, researchers published the results of a two-generation
reproductive toxicity study in rats exposed to 2-methylphenol (o-cresol) via gavage and a developmental
toxicity study in rats and rabbits. In 1992, the National Toxicology Program (NTP) released a technical
report on the toxicity of 2-methylphenol (o-cresol). This report summarized the findings of 13-week
studies in mice and rats fed diets containing 2-methylphenol (o-cresol). In 1992, researchers published the
results of a study in which mice received 2-methylphenol (o-cresol) in feed for 14 weeks.
A literature search conducted for the years 1994 to 2001 identified no additional studies that would be
directly useful in the derivation of an RfD for 2-methylphenol (o-cresol).
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for 2-methylphenol (o-cresol) was withdrawn from IRIS
(1991) does not contain study data that could potentially support the derivation of an inhalation RfC. A
literature search conducted for the years 1994 (the year before the WHO's Environmental Health Criteria
were published) to 2001 identified no new studies that would be directly useful in the derivation of an
inhalation RfC for 2-methyphenol (o-cresol).
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
In 1989, EPA designated 2-methylphenol (o-cresol) as a Class C carcinogen—possible human
carcinogen.
A review of the WHO 1995 Environmental Health Criteria did not identify studies that would likely
produce a change in the WOE. WHO summarized the results of several negative or inconclusive
mutagenicity studies of 2-methylphenol. WHO also summarized a 1993 study in which oral
administration of 2-methylphenol (o-cresol) increased the incidence and malignancy of tumors produced
by benzo(a)pyrene and shortened the latency period for tumor development in mice at the mid-dose level,
but not at higher or lower dose levels.
The results of the literature search conducted for the years 1994 to 2001 do not appear to include
additional studies that could potentially produce a change in the WOE classification.
F-81
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Screening-Level Review of the IRIS Database Phase I November 2001
Unknown Relevance
Eight studies were categorized as being of unknown relevance.
F-82
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Molinate (CAS No. 2212-67-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for molinate was derived (1988) does not appear to include
study data that could potentially produce a change in the RfD. A literature search conducted for the years
1987 to 2001 identified no new studies that would be directly useful in the derivation of an RfD for
molinate.
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 2001 identified four studies on cytogenetic
effects (1990), genotoxicity (1992, 1997), and promutagen activation (1999) relevant to the derivation of
a WOE classification.
Unknown Relevance
Three studies were categorized as being of unknown relevance.
F-83
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Naled (CAS No. 300-76-5)
Oral Reference Dose (RfD)
The literature published since the RfD for naled was derived (1986) does not appear to contain study data
that could potentially produce a change in the RfD.
The IRIS RfD was derived based on a 2-year dietary study using rats (1984). In 1999, EPA's Office of
Pesticide Programs (OPP) released an assessment in support of their Reregistration Eligibility Decision
(RED) for naled. The OPP RfD derived for the RED was the same as the IRIS RfD. A literature search
conducted for the years 1985 to 2001 identified no new studies that would be directly useful in the
derivation of an oral RfD for naled.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: OPP identified a no observable adverse effect level (NOAEL) of 0.23 ng/L for use in their risk
assessment based on a 13-week inhalation toxicity study in 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
No assessment of the WOE is included in IRIS.
Note: OPP classified naled as a Group E carcinogen—evidence of noncarcinogenicity for humans.
Unknown Relevance
Five studies were categorized as being of unknown relevance.
F-84
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Napropamide (CAS No. 15299-99-7)
Oral Reference Dose (RfD)
The literature published since the RfD for napropamide 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 2001 identified no new studies that would be directly useful in the derivation of an oral RfD for
napropamide.
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
Two studies were categorized as being of unknown relevance.
F-85
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Nickel Carbonyl (CAS No. 13463-39-3)
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 human epidemiological study published in 1993 examined the effects of long-term exposure to
low concentrations of nickel carbonyl on worker health.
Oral Slope Factor (CSF)
In 1987, EPA determined that insufficient data were available for the derivation of an oral CSF for nickel
carbonyl A review of the International Agency for Research on Cancer (IARC) monograph (1990) and
World Health Organization Environmental Health Criteria (1991) and a literature search conducted for
the years 1990 to 2001 identified no new studies that would be directly useful in the derivation of a CSF
for nickel carbonyl.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
In 1987, EPA classified nickel carbonyl as a Class B2 carcinogen—probable human carcinogen. The
literature published since the WOE classification does not appear to contain study data that could
potentially produce a change in the WOE classification.
In 1990, IARC determined that limited evidence was available in experimental animals to assess the
carcinogenicity of nickel carbonyl; however, IARC evaluated nickel compounds as a group based on the
combined results of epidemiological studies, carcinogenicity studies in experimental animals, and other
relevant data that supported the underlying concept that nickel compounds can generate nickel ions at
critical sites in target cells. As a result, IARC classified all nickel compounds as Group 1
carcinogens—carcinogenic to humans. In 1991, WHO completed a publication on the toxic and
carcinogenic effects of nickel and nickel compounds. Both the IARC and WHO publications were
reviewed No new studies were found that could potentially produce a change in the WOE.
A literature search conducted for the years 1990 to 2001 identified a genotoxic study in cultured
peripheral lymphocytes of 65 workers occupationally exposed to nickel carbonyl (1987) and a short-term
carcinogenicity bioassay (1990).
Unknown Relevance
Six studies were categonzed as being of unknown relevance, including one study titled, "Study on Lung
Function and Blood Gas Analysis of Nickel Carbonyl Workers."
F-86
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Nickel Subsulfide (CAS No. 12035-72-2)
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: Health Canada assessed nickel subsulfide in 1993 and the Agency for Toxic Substances and
Disease Registry (ATSDR) updated the toxicological profile for nickel subsulfide in 1997. Health Canada
derived an inhalation tolerable concentration (TC) based on a 1989 chronic toxicity study in rats. ATSDR
derived an inhalation Minimal Risk Level (MRL) based on a 1996 National Toxicity Program (NTP)
bioassay in rats. A literature search conducted for the years 1996 to 2001 found no additional studies that
would be directly useful in the derivation of an inhalation RfC for nickel subsulfide.
Oral Slope Factor (CSF)
No assessment of the CSF is included in IRIS.
Inhalation Unit Risk (IUR)
The literature published since the IUR for nickel subsulfide was derived (1987) may contain study data
that could potentially produce a change in the IUR.
The IRIS IUR for nickel subsulfide was derived based on four human epidemiological studies (1984,
1982 [2 studies], 1981). More recent research includes NTP's 2-year inhalation carcinogencity study in
mice and rats (1996). This study is discussed and referenced as Dunnick et al. (1995) in ATSDR's
toxicological profile.
Cancer Weight-of-Evidence (WOE) Classification
In 1987, EPA classified nickel subsulfide as a Class A carcinogen—human carcinogen. The literature
published since the WOE classification contains study data that may further support this WOE
classification.
Studies that could support the WOE classification were identified by a review of ATSDR's toxicological
profile and a literature search conducted for the years 1996 to 2001. In addition to the NTP bioassays in
the rat and mouse, more recent publications include genotoxicity studies in human lung cells and
lymphocytes, mice, and rats (1998, 1996 [two studies], 1992); a mutagenicity study in hamster cells
(1994); a study of both genotoxic and mutagenic effects in mice and rats (1998), a model designed to aid
in the understanding of the different carcinogenic potentials of nickel compounds (1997), studies of the
induction of DNA-protein crosslinks in rat renal cortical cells and lymphocytes (2001, 1999); and short-
term carcinogenicity bioassays (1999,1988). The 1992 genotoxicity study, 1994 mutagenicity study, and
1988 short-term carcinogenicity study are referenced in ATSDR's toxicological profile.
Unknown Relevance
One study, "Mutagenicity of Insoluble and Soluble Nickel Compounds in Transgenic Rat Embryonic
Fibroblasts," was categorized as being of unknown relevance.
F-87
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Nitroguanidine (CAS No. 556-88-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for nitroguanidine was derived (1989) may contain study data
that could potentially produce a change in the RfD.
The IRIS oral RfD was derived based on three 1988 studies—a 90-day dietary study in rats and two
studies assessing the developmental toxicity of nitroguanidine. A literature search conducted for the years
1988 to 2001 identified a study on the effects of nitroguanidine on reproduction and fertility in rats
(published in two parts in 1990).
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
In 1990, EPA designated nitroguanidine a Class D carcinogen—not classifiable as to human
carcinogenicity. The literature published since the WOE classification for nitroguanidine was derived
does not appear to include study data that could potentially produce a change in the WOE classification.
Study data relevant to a WOE determination identified in a literature search conducted for the years 1988
to 2001 were limited to four studies of the genotoxic potential of nitroguanidine (three studies published
in 1988 and one in 1993).
Unknown Relevance
One study was categorized as being of unknown relevance—an initial submission to EPA (2000) titled
"Preliminary Data from a Prenatal Developmental Toxicity Study in the Wistar Rat with Nitroguanidine"
The initial submission to EPA appears to be new study data not previously considered in IRIS.
Note: Although nitroguanidine has no synonyms, the literature search identified a number of references
that pertain to chemicals with similar names, including nitrosoguanidine and guanidine nitrate. These
documents were coded 8.
F-88
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
p-Nitrophenol (CAS No. 100-02-7)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
EPA conducted an IRIS assessment for p-nitrophenol in 1991 and determined that data were inadequate
for the derivation of an inhalation RfC. In 1992, the Agency for Toxic Substances and Disease Registry
(ATSDR) released a toxicological profile for nitrophenols, including p-nitrophenol. ATSDR found that
insufficient information was available to derive a Minimal Risk Level. A literature search conducted for
the years 1991 to 2001 identified no new studies that would be directly useful in deriving 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: In its toxicological profile, ATSDR listed several genotoxicity studies that indicated that p-
nitrophenol does not pose a genotoxic threat to humans. ATSDR also concluded that insufficient
information was available to assess the carcinogenicity of p-nitrophenol. A literature search conducted for
the years 1991 to 2001 identified three studies potentially relevant to the derivation of a WOE
classification for p-nitrophenol. These included two in vitro studies of p-nitrophenol genotoxicity (1997,
2000) and a National Toxicity Program (NTP) bioassay that evaluated the genetic toxicity and dermal
carcinogenicity of p-nitrophenol.
Unknown Relevance
Four studies were categorized as being of unknown relevance.
Note: Because the literature search identified over 600 references, only the results of secondary searches
conducted within EndNote were reviewed.
A secondary search in EndNote identified references containing common laboratory species and
toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog, human, rabbit, pig, monkey,
primate, worker, epidemiol*, genotox*, mutat*, and mutag*. Any studies not containing one of these
search terms were coded as N/A. The search results were further limited with a synonym search. The
approximately 230 remaining references were coded.
F-89
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
2-Nitropropane (CAS No. 79-46-9)
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 2-nitropropane was derived (1990) does not appear
to include study data that could potentially produce a change in the RfC. A review of the World Health
Organization 1992 Environmental Health Criteria and a literature search conducted for the years 1991 to
2001 identified no new studies that would be directly useful in the derivation of an RfC for 2-
nitropropane.
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 IARC monograph published in 1999 classified 2-nitropropane as a group 2B
carcinogen—possibly carcinogenic to humans.
Unknown Relevance
Eleven studies were categorized as being of unknown relevance, including a chronic (6-month) inhalation
study with 2-nitropropane in rats apparently completed in 1978 and submitted to EPA's Office of Toxic
Substances in 1992.
F-90
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
N-Nitrosopyrrolidine (CAS No. 930-55-2)
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)
The literature published since the CSF for N-nitrosopyrrolidine was derived (1986) contains study data
that could potentially produce a change in the CSF.
The IRIS CSF was derived based on a 1977 study reporting heptacellular carcinoma and adenoma in rats.
A literature search conducted for the years 1985 to 2001 identified one study, published in 1985, that
reported increased liver tumors to rats intermittently exposed to N-nitrosopyrrolidme over 600 days. This
study was not referenced in the IRIS assessment. In 1990 and 1991, investigators published a model of
liver tumor incidences resulting from low-dose exposure.
Inhalation Unit Risk (IUR)
The literature published since the IUR for N-nitrosopyrrolidine was derived (1986) does not appear to
include study data that could potentially produce a change in the IUR. A literature search conducted for
the years 1985 to 2001 did not identify any 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) for N-
nitrosopyrrolidine was derived does not appear to contain study data that could potentially produce a
change in the WOE classification. A literature search conducted for the years 1985 to 2001 found a
number of studies that could further support the current WOE classification.
Unknown Relevance
Eleven studies were categorized as being of unknown relevance.
F-91
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Norflurazon (CAS No. 27314-13-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for norflurazon was derived (1986) does not appear to include
study data that could potentially produce a change in the RfD.
The IRIS RfD was based on a 6-month feeding study in dogs (1973). The Reregistration Eligibility
Decision (RED) for norflurazon was published in 1999. The RfD provided in the RED differed from the
IRIS RfD, although both were based on the same 6-month study in dogs A literature search conducted for
the years 1997 to 2001 identified no new studies that appear to contain study data that could potentially
produce a change in the RfD for norflurazon.
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
No studies were categorized as being of unknown relevance.
F-92
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Oryzalin (CAS No. 19044-88-3)
Oral Reference Dose (RfD)
The literature published since the oral RfD for oryzalin was derived (1989) does not appear to include
study data that could potentially produce a change in the RfD.
The IRIS oral RfD was based on a 1-year feeding study in dogs (1986). The EPA's Office of Pesticide
Programs' (OPP's) Reregistration Eligibility Decision (RED) for oryzalin was published in 1994. The
RED oral RfD was based on a chronic feeding study in rats (1980); this study was considered in
establishing the IRIS RfD but was not selected as the principal study. A literature search conducted for
the years 1993 to 2001 identified no new studies that appear to contain study data that could potentially
produce a change in the RfD for oryzalin.
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 1994 RED, EPA derived a CSF for oryzalin based on a 1980 rat study. This rat study was
reviewed in the IRIS evaluation of the carcinogenic potential of oryzalin, but was not used as the basis for
a quantitative risk estimate.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
In 1987, EPA designated oryzalin a Class C carcinogen—possible human carcinogen. The literature
published since the WOE classification for oryzalin was derived does not appear to include study data
that are likely to produce a change in the WOE classification.
In the 1994 RED, OPP also designated oryzalin a Class C carcinogen. A literature search conducted for
the years 1993 to 2001 identified an in vitro study (1997) of oryzalin's antirumor activity in human cells.
Unknown Relevance
One study was categorized as being of unknown relevance.
F-93
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Paclobutrazol (CAS No. 76738-62-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for paclobutrazol was derived (1986) includes study data that
could potentially produce a change in the RfD. A search of the Office of Pesticide Programs' (OPP's)
Web site identified a document entitled "Index of Cleared Science Reviews, Paclobutrazol (PC Code
125601)" (http://www.epa.gov/opppmsdl/foia/reviews/125601.htm). This index referenced two
developmental toxicity studies (dated 1993 and 1994) and two 104-week oral (dietary administration)
combined toxicity and carcinogenicity studies in the rat and mouse (dated 1994). These studies are not
referenced in the current IRIS assessment.
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 search of the OPP Web site identified a document entitled "Index of Cleared Science Reviews,
Paclobutrazol (PC Code 125601)" (http://www.epa.gov/opppmsdl/foia/reviews/125601.htm). This index
referenced two 104-week oral (dietary administration) combined toxicity and carcinogenicity studies in
the rat and mouse (dated 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 classification is included in IRIS.
Note: A search of the OPP Web site revealed a document entitled "Index of Cleared Science Reviews,
Paclobutrazol (PC Code 125601)" (http://www.epa.gov/opppmsdl/foia/reviews/125601.htm). This index
referenced two 104-week oral (dietary administration) combined toxicity and carcinogenicity studies in
the rat and mouse (dated 1994).
Unknown Relevance
No studies were categorized as being of unknown relevance
F-94
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Phosalone (CAS No. 2310-17-0)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS. Under Section VET of the IRIS summary, Revision History,
it is noted that the RfD was withdrawn in 1988 because the summary was inadvertently loaded. Available
assessments prepared by EPA's Office of Pesticide Programs (OPP) indicate that study data are available
that would be applicable to the derivation of an RfD. An OPP document, "Phosalone: Revised Human
Health Risk Assessment" (6/12/01), refers to developmental toxicity studies in the rat and rabbit, a rat
reproductive toxicity study, a mouse carcinogenicity study, and a rat combined chronic
toxicity/carcinogenicity study. In this document, OPP presents a chronic oral RfD of 0.002 mg/kg/day for
phosalone based on plasma and red blood cell cholinesterase inhibition and decreased testicular weight
and lesions in a 2-year rat study. A literature search conducted for the years 1987 to 2001 identified no
additional studies that would be directly useful in the derivation of an RfD for phosalone.
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: According to the OPP risk assessment, a mouse carcinogenicity and a rat combined chronic
toxicity/carcinogemcity study of phosalone have been conducted; both show no treatment-related increase
in tumor incidence.
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: According to the OPP risk assessment, a mouse carcinogenicity and a rat combined chronic
toxicity/carcinogenicity study of phosalone have been conducted; both show no treatment-related increase
in tumor incidence. OPP's Hazard Identification Assessment Review Committee classified phosalone as a
"not likely" human carcinogen.
Unknown Relevance
A total of 17 studies were categorized as being of unknown relevance.
Note: Because the literature search identified over 400 references, only the results of secondary searches
conducted within EndNote were reviewed.
A secondary search in EndNote identified references containing common laboratory species and
toxicological terms, including: rat, mouse/mice, gerbil, hamster, beagle, dog, human, rabbit, pig, monkey,
primate, worker, epidemiol*, genotox*, mutat*, and mutag*. Any studies not containing one of these
search terms were coded as N/A.
F-95
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Screening-Level Review of the IRIS Database Phase 1 November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Phosphoric Acid (CAS No. 7664-38-2)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Note: The literature search looked specifically for studies of phosphoric acid. The IRIS summary,
however, cites studies of yellow, red, and elemental phosphorus as contributing to the assessment of
phosphoric acid. Studies of yellow, red, and white phosphorus were identified in the literature. It was
beyond the scope of the current screening level review, however, to determine the relevance of these
studies to phosphoric acid.
Inhalation Reference Concentration (RfC)
The literature published since the inhalation RfC for phosphoric acid was derived (1995) does not appear
to include study data that could potentially produce a change in the RfC. A literature search conducted for
the years 1994 to 2001 identified no new studies that would be directly useful in the derivation of an
inhalation RfC for phosphoric acid.
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 study was categorized as being of unknown relevance.
Note: Because the literature search identified 298 references, ERG reviewed only the results of secondary
searches conducted within EndNote.
A synonym search did not effectively reduce the total number of references to review. Therefore, ERG
further limited the search results with another 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, epidemiol*, genotox*, mutat*, and
mutag*. Any studies not containing one of these search terms was coded as N/A
F-96
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Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Prochloraz (CAS No. 67747-09-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for prochloraz 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 2001 identified no new studies that would be directly useful in the derivation of a RfD.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Oral Slope Factor (CSF)
The literature published since the CSF for prochloraz was derived (1989) 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 2001 identified no new studies that would be directly useful in the derivation of a CSF.
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 prochloraz
was derived (1989) does not appear to contain study data that could potentially produce a change in the
WOE classification. A literature search conducted for the years 1987 to 2001 identified no new studies
that would be directly useful in the derivation of a WOE classification.
Unknown Relevance
Two studies were categorized as being of unknown relevance.
F-97
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Propazine (CAS No. 139-40-2)
Oral Reference Dose (RfD)
The literature published since the oral RfD for propazine was derived (1987) includes study data that
could potentially produce a change in the RfD.
The IRIS oral RfD was derived based on a 2-year study in rats (1980). A literature search conducted for
the years 1986 to 2001 identified one study, a 2-year dietary 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: A literature search conducted for the years 1986 to 2001 identified a 2-year dietary study that
examined mammary tumorigenesis in the rat (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.
Note: A literature search conducted for the years 1986 to 2001 identified a 2-year dietary study that
examined mammary tumorigenesis in the rat (1994).
Unknown Relevance
Four studies were categorized as being of unknown relevance.
F-98
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Propylene Glycol Monoethyl Ether (CAS No. 52125-53-8)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
EPA conducted an IRIS assessment for propylene glycol monoethyl ether in 1991 and determined the
data to be inadequate for the derivation of an inhalation RfC. A literature search conducted for the years
1990 to 2001 identified no new studies that would be directly useful in the derivation of an inhalation
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 is included in IRIS.
Unknown Relevance
No studies were categorized as being of unknown relevance.
F-99
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Rotenone (CAS No. 83-79-4)
Oral Reference Dose (RfD)
The literature published since the oral RfD for rotenone was derived (1988) includes study data that could
potentially produce a change in the RfD.
The IRIS RfD was derived based on a two generation reproduction study in rats (1983). A literature
search conducted for the years 1987 to 2001 identified one study that may be directly useful in the
derivation of an RfD for rotenone. The National Toxicology Program (NTP) published 2-year toxicology
and carcinogenesis studies in the rat and mouse in 1988. The mouse study is cited in the IRIS summary
and was considered by EPA in developing an RfD. The rat study was apparently not available at the time
the assessment was prepared and was not considered in the development of 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.
Note: NTP published 2-year toxicology and carcinogenesis studies in the rat and mouse in 1988. The
mouse bioassay (negative), but not the rat bioassay (equivocal in males; negative in females), was
available at the time that the IRIS assessment was conducted.
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 2001 identified study data that could be relevant
to the development of a WOE classification. Research published since 1987 includes a 2-year cancer
bioassay in rats and mice (1988); a cancer bioassay in rats (1993); a genotoxicity study (1998); studies of
induced aneuploidy, polyploidy, and endoreduplication (1993, 1992, 1991 [2 reports]); and studies of
anticarcmogenic inhibition of hepatic lesions and cellular proliferation (1999, 1998, 1997, 1996 [2
studies], 1995).
Unknown Relevance
Thirteen studies were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (871), the 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, epidemiol*, genotox*, mutat*, and mutag*. Any references not containing
one of these search terms were coded as N/A.
F-100
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Screening-Level Review of the IRIS Database Phase I November 2001
References were further limited by searching for "rotenone" and "pharmacol*" that indicated rotenone
was used as a laboratory chemical in unrelated experiments. Any references containing the keyword but
not containing the word rotenone in either the abstract or the title were coded as N/A.
F-101
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Strontium (CAS No. 7440-24-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for strontium was derived (1992) includes study data that
could potentially produce a change in the RfD.
The IRIS RfD was derived based on 20-day, 9-week, and 3-year oral studies in young and adult rats
(1961, 1985, 1981). A literature search conducted for the years 1991 to 2001 identified only limited
' literature on the repeat-dose toxicity of strontium. A 13-week oral study in monkeys analyzed the
strontium distribution and interaction in monkey iliac bone (1996). A larger body of literature, however,
has been published that examines the physiological effects of strontium on bone and calcium metabolism.
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
Twenty studies were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (1,334), 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, epidemiol*, genotox*, mutat*, and mutag*. Any references not containing one
of these search terms were coded as N/A.
F-102
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Thallium Chloride (CAS No. 7791-12-0)
Oral Reference Dose (RfD)
The literature published since the oral RfD for thallium chloride was derived (1988) does not appear to
include study data that could potentially produce a change in the RfD. A review of the World Health
Organization (WHO) 1996 Environmental Health Criteria and a literature search conducted for the years
1995 to 2001 identified no new studies that would be directly useful in the derivation of an RfD for
thallium chloride.
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 thallium chloride was derived (1989) does not appear to include study data that could potentially
produce a change in the WOE classification. A review of the WHO 1996 Environmental Health Criteria
and a literature search conducted for the years 1995 to 2001 identified no new studies that would be
directly useful in the derivation of a WOE classification for thallium chloride.
Unknown Relevance
Two studies were categorized as being of unknown relevance.
F-103
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Triasulfuron (CAS No. 82097-50-5)
Oral Reference Dose (RfD)
The literature published since the oral RfD for triasulfuron 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 2001 identified no new studies that would be directly useful in the derivation of an RfD for
triasulfuron.
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
Seven studies were categorized as being of unknown relevance.
Note: Because of the large number of references found in the literature search (462), the 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, epidemiol*, genotox*, mutat*, and mutag*. Any references not containing
one of these search terms were coded as N/A.
F-104
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
1,2,4-Trichlorobenzene (CAS No. 120-82-1)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 1,2,4-trichlorobenzene was derived (1991) does not appear
to contain study data that could potentially produce a change in the RfD. A literature search conducted for
the years 1990 to 2001 found no new studies that would be directly useful in the derivation of an RfD for
1,2,4-trichlorobenzene.
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 104-week dietary carcinogenicity study in mice was submitted to the Office of Toxic Substances
by the Chemical Manufacturers Association in 1994. An abstract with study findings was not provided.
Inhalation Unit Risk (IUR)
No assessment of the IUR is included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
In 1988, EPA designated 1,2,4-trichlorobenzene as a Class D carcinogen—not classifiable as a human
carcinogen.
The literature search conducted for the years 1990 to 2001 identified one study that could potentially
produce a change in the WOE classification. A 104-week dietary carcinogenicity study in mice was
submitted to the Office of Toxic Substances by the Chemical Manufacturers Association in 1994. An
abstract with study findings was not provided.
Unknown Relevance
Twelve studies were categorized as being of unknown relevance.
F-105
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
1,1,1-Trichloroethane (CAS No. 71-55-6)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 1,1,1-trichloroethane was withdrawn from IRIS (1991)
contains study data that could potentially produce a change in the RfD.
NCEA derived a provisional RfD for 1,1,1-trichloroethane in 1999 based on a 1979 chronic inhalation
study with rats. Since 1999, three oral toxicity studies of 1,1,1-trichloroethane have been published. In
2000, the National Toxicology Program (NTP) published a 13-week study in which mice and rats were
fed microcapsules containing 1,1,1-trichloroethane. A second 13-week study (2001) involving oral
gavage administration of 1,1,1-trichloroethane to rats focused on potential liver toxicity1. In 1999,
researchers published the results of a study in which pregnant rats were intermittently exposed to 1,1,1-
trichloroethane in the air during the last week of gestation.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: In 1995, the Agency for Toxic Substances and Disease Registry (ATSDR) derived an intermediate
inhalation minimal risk level (3.8 mg/m3) based on a 1985 gerbil study. Similarly, NCEA published a
provisional RfC (2.2 mg/m3) in 1999, based on the same 1985 gerbil study.
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
In 1987, EPA designated 1,1,1-trichloroethane as a Class D carcinogen—not classifiable as a human
carcinogen. The literature published since the WOE was established does not appear to include studies
that could potentially produce a change in the WOE classification. In 1999, the International Agency for
Research on Cancer (IARC) released a monograph evaluating the carcinogenicity of 1,1,1-trichloroethane
(Volume 71). Consistent with the EPA's WOE designation, IARC classified 1,1,1-trichloroethane as a
group 3 carcinogen—unclassifiable as to carcinogenicity in humans. In NTP's 2000 technical report on
1,1,1-trichloroethane, mutagemcity results in Salmonella typhimurium, a mouse lymphoma assay, and a
sister chromatid exchange test in cultured Chinese hamster ovary cells were reported.
Unknown Relevance
Four documents were categorized as being of unknown relevance.
1 This study was identified after the completion of the literature search. The full-reference is as follows:
Bruckner, J.V., G.M. Kyle, R. Luthra, D. Acosta, S.M. Mehta, S. Sethuraman, and S.
Muralidhara. 2001. Acute, short-term, and subchromc oral toxicity of 1,1,1-trichloroethane.
Toxicol. Sci. 60(2):363-72.
F-106
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
2,2,4-Trimethylpentane (CAS No. 540-84-1)
Oral Reference Dose (RfD)
No assessment of the RfD is included in IRIS.
Inhalation Reference Concentration (RfC)
EPA determined in 1991 that there were insufficient data for the derivation of an inhalation RfC for 2,2,4-
trimethylpentane. A literature search conducted for the years 1990 to 2001 identified no new studies that
would be directly useful in the derivation of an RfC for 2,2,4-trimethylpentane.
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
In reviewing the literature search results, four studies were categorized as being of unknown relevance,
including a chronic nephrotoxicity study of 2,2,4-trimethylpentane and other branch chain hydrocarbons
published in 1990.
F-107
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
2,4,6-Trinitrotoluene (CAS No. 118-96-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for 2,4,6-trinitrotoluene was derived (1988) does not appear to
contain study data that could potentially produce a change in the RfD.
The IRIS RfD for 2,4,6-trinitrotoluene was derived based on a 26-week feeding study in dogs conducted
by the Department of Defense (DOD) in 1983 The Agency for Toxic Substances and Disease Registry
(ATSDR) completed a toxicological profile for 2,4,6-trinitrotoluene in 1995 and derived an oral minimal
risk level (0.0005 mg/kg/day) based on a 1990 6-month study of hepatic effects in dogs. The 1990 study
appears to a publication of the 1983 DOD study and, thus, does not represent new data. A literature search
conducted for the years 1994 to 2001 identified no new studies that would be directly useful in the
derivation of an RfD for 2,4,6-trinitrotoluene.
Inhalation Reference Concentration (RfC)
No assessment of the RfC was included in IRIS.
Oral Slope Factor (CSF)
The literature published since the oral CSF for 2,4,6-trinitrotoluene was derived (1988) does not appear to
contain study data that could potentially produce a change in the CSF. A review of the 1996 International
Agency for Research on Cancer (LARC) monograph and a literature search conducted for the years 1995
to 2001 identified no new studies that would be directly useful in the derivation of a CSF for 2,4,6-
trinitrotoluene.
Inhalation Unit Risk (IUR)
No assessment of the IUR was included in IRIS.
Cancer Weight-of-Evidence (WOE) Classification
The literature published since the WOE was derived (1988) does not appear to include study data that
could potentially produce a change in the WOE.
The IRIS WOE of C (possible human carcinogen) was derived based on a 1984 chronic dietary study in
rats and a 1978 study on mutagenic activity in Salmonella typhimurium. In 1996, IARC categorized 2,4,6-
trinitrotoluene as a Group 3 chemical—unclassifiable as to carcinogenicity in humans.
A literature search conducted for the years 1995 to 2001 found that more recent literature is limited to
mutagenicity studies. More recent research includes studies of the mutagenicity of 2,4,6-trinitrotoluene in
Salmonella (2001, 1999, 1998 [two studies], 1997, 1996, 1994), in hamster lung cells (1999, 1998) and
hamster ovary cells (2000), and using two other assays (1996); mutagenicity studies of 2,4,6-
trinitrotoluene metabolites from rats in Salmonella (1997, 1995); two genotoxicity studies (1997, 1995); a
DNA adduct study (1995); and the discovery of a heme adduct generated by 2,4,6-trinitrotoluene in
human hemoglobin (1997).
Unknown Relevance
Five studies were categorized as being of unknown relevance.
F-108
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Zinc Phosphide (CAS No. 1314-84-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for zinc phosphide was derived (1986) contains study data that
could potentially produce a change in the RfD.
The IRIS oral RfD was derived based on a subchronic oral study in rats (1980). EPA completed a
pesticide Reregistration Eligibility Decision (RED) for zinc phosphide in 1997 and derived an oral RfD
based on a 1994 subchronic rat study. Rats were exposed to zinc phosphide by gavage for 90 days. A
literature search conducted for the years 1996 to 2001 identified no additional studies that would be
directly useful in the derivation of an RfD for zinc phosphide.
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 RED states that the requirement for carcinogenicity studies was waived because chronic
exposure to zinc phosphide was expected to be negligible.
Unknown Relevance
Two studies were categorized as being of unknown relevance.
F-109
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Evaluation of the Recent Literature and Determination of Currency for:
Zineb (CAS No. 12122-67-7)
Oral Reference Dose (RfD)
The literature published since the oral RfD for zineb was derived (1986) contains study data that could
potentially produce a change in the RfD.
The IRIS RfD for zineb was derived based on a 1953 chronic oral bioassay using rats. The more recent
literature includes a 90-day dietary study in rabbits published in 199S and a 1988 study of thyroid
function in calves exposed to zineb for 270 days.
Inhalation Reference Concentration (RfC)
No assessment of the RfC is included in IRIS.
Note: The only inhalation study identified was a 1989 subchronic inhalation study of zineb in the rat
conducted by Bulgarian researchers and published in the Journal of Hygiene, Epidemiology,
Microbiology, and Immunology.
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 most recent review of zineb carcinogenicity identified was a 1987IARC monograph, which
classified zineb as Group 3—unclassifiable as to carcinogenicity in humans.
Unknown Relevance
Six studies were categorized as unknown relevance.
F-110
-------
Screening-Level Review of the IRIS Database Phase 1 November 2001
Appendix G: Summary of Findings
-------
Screening-Level Review of the IRIS Database Phase I
November 2001
Appendix G: Summary of Findings
Chemical
Acctochlor
Acctyl chloride
Acifluorfcn (sodium)
Ammonium mcthacrylatc
Asulam
Atrazinc
Baylcton
Bcnzidmc
Bcnzotnchlondc
Beryllium and Compounds
bcta-Chloronaphthalcnc
Bis(chlorocthyl)cthcr
Bis(chloromcthyl)cthcr
Bromomcthanc
Calcium cyanide
Caprolactam
Chloral hydrate
Chlordanc
1 -Chloro- 1 , 1 -di fluorocthanc
Chlorocyclopcntadicnc
Chlorsulfuron
Chromium (HI), insoluble salts
Copper Cyanide
Creosote
Crotonaldchydc
Cypcrmcthrm
Cyromazmc
Dacthal
Dcmcton
Diazomcthanc
Dibutyl phthalatc
CAS Number
34256-82- 1
75-36-5
62476-59-9
16325-47-6
3337-71-1
1912-24-9
43121-43-3
92-87-5
98-07-7
7440-41-7
91-58-7
111-44-4
542-88-1
74-83-9
592-01-8
105-60-2
302-17-0
12789-03-6
75-68-3
41851-50-7
64902-72-3
16065-83-1
544-92-3
8001-58-9
123-73-9
52315-07-8
66215-27-8
1861-32-1
8065-48-3
334-88-3
84-74-2
RfD
N
C
C
N
N
C
C
C
N
C
N
C
C
C
C
C
N
C
C
C
N
RfC CSF IUR WOE
0
c
c
o
o
C N N C
-- C -- C
C C N C
C C C C
C C N C
N -- -- C
N O -- O
C C C C
C C C C
c
c
c -- -- c
c
c
o
o
c -- -- o
c -- -- c
UR
4
0
1
0
0
N/A
3
4
0
3
1
1
11
16
1
36
2
17
9
0
3
4
0
1
1
42
2
0
1 1
1
2
G-l
-------
Screening-Level Review of the IRIS Database Phase I
November 2001
Chemical
3,3'-Dichlorobcnzidmc
Dichlorodifluoromcthanc
p,p'-Dichlorodiphcnyldichlorocthanc
2,4-D ichloro phcno 1
2,4-DichlorophcnoxyaccBc acid
Dichlorvos
Dicthylcnc glycol dmitratc
Dnsopropyl mcthylphosphonatc
Dimethyl tcrcphthalatc
Dimcthylaminc
N-N-Dimcthylanilmc
Diquat
Dodinc
Endrin
2-Ethoxycthanol
Ethyl acetate
Ethyl carbamatc
Ethyl ether
Express
Fcnamiphos
Fluorine (soluble fluoride)
Folpct
Fonofos
Furfural
Glufoanatc-ammomum
Hcptachlor
Hcxabromobcn zcnc
Hcxabromodiphcnyl ether
Hcxachlorodibcnzo-p-dioxm, mixture
n-Hcxanc
Imazalil
Iprodionc
CAS Number
91-94-1
75-71-8
72-54-8
120-83-2
94-75-7
62-73-7
693-21-0
1445-75-6
120-61-6
124-40-3
121-69-7
85-00-7
2439-10-3
72-20-8
110-80-5
141-78-6
51-79-6
60-29-7
101200-48-0
22224-92-6
7782-41-4
133-07-3
944-22-9
98-01-1
77182-82-2
76-44-8
87-82-1
36483-60-0
19408-74-3
110-54-3
35554-44-0
36734-19-7
RfD
C
O
C
N
N
N
N
N
N
N
C
O
C
O
C
C
N
N
C
C
N
N
C
C
0
N
N
RfC CSF IUR WOE
C C -- C
0 C -- C
o
O O O O
C C -- C
c
c
0
N
0 -- 0
0
c
c
c -- -- o
0
-- N -- C
o
o
c c c
c
C C N
N
0 -- 0
UR
2
16
0
3
18
4
2
0
12
16
12
10
6
17
38
15
II
6
5
9
13
4
19
17
12
11
5
0
1
N/A
7
1
G-2
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Screening-Level Review of the IRIS Database Phase I
November 2001
Chemical
Isopropahn
Isoxabcn
Lactofcn
Mancb
Mcthomyl
Methyl iodide
4-(2-Mcthyl-4-chlorophenoxy) butync acid
4,4'-Mcthylcnc bis(N,N'-dimcthyl)anitmc
Mcthylcnc Diphcnyl Dnsocyanatc
(monomcnc and polymeric)
2-Mcthylphcnol
Molmatc
Nalcd
Napropamidc
Nickel carbon yl
Nickel subsulfidc
Nitroguanidinc
p-Nitro phenol
2-Nitropropanc
N-Nitrosopyrrohdmc
Norflurazon
Oryzalm
Paclobutrazol
Phosalonc
Phosphoric acid
Prochloraz
Propazmc
Propylcnc glycol monocthyl ether
Rotcnonc
Strontium
Thallium chloride
Triasulfuron
1 ,2,4-Tnchlorobcnzcnc
CAS Number
33820-53-0
82558-50-7
77501-63-4
12427-38-2
16752-77-5
74-88-4
94-81-5
101-61-1
101-68-8/9016-87-9
95-48-7
2212-67-1
300-76-5
15299-99-7
13463-39-3
12035-72-2
556-88-7
100-02-7
79-46-9
930-55-2
27314-13-2
19044-88-3
76738-62-0
2310-17-0
7664-38-2
67747-09-5
139-40-2
52125-53-8
83-79-4
7440-24-6
7791-12-0
82097-50-5
120-82-1
RfD
C
N
C
N
C
--
C
--
N
C
C
C
N
C
C
N
N
C
N
N
N
C
C
C
RfC CSF 1UR WOE
c
o -- -- o
o
0 -- -- 0
-- c -- c
N -- -- C
C -- -- C
o
0 -- -- 0
o c -- c
O -- N C
c
c -- -- o
C -- -- 0
N C C
-- 0 -- C
-- 0 -- O
o -- o
c
-- c -- c
o -- o
c
0 -- 0
c
O -- N
UR
0
17
3
20
8
13
1
5
22
8
3
5
2
6
1
1
4
11
11
0
1
0
17
1
2
4
0
13
20
2
7
12
G-3
-------
Screening-Level Review of the IRIS Database Phase I November 2001
Chemical
1,1,1 -Trichloroethanc
2,2,4-Tnmcthylpentane
2,4,6-Trimtrotolucnc
Zinc phosphide
Zmcb
CAS Number
71-55-6
540-84-1
118-96-7
1314-84-7
12122-67-7
RfD
N
C
N
N
RfC
0
C
--
o
CSF IUR WOE
C
C -- C
0
o
UR
4
4
5
2
6
Number of values:
Available in the existing IRIS summary 70 25 18 10 39
Not available in the existing IRIS summary 30 75 82 90 61
No literature likely to produce a significant change in the IRIS 38 20 15 6 37
summary was identified
New literature was identified that could potentially produce a 32 5 3 4 2
significant change in the IRIS summary1
Not available in IRIS, but potentially relevant information was 4 9 10 1 30
identified
Notes.
1 The screening-level review of the IRIS summaries for 43 chemicals (43%) 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 docs 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
CAS chemical abstracts registry service
CSF oral cancer slope factor
IRIS Integrated Risk Information System
IUR inhalation unit risk
N/A not applicable, no literature search was deemed necessary
RfD oral reference dose
RfC inhalation reference concentration
G-4
-------
Screening-Level Review of the IRIS Database Phase 1 November 2001
U R unknow n relevance, num her of studies identified as being of unkn own relevance d uring literature
sorting
WOE cancer wcight-of-cvidcnce
G-5
------- |