SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
SPONSORED CHEMICAL
Thiocarbazide (CAS No. 2231-57-4)
[9th CI Name: Carbonothioic dihydrazide]
June 2008
INTERIM
Prepared by
High Production Volume Chemicals Branch
Risk Assessment Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001

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SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making
publicly available screening-level health and environmental effects information on chemicals manufactured in or
imported into the United States in quantities greater than one million pounds per year. In the Challenge Program,
producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and
initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do
not exist, and making both new and existing data and information available to the public. Each complete data
submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2) endpoints that
are screening-level indicators of potential hazards (toxicity) for humans or the environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data
submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals. OPPT is using a hazard-
based screening process to prioritize review of the submissions. The hazard-based screening process consists of two
tiers described below briefly and in more detail on the Hazard Characterization website3.
Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established
criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as
submitted by the sponsor. It does not include evaluation of the quality or completeness of the data.
In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is
performed according to established EPA guidance2'4 and is based primarily on hazard data provided by sponsors.
EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have
become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent
data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar
chemical structures, properties and biological activities may be grouped together and their data shared across the
resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all
category members. As part of Tier 2, evaluation of chemical category rationale and composition and data
extrapolation(s) among category members is performed in accord with established EPA2 and OECD5 guidance.
The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing
chemicals review process. These hazard characterizations are technical documents intended to support subsequent
decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general
public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on
HPV chemicals and provide information previously not readily available to the public. The public, including
sponsors, may offer comments on the hazard characterization documents.
The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical
or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of
and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the
Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the
IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the
screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level
risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts
are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk-
based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production
Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action.
1	U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2	U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3	U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html).
4	U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
5	OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf.
6	U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm.
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SCREENING-LEVEL HAZARD CHARACTERIZATION
Thiocarbazide (CAS No. 2231-57-4)
Introduction
The sponsor, Bayer Corporation, submitted a Test Plan and Robust Summaries to EPA for thiocarbazide (CAS No.
2231-57-4; 9th CI name: carbonothioic dihydrazide) on December 29, 2003. EPA posted the submission on the
ChemRTK HPV Challenge website on February 25, 2004
(http://www.epa.gov/chemrtk/pubs/summaries/crbndhYd/cl4999tc.htm'). EPA comments on the original submission
were posted to the website on January 19, 2005. Public comments were also received and posted to the website.
This screening level hazard characterization is based primarily on the review of the test plan and robust summaries
of studies submitted by the sponsor(s) under the HPV Challenge Program. In preparing the hazard characterization,
EPA considered its own comments and public comments on the original submission as well as the sponsor's
responses to comments and revisions made to the submission. A summary table of SIDS endpoint data with the
structure(s) of the sponsored chemical(s) is included in the appendix. The screening-level hazard characterization
for environmental and human health effects is based largely on SIDS endpoints and is described according to
established EPA or OECD effect level definitions and hazard assessment practices.
The sponsor proposed reduced health effects testing, claiming that thiocarbazide is a closed-system intermediate
(CSI). EPA's evaluation of the submitted information indicated that the chemical does not meet the criteria to fully
support the CSI claim for this chemical. Therefore, EPA has determined that thiocarbazide does not qualify for
reduced testing and data for the repeated-dose and reproductive toxicity endpoints are needed for the purposes of the
HPV Challenge Program.
Summary-Conclusion
The log Kow of Ihiocarba/ide indicates thai its potential to bioaccumulalc is expected to be low. The potential of
Ihiocarbazidc to persist in the environment cannot be determined because the biodegradation endpoint remains as a
data gap.
The potential acute hazard of Ihiocarba/ide to aquatic organisms could not be assessed because adequate data for
fish, aquatic invertebrates and aquatic plants arc not available. The acute toxicity to fish and aquatic invertebrates
and the toxicity to aquatic plants endpoints remain as data gaps.
Acute oral and inhalation toxicity of thiocarbazide to rats is high. The acute dermal toxicity to rats is moderate.
Thiocarbazide is not irritating to rabbit skin or rabbit eyes. No data were submitted to address the repeated-dose,
reproductive or developmental toxicity endpoints and these remain as data gaps. Thiocarbazide induced gene
mutation in bacteria and unscheduled DNA synthesis in primary rat hcpalocylcs in vitro. The chromosomal
aberrations endpoint remains as a data gap.
The potential health hazard of thiocarbazide cannot be determined because no data were submitted for the repeated-
dose. reproductive and developmental toxicity endpoints. Available data suggest that thiocarbazide has the potential
to be gcnotoxic.
Data gaps for the biodegradation. acute toxicity to fish and aquatic invertebrates, toxicity to aquatic plants, repeated-
dose. reproductive and developmental toxicity and chromosomal aberrations endpoints were identified under the
HPV Challenge Program.
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1. Physical-Chemical Properties and Environmental Fate
A summary of physical-chemical and environmental fate data submitted is provided in the Appendix. For the
purpose of the screening-level hazard characterization, the review and summary of these data was limited to the
octanol-water partition coefficient and biodegradation endpoints as indicators of bioaccumulation and persistence,
respectively.
Octanol-Water Partition Coefficient
Log Kow:	-2.04 (estimated)
Biodegradation
Data gap
Conclusion: The log Kow of thiocarbazide indicates that its potential to bioaccumulate is expected to be low. The
potential of thiocarbazide to persist in the environment cannot be determined because the biodegradation endpoint
remains as a data gap.
2. Environmental Effects - Aquatic Toxicity
Acute Toxicity to Fish
Data gap
Acute Toxicity to Aquatic Invertebrates
Data gap
Toxicity to Aquatic Plants
Data gap
Conclusion: The potential acute hazard of thiocarbazide to aquatic organisms could not be assessed because
adequate data for fish, aquatic invertebrates and aquatic plants are not available. The acute toxicity to fish and
aquatic invertebrates and the toxicity to aquatic plants endpoints remain as data gaps.
3. Human Health Effects
Acute Oral Toxicity
(1)	Wistar rats (15 males/dose) were administered thiocarbazide (in polyethylene glycol 400) via gavage at 2.5, 5,
10, 25, 35, 50, 65 (1 study only) or 100 mg/kg-bw and observed for 14 days, in two separate studies. Deaths
occurred within 3-24 hours in animals at and above 25 mg/kg-bw. Deterioration of overall physical condition and
muscle spasms were noted at and above 5 mg/kg-bw.
LDS0 = 34.8 - 41.2 mg/kg-bw
(2)	Wistar rats (15 females/dose) were administered thiocarbazide (in polyethylene glycol 400) via gavage at 2.5, 5,
| 10, 15 (1 study only),_17.5 (1 study only), 25, 30 (1 study only), 35, 50 or 100 mg/kg-bw and observed for 14 days,
in two separate studies. Deaths occurred within 4.5 - 24 hours in animals at and above 17.5 mg/kg-bw.
Deterioration of overall physical condition and muscle spasms were noted at and above 5 mg/kg-bw.
LDS0 = 26.5 - 35.7 mg/kg-bw
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Acute Inhalation Toxicity
(1)	Wistar rats (10/sex/concentration) were exposed to thiocarbazide dust (head/nose only) at 10, 45, 50 or 60 mg/m3
(approximately 0.01, 0.045, 0.05 and 0.06 mg/L) for 4 hours and observed for 7 days. Mortality occurred 1-4 days
post-exposure in males exposed to concentrations at and above mg/L and in females exposed to concentrations at
and above 0.05 mg/L. Clinical signs were noted within 24 hours of exposure and included muscle spasms and
general deterioration in physical condition.
LC50 = ~ 0.05 mg/L
(2)	Wistar rats (10/sex/concentration) were exposed to thiocarbazide dust (head/nose only) at 45 or 75.5 mg/m3
(approximately 0.045 and 0.076 mg/L) for 1 hour and observed for 7 days. Mortality occurred 1-4 days post-
exposure in both males and females exposed 0.076 mg/L. Clinical signs were noted at 0.075 mg/L within 24 hours
of exposure and included muscle spasms and general deterioration in physical condition. No effects were observed
in animals exposed at 0.045 mg/L.
LC50 > ~ 0.076 mg/L
Acute Dermal Toxicity
Wistar rats (males and female, number not specified) were administered thiocarbazide (in polyethylene glycol 400)
dermally at 500 mg/kg-bw on to clipped, intact skin under occlusive conditions for 24 hours and were observed for 7
days. No deaths occurred. Deterioration of general physical condition was noted and lasted 3-4 days after
treatment.
LDS0 > 500 mg/kg-bw
Repeated-Dose Toxicity
Data gap
[No data were submitted for this endpoint. The sponsor claimed reduced testing based on its claim that
thiocarbazide is a closed-system intermediate. EPA's evaluation of the original information indicated that the
chemical does not meet the criteria to fully support the CSI status request for this chemical and that thiocarbazide
does not qualify for reduced testing and that repeated-dose toxicity endpoint data are needed for the purposes of the
HPV Challenge Program.]
Reproductive Toxicity
Data gap
[No data were submitted for these endpoints. The sponsor claimed reduced testing based on its claim that
thiocarbazide is a closed-system intermediate. EPA's evaluation of the original information indicated that the
chemical does not meet the criteria to fully support the CSI status request for this chemical and that thiocarbazide
does not qualify for reduced testing and data for reproductive toxicity endpoint are needed for the purposes of the
HPV Challenge Program.]
Developmental Toxicity
Data gap
[No data were submitted for this endpoint. The sponsor claimed reduced testing based on its claim that
thiocarbazide is a closed-system intermediate. EPA's evaluation of the original information indicated that the
chemical does not meet the criteria to fully support the CSI status request for this chemical and that thiocarbazide
does not qualify for reduced testing and that developmental toxicity endpoint data are needed for the purposes of the
HPV Challenge Program.]
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Genetic Toxicity - Gene Mutation
In vitro
Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to thiocarbazide at
concentrations of 6.7, 10, 33, 67, 100, 333, 667, 1000, 3333 and 5000 |ig/plate in the presence and absence of
metabolic activation. The maximum dose tested in the preliminary toxicity determination was 5 mg/plate due to the
limited solubility of thiocarbazide. Cytotoxicity data were not provided. Positive controls were tested concurrently,
but their responses were not provided. Thiocarbazide caused a weak reproducible increase in TA1535 revertants per
plate in the presence of metabolic activation. All other tester strains were unaffected.
Thiocarbazide was mutagenic in this assay.
Genetic Toxicity - Chromosomal Aberrations
Data gap
Genetic Toxicity - Other
In vitro
In an unscheduled DNA synthesis (UDS) assay, primary rat hepatocytes were exposed to thiocarbazide at 2.2 -
666.7 iig/mL Positive and negative controls were tested concurrently, but their responses were not provided. There
was an increase in the mean number of net nuclear grain counts at the highest dose with a dose-response
relationship.
Thiocarbazide induced unscheduled DNA synthesis in this assay.
Additional Information
Skin Irritation
A single rabbit (sex and strain were not specified) was administered thiocarbazide dermally at 500 mg/kg-bw to the
clipped, intact skin of the outer ear under occlusive conditions for 24 hours and was observed for 7 days. No
alteration of the treated skin was observed.
Thiocarbazide was not irritating to rabbit skin in this study.
Eye Irritation
Thiocarbazide (50 mg) was instilled into the conjunctival sac of the right eye of one rabbit. The test eye was not
washed. Following dose administration, the animal was observed for irritation (observation period was not stated).
No irritation or alterations of the eyelid, connective tissue or cornea were observed.
Thiocarbazide was not irritating to the rabbit eye in this study.
Conclusion: Acute oral and inhalation toxicity of thiocarbazide to rats is high. The acute dermal toxicity to rats is
moderate. Thiocarbazide is not irritating to rabbit skin or rabbit eyes. No data were submitted to address the
repeated-dose, reproductive or developmental toxicity endpoints and these remain as data gaps. Thiocarbazide
induced gene mutation in bacteria and unscheduled DNA synthesis in primary rat hepatocytes in vitro. The
chromosomal aberrations endpoint remains as a data gap.
The potential health hazard of thiocarbazide cannot be determined because no data were submitted for the repeated-
dose, reproductive and developmental toxicity endpoints. Available data suggest that thiocarbazide has the potential
to be genotoxic.
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4. Hazard Characterization
The log Kow of thiocarbazide indicates that its potential to bioaccumulate is expected to be low. The potential of
thiocarbazide to persist in the environment cannot be determined because the biodegradation endpoint remains as a
data gap.
The potential acute hazard of thiocarbazide to aquatic organisms could not be assessed because adequate data for
fish, aquatic invertebrates and aquatic plants are not available. The acute toxicity to fish and aquatic invertebrates
and the toxicity to aquatic plants endpoints remain as data gaps.
Acute oral and inhalation toxicity of thiocarbazide to rats is high. The acute dermal toxicity to rats is moderate.
Thiocarbazide is not irritating to rabbit skin or rabbit eyes. No data were submitted to address the repeated-dose,
reproductive or developmental toxicity endpoints and these remain as data gaps. Thiocarbazide induced gene
mutation in bacteria and unscheduled DNA synthesis in primary rat hepatocytes in vitro. The chromosomal
aberrations endpoint remains as a data gap.
The potential health hazard of thiocarbazide cannot be determined because no data were submitted for the repeated-
dose, reproductive and developmental toxicity endpoints. Available data suggest that thiocarbazide has the potential
to be genotoxic.
5. Data Gaps
Data gaps for the biodegradation, acute toxicity to fish and aquatic invertebrates, toxicity to aquatic plants, repeated-
dose, reproductive and developmental toxicity and chromosomal aberrations endpoints were identified under the
HPV Challenge Program.
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APPENDIX
Summary Tabic of the Screening Information Data Set
as Submitted underthe U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
Thiocarbazidc
(CAS No. 2231-57-4)
Structure
H H
H2N Y NH2
S
Summary of Physical-Chemical Properties and Environmental Fate Data
Melting Point (°C)
170 (decomposition)
Boiling Point (°C)
Decomposes
Vapor Pressure
(hPa at 25°C)
0.002706 (estimated)
Log K„w
-2.04 (estimated)
Water Solubility
(mg/L at 25°C)
5500 (24.7 °C)
Indirect (OH) Photodegradation
Half-life (t1/2)
1 h (estimated)
Fugacity
(Level III Model)
Air (%)
Water (%)
Soil (%)
Sediment (%)
8.95 x 10"5
45.3
54.6
0.0755
Biodegradation at 28 days (%)
-
Summary of Environmental Effects - Aquatic Toxicity Data
Fish
96-h LCS0 (mg/L)
Data gap.
Aquatic Invertebrates
48-h ECS0 (mg/L)
Data gap
Aquatic Plants
72-h ECS0 (mg/L)
Data gap
Summary of Human Health Data
Acute Oral Toxicity
LDS0 (mg/kg-bw)
26.5
Acute Inhalation Toxicity
LCS0 (mg/L)
-0.05
Acute Dermal Toxicity
LDS0 (mg/kg-bw)
>500
Repeated-Dose Toxicity
NOAEL/LOAEL
Data gap
Reproductive Toxicity
NOAEL/LOAEL
Data gap
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Summary Tabic of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
Thiocarbazidc
(CAS No. 2231-57-4)
Developmental Toxicity
NOAEL/LOAL
Data gap
Genetic Toxicity - Gene Mutation
In vitro
Positive
Genetic Toxicity - Chromosomal Aberrations
In vitro
Data gap
Genetic Toxicity - Other
In vitro
Unscheduled DNA Synthesis
Positive
Additional Information
Skin Irritation
Eye Irritation
Not irritating
Not irritating
- Indicates that endpoint was not addressed for this chemical.
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