U.S. Environmental Protection Agency
Hazard Characterization Document

September, 2009

SCREENING-LEVEL HAZARD CHARACTERIZATION
SPONSORED CHEMICAL

Carbonothioic dihydrazide
(CASRN 2231-57-4)

The High Production Volume (HPV) Challenge Program1 was conceived as 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 sponsored chemicals; sponsorship
entailed the identification and initial assessment of the adequacy of existing toxicity
data/information, conducting new testing if adequate data did 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 by developing hazard characterizations (HCs). These HCs consist of an evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions.

They are not intended to be definitive statements regarding the possibility of unreasonable risk of
injury to health or the environment.

The evaluation is performed according to established EPA guidance2'3 and is based primarily on
hazard data provided by sponsors; however, 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. In order to determine
whether any new hazard information was developed since the time of the HPV submission, a
search of the following databases was made from one year prior to the date of the HPV
Challenge submission to the present: (ChemID to locate available data sources including
Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.),
STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS,
Merck, etc.) and Science Direct. OPPT's focus on these specific sources is based on their being
of high quality, highly relevant to hazard characterization, and publicly available.

OPPT does not develop HCs for those HPV chemicals which have already been assessed
internationally through the HPV program of the Organization for Economic Cooperation and
Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment
Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are

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. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.

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presented in an international forum that involves review and endorsement by governmental
authorities around the world. OPPT is an active participant in these meetings and accepts these
documents as reliable screening-level hazard assessments.

These hazard characterizations are technical documents intended to inform 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.

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Hazard Characterization Document

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Chemical Abstract
Registry Number
(CASRN)

CASRN 2231-57-4

Chemical Abstract Index
Name

Carbonothioic dihydrazide

Structural Formula

S

Summary

Carbonothioic dihydrazide is a solid with high water solubility and moderate vapor pressure. It
is expected to have high mobility in soil. Volatilization of carbonothioic dihydrazide is
considered low based on its Henry's Law constant. The rate of hydrolysis was not available and
could not be estimated for this compound. The rate of atmospheric photooxidation is considered
rapid. Carbonothioic dihydrazide is expected to have moderate persistence (P2) based on the
slow rate of biodegradation of a structurally similar compound (thiosemicarbizide) and low
bioaccumulation potential (Bl).

Acute oral and inhalation toxicity of this chemical is high. There are no available repeated-dose,
developmental or reproductive toxicity tests. It induced gene mutations in bacteria and
unscheduled DNA synthesis in vitro. There are no available tests for the chromosomal
aberrations endpoint.

The estimated 96-hour LC50 for fish is 30 mg/L, the estimated 48-hour EC50 for aquatic
invertebrates is 12 mg/L, and the estimated 96-hour EC50 for aquatic plants is 15 mg/L.

Data gaps for biodegradation, repeated-dose, reproductive and developmental toxicity,
chromosomal aberrations, acute toxicity to fish, aquatic invertebrates, and toxicity to aquatic
plants endpoints were identified under the HPV Challenge Program.

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The sponsor, Bayer Corporation, submitted a Test Plan and Robust Summaries to EPA for
carbonothioic dihydrazide (CASRN 2231-57-4; CA Index 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.

The sponsor proposed reduced health effects testing, claiming that carbonothioic dihydrazide
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 carbonothioic dihydrazide 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.

1 Chemical Identity

1.1	Identification and Purity

There is no discussion of the identification and purity of this chemical in the sponsor's Test
Plan.

1.2	Physical-Chemical Properties

The physical-chemical properties of carbonothioic dihydrazide are summarized in Table 1.
Carbonothioic dihydrazide is a solid with high water solubility and moderate vapor pressure.

Table 1. Physical-Chemical Properties of Carbonothioic Dihydrazide 1

Property

Value

CASRN

2231-57-4

Molecular Weight

106.15

Physical State

Solid

Melting Point

170°C (decomposes)

Boiling Point

decomposes

Vapor Pressure

0.002 mm Hg at 25°C (estimated)

Water Solubility

5,500 mg/L at 24.7°C 2
1,800 mg/L at 0°C 2

Dissociation Constant (pKa)

0.29 (estimated)3

Henry's Law Constant

2.76x 10"12 atm-m3/mole (estimated)

Log K0w

-2.04 (estimated)

Bayer CropScience LP. January 6, 2004. Robust Summary for Carbonothioic Dihydrazide.
http://www.epa. gov/chemrtk/pubs/summaries/crbndhvd/c 14999tc.htm.

2 Beilstein, E4, Vol 3, part 1, page 388.

3SPARC. 2008. Online pKa and Property Calculator v. 4.2.1405-s4.2.1408. Accessed October 30, 2008.
http://ibmlc2.chem.uga. edu/sparc/index.cfm?CFID=32727&CFTOKEN=65477992.

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2 General Information on Exposure

2.1	Production Volume and Use Pattern

This chemical had an aggregated production and/ or import volume in the United States between
1 million and 10 million pounds during calendar year 2005.

Non-confidential information in the IUR indicated that the industrial processing and uses of the
chemical include intermediates in the manufacturing of pesticides and other agricultural
chemicals. The HSDB information states that the chemical is primarily used in electron
microscopy to produce electron-opaque deposits for ultrastructural analysis. It is also used in
veterinary medicine. The HPV submission states that the chemical is primarily used as an
intermediate in the production of an agricultural herbicide and, in limited quantities, as an
intermediate in the production of a "fine" chemical.

2.2	Environmental Exposure and Fate

No quantitative information is available on releases of this chemical to the environment.

The environmental fate properties are provided in Table 2. Carbonothioic dihydrazide is
expected to have high mobility in soil. No biodegradation data were submitted by the sponsor
for carbonothioic dihydrazide. EPA used data for thiosemicarbazide (CASRN 79-19-6) to
address the biodegradation of the sponsored chemical because the two chemicals are structurally
similar chemicals and their biodegradation rates are expected to be similar. Thiosemicarbazide
(CASRN 79-19-6) achieved 0% of its theoretical BOD over a 28-day incubation period using a
modified MITI test (OECD 301C) and was determined to be not readily biodegradable.4 The
rate of volatilization of carbonothioic dihydrazide from water and moist soil is considered low
based on its estimated Henry's Law constant. The rate of hydrolysis was not available and could
not be estimated for this compound. Carbonothioic dihydrazide is expected to have moderate
persistence (P2) based on the lack of biodegradability of thiosemicarbazide and low
bioaccumulation potential (Bl).

4National Institute of Technology and Evaluation. 2002. Biodegradation and Bioaccumulation of the Existing Chemical
Substances under the Chemical Substances Control Law. http://www.safe.nite.go.ip/english/kizon/KIZON start hazkizon.html.

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Table 2. Environmental Fate Characteristics of Carbonothioic dihydrazide 1

Property

Value

Photodegradation Half-life

1 hour (estimated)

Hydrolysis Half-life

Not available

Biodegradation

0% in 28 days (data for structural analog
thi osemi carb azi de)2

Bi oconcentrati on

BCF = 3.162 (estimated);

BCF = 3.8-39 (measured in carp for structural analog
thi osemi carb azi de)2

Log Koc

1.016 (estimated)3

Fugacity

(Level III Model)

Air = <0.01%
Water = 45.3%

Soil = 54.6%
Sediment = <0.01%

Persistence4

P2 (moderate)

Bi oaccumul ati on4

Bl (low)

1 Bayer CropScience LP. January 6, 2004. Robust Summary for Carbonothioic Dihydrazide.
http://www.epa. gov/chemrtk/pubs/summaries/crbndhvd/c 14999tc.htm.

2National Institute of Technology and Evaluation. 2002. Biodegradation and Bioaccumulation of the Existing
Chemical Substances under the Chemical Substances Control Law.
http://www.safe.nite.go.ip/english/kizon/KIZON start hazkizon.html.

3U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v 3.20. U.S. Environmental
Protection Agency, Washington, DC, USA. http://www.epa.gov/opptintr/exposure/pubs/episuite.htm.

4Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances.

Federal Register 64, Number 213 (November 4, 1999) pp. 60194-60204.

Conclusion: Carbonothioic dihydrazide is a solid with high water solubility and moderate vapor
pressure. It is expected to have high mobility in soil. Volatilization of carbonothioic
dihydrazide is considered low based on its Henry's Law constant. The rate of hydrolysis was not
available and could not be estimated for this compound. The rate of atmospheric photooxidation
is considered rapid. Carbonothioic dihydrazide is expected to have moderate persistence (P2)
based on the slow rate of biodegradation of a structurally similar compound (thiosemicarbizide)
and low bioaccumulation potential (Bl).

A data gap for biodegradation was identified under the HPV Challenge Program.

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3 Human Health Hazard

A summary of health effects data submitted for SIDS endpoints is provided in Table 2.

Acute Oral Toxicity

(1)	In two separate studies, Wistar rats (15 males/dose) were administered carbonothioic
dihydrazide (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. Deaths occurred within 3-24 hours in animals at and
above 25 mg/kg-bw.

LD50 = 35 -41 mg/kg-bw

(2)	In two separate studies, Wistar rats (15 females/dose) were administered carbonothioic
dihydrazide (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. Deaths occurred
within 4.5 - 24 hours in animals at and above 17.5 mg/kg-bw.

I,I)5u = 26-36 mg/kg-bw

Acute Inhalation Toxicity

(1)	Wistar rats (10/sex/concentration) were exposed to carbonothioic dihydrazide 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 0.045 mg/L and in females exposed to concentrations at and above
0.05 mg/L.

LC50 = 0.05 mg/L

(2)	Wistar rats (10/sex/concentration) were exposed to carbonothioic dihydrazide 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 to 0.076
mg/L (2/10 males and 1/10 females died). All 20 high dose animals showed signs of toxicity.
No effects were observed in animals exposed at 0.045 mg/L. (If the toxic response is assumed to
be linear, 4 hour exposure would have 12/20 mortality ~ 60%.)

LC50 > 0.075 mg/L (one hour exposure)

Acute Dermal Toxicity

Wistar rats (males and female, number not specified) were administered carbonothioic
dihydrazide (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.
LD50 > 500 mg/kg-bw (only dose tested)

Repeated-Dose, Reproductive, and Developmental Toxicity

[No data were submitted for these endpoints.]

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Genetic Toxicity - Gene Mutation
In vitro

Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to
carbonothioic dihydrazide 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
carbonothioic dihydrazide. Cytotoxicity data were not provided. Positive controls were tested
concurrently, but their responses were not provided. Carbonothioic dihydrazide caused a small
but reproducible increase in TA1535 revertants per plate in the presence of metabolic activation
(2.5 and 3.1 fold increases in 2 separate experiments). In the absence of rat liver microsomes,
TA1535 did not demonstrate a positive response. All other tester strains did not demonstrate
positive responses.

Carbonothioic dihydrazide 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
carbonothioic dihydrazide at 2.2 - 666.7 |ag/m L 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.

Carbonothioic dihydrazide induced unscheduled DNA synthesis in this assay.

Additional Information

Skin Irritation

A single rabbit (sex and strain not specified) was administered carbonothioic dihydrazide
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.
Carbonothioic dihydrazide was not irritating to one rabbit skin in this study.

Eye Irritation

Carbonothioic dihydrazide (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.

Carbonothioic dihydrazide was not irritating to one rabbit eye in this study.

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Conclusion: Acute oral and inhalation toxicity of carbonothioic dihydrazide is high. There are
no available repeated-dose, developmental or reproductive toxicity tests. Carbonothioic
dihydrazide induced gene mutations in bacteria and unscheduled DNA synthesis in vitro. There
are no available tests for the chromosomal aberrations endpoint.

Data gaps for repeated-dose, reproductive and developmental toxicity and chromosomal
aberrations endpoints were identified under the HPV Challenge Program.

4 Hazards to the Environment

The sponsor did not submit measured aquatic toxicity data for carbonothioic dihydrazide.
ECOSAR vl.OOa was used to assess the acute toxicity of the chemical to fish, aquatic
invertebrates and aquatic plants.

Acute Toxicity to Fish

A 96-hour LC50 for fish estimated by ECOSAR vl ,00a was used to evaluate the acute toxicity of

carbonothioic dihydrazide.

96-hr LC50 = 30 mg/L (estimated)

Acute Toxicity to Aquatic Invertebrates

A 48-hour EC50 for Daphnia estimated by ECOSAR vl ,00a was used to evaluate the acute
toxicity of carbonothioic dihydrazide.

48-hr EC50 = 12 mg/L (estimated)

Toxicity to Aquatic Plants

A 96-hour EC50 for algae estimated by ECOSAR vl.OOa was used to evaluate the acute toxicity
of carbonothioic dihydrazide.

96-hr EC50 = 15 mg/L (estimated)

Conclusion: The estimated 96-hour LC50 for fish is 30 mg/L, the estimated 48-hour EC50 for
aquatic invertebrates is 12 mg/L, and the estimated 96-hour EC50 for aquatic plants is 15 mg/L.

Data gaps for acute toxicity to fish and aquatic invertebrates, and toxicity to aquatic plants were
identified under the HPV Challenge Program.

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Table 3. Summary Table of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program

Endpoints

SPONSORED CHEMICAL
Carbonothioic dihydrazide (CASRN 2231-57-4)

Summary of Human Health Data

Acute Oral Toxicity
LD5o (mg/kg-bw)

35 - 41 males
26 - 36 females

Acute Inhalation Toxicity
LCso (mg/L)

0.05

Repeated-dose/

Reproductive/Developmental Toxicity

No data

Genetic Toxicity - Gene Mutations
In vitro

Positive

Genetic Toxicity - Chromosomal

Aberrations

In vitro

No data

Summary of Environmental Effects - Aquatic Toxicity Data

Fish

96-h LCso (mg/L)

30 (estimated)

Aquatic Invertebrates
48-h ECso (mg/L)

12 (estimated)

Aquatic Plants
72-h ECso (mg/L)

15 (estimated)

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