Supporting Documents for Initial Risk-Based Prioritization of High Production Volume Chemicals 1, 3, 5-Trioxane (CASRN 110-88-3)


U.S. Environmental Protection Agency
Supporting Documents for Risk-Based Prioritization

September 2008

Supporting Documents for Initial Risk-Based Prioritization of
High Production Volume Chemicals

1, 3, 5-Trioxane (CASRN 110-88-3)

Contents:

•	Page 2: Background

•	Page 4: Screening-Level Risk Characterization: September 2008

•	Page 8: Screening-Level Hazard Characterization: September 2008

•	Page 18: Screening-Level Exposure Characterization: September 2008

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BACKGROUND

Screening-level hazard, exposure and risk characterizations for high production volume chemicals (HPV)
are important contributions to the chemicals cooperation work being done in North America1 through the
EPA Chemical Assessment and Management Program (ChAMPjr. These screening-level
characterizations are developed by EPA for individual chemicals or chemical categories to support initial
Risk-Based Prioritizations (RBPs) for HPV chemicals. These screening-level characterizations are
technical documents intended primarily to inform the Agency's internal decision-making process.
Accordingly, they are written for assessment professionals and assume a degree of technical
understanding. Each of the support documents is described below.

The Risk-Based Prioritizations are found in an accompanying document and are written for a general
audience. They present EPA's initial thinking regarding the potential risks presented by these chemicals
and future possible actions that may be needed.

Hazard Characterizations for HPV Chemicals

EPA's screening-level hazard characterizations are based primarily on the review of the summaries of
studies and other information submitted by the chemical sponsor(s) under the HPV Challenge Program'.
These studies included in the scope of the HPV Challenge comprise the Screening Information Data Set
(SIDS) of the Organization for Economic Cooperation and Devebpment (OECD)4, an internationally
recognized battery of tests that provides the basic data necessary to make an initial evaluation of a
chemical's hazards and fate. In preparing the initial hazard characterizations, EPA also consulted a
variety of reliable sources5 for additional relevant information and 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 an HPV submission, EPA also searched publicly available databases6 for information entered
from one year prior to the HPV submission through May 2008. The screening-level hazard
characterization is performed according to established EPA guidance7. A more detailed description of the
hazard characterization process is available on the EPA website8.

With respect to chemicals for which internationally-accepted OECD SIDS Initial Assessment Profiles
(SIAP) and Initial Assessment Reports (SIAR) were available, EPA did not generate its own screening-
level hazard characterization, but did check for and incorporate updated information in the risk
characterization

Exposure Characterizations for HPV Chemicals

EPA recently received exposure-related data on chemicals submitted in accordance with the requirements
of Inventory Update Reporting (IUR)9. The 2006 IUR submissions pertain to chemicals manufactured in

1 U.S. EPA - U.S. Commitments to North American Chemicals Cooperation:
http: //www. ep a. go v/hp v/pub s/general/sppframework. htm.

2 U.S. EPA-ChAMP information: http://www.epa.gov/champ/.

3 U.S. EPA - HPV Challenge Program information: http://www.epa.gov/hpv.

4 U.S. EPA - Technical Guidance Document, OECD SIDS Manual Sections 3.4 and 3.5:
http: //www, epa. gov/chemrtk/pubs/general/sidsappb. htm

5 U.S. EPA-Public Database Hazard Information: http: //www .epa. go v/hp vi s/haz ardinfo. htm

6 U.S. EPA - Public Database Update Information: http://www.epa.gov/chemrtk/hpvis/updateinfo.htm

7 U.S. EPA - Risk Assessment Guidelines: http: //cfpub. ep a. go v/ncea/raf/raf guid. cfhi

8 U.S. EPA - About HPV Chemical Hazard Characterizations: http: //www .epa. go v/hp vi s/abouthc. htm

9 U.S. EPA-Basic IUR Information: http://www.epa.gov/opptintr/iur/pubs/guidance/basic-information.htm.

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September 2008

(including imported into) the U.S. during calendar year 2005 in quantities of 25,000 pounds or more at a
single site. The reports include the identity, the quantity, and the physical form of the chemical
manufactured or imported, and the number of workers reasonably likely to be exposed during
manufacture of the chemical. For chemicals manufactured or imported in quantities of 300,000 pounds or
more at a single site, additional reported information includes: the industrial processing and uses of the
chemical; the number of industrial processing sites and workers reasonably likely to be exposed to the
chemical at those sites; the consumer and commercial uses of the chemical; and an indication whether the
chemical was used in products intended for use by children under 14 years of age.

EPA's screening-level exposure characterizations are based largely on the information submitted under
the IUR reporting, although other exposure information submitted to the Agency (for example, in HPV
submissions) or readily available through a limited set of publicly accessible databases10 was also
considered. The screening-level exposure characterizations identify a potential (high, medium, or low)
that each of five populations - the environment, the general population, workers, consumers, and children
- might be exposed to the chemical In most cases, this potential doesn't address the quantity, frequency,
or duration of exposure, but refers only to the likelihood that an exposure could occur.

In many instances EPA is not able to fully disclose to the public all the IUR exposure-related data
reviewed or relied upon in the development of the screening-level documents because some of the
material was claimed as confidential business information (CBI) when it was submitted to the Agency.
These CBI claims do limit the Agency's ability to be completely transparent in presenting some
underlying exposure and use data for chemicals in public documents. EPA does consider all data,
including data considered to be CBI, in the screening-level exposure and risk characterization process,
and endeavors whenever possible to broadly characterize supporting materials claimed as confidential in
ways that do not disclose actual CBI.

Risk Characterizations for HPV Chemicals

EPA combines the information from the screening-level exposure characterization with the screening-
level hazard characterization to develop a qualitative screening-level risk characterization, as described in
the Agency's guidance on drafting risk characterizations11. These screening-level risk characterizations
are technical documents intended to support subsequent priority-setting decisions and actions by OPPT.
The purpose of the qualitative screening-level risk characterization is two-fold: to support initial risk-
based decisions to prioritize chemicals, identify potential concerns, and inform risk management options;
and to identify data needs for individual chemicals or chemical categories.

These initial characterization and prioritization documents do not constitute a final Agency determination
as to risk, nor do they determine whether sufficient data are available to characterize risk. Recommended
actions reflect EPA's relative judgment regarding this chemical or chemical category in comparison with
others evaluated under this program, as well as the uncertainties presented by gaps that may exist in the
available data.

10 U.S. EPA - Summary of Public Databases Routinely Searched:
http: //www. ep a. go v/chemrtk/hp vis/pubdt sum. htm.

11 U.S. EPA - Risk Characterization Program: http://www.epa.gov/osa/spc/2riskchr.htm.

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U.S. Environmental Protection Agency
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September 2008

QUALITATIVE SCREENING-LEVEL RISK CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS

SPONSORED CHEMICAL

1, 3, 5-Trioxane (CAS No. 110-88-3)

[9th CI Name: 1, 3, 5-Trioxane]

September 2008

Prepared by

Risk Assessment Division
Economics, Exposure and Technology Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001

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September 2008

QUALITATIVE SCREENING-LEVEL RISK CHARACTERIZATION FOR
1, 3, 5-Trioxane (CAS No. 110-88-3)

1. Physical-Chemical Properties and Environmental Fate

1,3,5-Trioxane is a white, crystalline solid at room temperature with a high vapor pressure and
high water solubility. 1,3,5-Trioxane is expected to partition primarily to soil and water. It is
highly mobile in soil and moderately volatile from water and moist soil surfaces. The rate of
hydrolysis of 1,3,5-trioxane is considered negligible. In the atmosphere, 1,3,5-trioxane exists
primarily in the vapor phase, where it is subject to slow photooxidation by the hydroxyl radical.
It does not undergo direct photolysis. A bioconcentration factor (BCF) of 3.2 was estimated.
1,3,5-Trioxane is expected to have high persistence in the environment (P3) and low
bioaccumulation potential (Bl).

2. Hazard Characterization

Aquatic Organism Toxicity: The acute toxicity of 1,3,5-trioxane to fish, aquatic invertebrates
and aquatic plants is low.

Human Health Toxicity: The acute oral and inhalation toxicity of 1,3,5-trioxane in rats and acute
dermal toxicity in rabbits is low. Repeated-dose studies showed route-specific toxicity. An oral
repeated-dose study in rats showed low toxicity and an inhalation study in rats showed high
toxicity. Two dominant lethal studies (one oral and one inhalation), showed low reproductive
toxicity. A separate oral repeated-dose toxicity study, conducted in female rats to evaluate
estrous cycle, showed low toxicity. An oral prenatal developmental study in rats showed low
developmental and maternal toxicity. 1,3,5-Trioxane did not induce gene mutations in bacteria.
However, a dose-dependent increase in mutations was seen in mammalian cells with metabolic
activation, but not in the absence of metabolic activation. 1,3,5-Trioxane did not induce
chromosomal aberrations in an in vivo assay.

3. Exposure Characterization

1,3,5-Trioxane (CAS # 110-88-3) has an aggregated production and/or import volume in the
United States of 100 million to 500 million pounds. Non-confidential Inventory Update
Reporting (IUR) information for this chemical indicates that it is used as an intermediate in resin
and synthetic manufacturing. Other minor uses associated with this chemical are as an adhesive
and binding agent in electric lamp bulb and parts manufacturing, and other chemical products
and preparations. There are no reported commercial or consumer uses. The High Production
Volume (HPV) Challenge submission for this chemical stated that it is used primarily as a
monomer for production of high-molecular weight polyacetals and secondarily as a chemical
intermediate.

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September 2008

water and/or air during manufacturing, processing, and use. Persistence and bioaccumulation
ratings for this chemical are P3 and Bl. These ratings suggest that this chemical is very
persistent in the environment, and is not bioaccumulative.

Potential Exposures to Workers: Based on the information considered, including the HPV
Revised Test Plan and IUR data (both confidential business information (CBI) and non-CBI),
and the Agency's professional judgment, EPA identifies, for the purposes of risk-based
prioritization, a high relative ranking for potential worker exposure. The high relative ranking is
primarily based on the relatively high vapor pressure, which could result in significant worker
exposure to vapor, as well as the potential for inhalation exposure to solid material. This
chemical does not have OSHA Permissible Exposure Limits (PELs).

Potential Exposures to Consumers: EPA identifies, for the purposes of risk-based prioritization,
a low potential that consumers might be exposed to 1,3,5-trioxane from products containing this
chemical, based on the IUR data. IUR submissions indicate no uses in consumer products, nor
were any found in other data sources.

Potential Exposures to Children: No uses in products specifically intended to be used by
children were reported in the IUR, nor were any found in other data sources. Therefore, EPA
identifies a low potential that children might be exposed to 1,3,5-trioxane.

4. Risk Characterization

The statements and rationale provided below are intended solely for the purpose of this
screening-level and qualitative risk characterization and will be used for prioritizing substances
for future work in the Chemical Assessment and Management Program (ChAMP).

Risk Statement and Rationale

Potential Risk to Aquatic Organisms from Environmental Releases: (LOW CONCERN).
EPA identifies a medium potential that aquatic organisms might be exposed from
environmental releases. 1,3,5-Trioxane has a high persistence and low bioaccumulation.
These characteristics in combination with the low toxicity to fish, aquatic invertebrates
and plants indicate a low concern for potential risk to fish, aquatic invertebrates and
plants.

Potential Risk to the General Population from Environmental Releases: (HIGH
CONCERN). EPA identifies a medium potential that the general population might be
exposed from environmental releases to the air and water. The potential human health
hazard is low for oral exposure. Therefore, there is a low concern for potential risk to the
general population due to oral exposure from environmental releases. The potential
human health hazard is high for inhalation exposure. Therefore, there is a high concern
for potential risk to the general population from inhalation exposures from environmental
releases.

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Potential Risk to Workers: (HIGH CONCERN). EPA identifies a high relative ranking
for potential worker exposure. The ranking is primarily based on the relatively high
vapor pressure, which could result in significant worker exposure to vapor, as well as
potential for inhalation exposure to solid material. There is not an OSHA Permissible
Exposure Limit (PEL) for this chemical. The potential human health hazard is high for
inhalation exposure. Therefore, there is a high concern for potential risk to workers.

Potential Risk to Consumers: (LOW CONCERN). EPA identifies a low potential that
consumers might be exposed. The potential human health hazard is low for oral exposure
and high for inhalation exposure. Therefore taken together, there is a low concern for
potential risk to consumers.

Potential Risk to Children: (LOW CONCERN). EPA identifies a low potential that
children might be exposed. There are no toxicology studies that specifically address
potential toxicity at early life stages. However, 1,3,5-trioxane is not present in children's
products or consumer products. Therefore, the available information suggests a low
concern for potential risks to children.

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U.S. Environmental Protection Agency
Supporting Documents for Risk-Based Prioritization

September 2008

SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS

SPONSORED CHEMICAL

1,3,5-Trioxane (CAS No. 110-88-3)
[9th CI Name: 1,3,5-Trioxane]

September 2008

Prepared by

Risk Assessment Division
Economics, Exposure, and Technology Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001

8

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U.S. Environmental Protection Agency
Supporting Documents for Risk-Based Prioritization

September 2008

SCREENING-LEVEL HAZARD CHARACTERIZATION
1,3,5-Trioxane (CAS No. 110-88-3)

Introduction

The sponsor, Trioxane Manufacturers Consortium and its member companies, BASF Performance Copolymers,
LLC and Ticona, submitted a Test Plan and Robust Summaries to EPA for 1,3,5-trioxane (CAS No. 110-88-3;

9th CI name: 1,3,5-trioxane) on December 22, 2000. EPA posted the submission on the ChemRTK HPV
Challenge website on January 12, 2001 fhttp://www.epa.gov/chemrtk/pubs/summaries/triox/trioxtc.htm). EPA
comments on the original submission were posted to the website on May 14, 2001. Public comments were also
received and posted to the website. The sponsor submitted updated/revised documents on July 16, 2001.

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. 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 July 2000 to May 2008: the NLM databases (ChemID to locate available data sources including
Medline/PubMed, Toxlme, HSDB, IRIS, NTP, AT SDR, EXTOXNET, EPA SRS, etc.), STN/CAS online databases
(Registry file for locators, ChemAbs for toxicology data, RTECS, Merck, etc.) and Science Direct. 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 toxicity is based largely on SIDS
endpoints and is described according to established EPA or OECD effect level definitions and hazard assessment
practices.

11ii/iircl C 'hiiriKiori/iilion

1,3.5-Trioxane is a white, crystalline solid at room temperature with a high vapor pressure and high w ater solubility.
1,3,5-Trio\ane is expected to partition primarily to soil and w ater. It is highly mobile in soil and moderately volatile
from w ater and moist soil surfaces. The rate of hydrolysis of 1.3.5-trioxane is considered negligible. In the
atmosphere, 1.3.5-trioxane exists primarily in the vapor phase, where it is subject to slow photooxidation by the
hydroxy 1 radical. It does not undergo direct photolysis. A bioconcentration factor (BCT) of 3.2 was estimated.
1.3.5-Trioxane is expected to have high persistence in the environment (P3) and low bioaceumulation potential (HI).

The acute toxicity of 1.3.5-trioxane to fish, aquatic invertebrates and aquatic plants is low.

The acute oral and inhalation toxicity of 1.3.5-trioxane in rats and acute dermal toxicity in rabbits is low. Repeated-
dose studies showed route-specific toxicity. An oral repeated-dose study in rats showed low toxicity and an
inhalation study in rats showed high toxicity. Two dominant lethal studies (one oral and one inhalation), showed
low reproductive toxicity. A separate oral repeated-dose toxicity study, conducted in female rats to evaluate estrous
cycle, showed low toxicity. An oral prenatal developmental study in rats showed low developmental and maternal
toxicity. 1.3,5-Trioxane did not induce gene mutations in bacteria. I low ever, a dose-dependent increase in
mutations was seen in mammalian cells with metabolic activation, but not in the absence of metabolic activation.
1.3,5-Trioxane did not induce chromosomal aberrations in an in vivo assay.

No data gaps were identified under the IIPV Challenge Program.

1. Physical-Chemical Properties and Environmental Fate

The physical-chemical properties of 1,3,5-trioxane are summarized in Table la, while its environmental fate
properties are given in Table lb. The structure of the compound is provided in the Appendix.

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Physical-Chemical Properties Characterization

1,3,5-Trioxane is a white, crystalline solid at room temperature. It has both a high vapor pressure and high water
solubility.

Tabic la. Phvsical-Chemical Properties of 1,3,5-Trioxane1

Property

Value

CAS No.

110-88-3

Molecular Weight

90.08

Physical State

White, crystalline solid2'3

Melting Point

64°C (measured)

Boiling Point

114.5°C at 759 mm Hg (measured)

Vapor Pressure

10 mm Hg at 20°C (measured)

Water Solubility

17.2 g/100 mL at 18°C (measured)
21.2 g/100 mL at 25°C (measured)

Dissociation Constant(s) (pKa)

Not applicable

Henry's Law Constant

1.97 x 10"' atm-ffiVmol (estimated)4

Log Kow

-0.47 (measured)

Trioxane Manufacturers Consortium. 2001. Robust Summary for 1,3,5-Trioxane.
http://www.epa.gov/chemrtk/pubs/summaries/triox/trioxtc.htm.

2HSDB. 2008. Hazardous Substances Data Bank., Accessed May 12, 2008. http://toxnet.nlm.nih.gov/

3Data not provided in robust summary.

4US EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v3.20. United States
Environmental Protection Agency, Washington, DC, USA. http://www.epa.gov/opptintr/exposure/pubs/episuite.htm

Environmental Fate Characterization

1,3,5-Trioxane is expected to partition primarily to soil and water, according to the results of a Level III fugacity
model that assumes equal emissions to air, water, and soil. 1,3,5-Trioxane is expected to be highly mobile in soil
based upon its Koc. Its Henry's Law constant suggests that it is moderately volatile from water and moist soil
surfaces. The rate of hydrolysis of 1,3,5-trioxane is considered negligible. In the atmosphere, 1,3,5-trioxane exists
primarily in the vapor phase, where it is subject to slow photooxidation by the hydroxyl radical. It does not undergo
direct photolysis. An estimated bioconcentration factor (BCF) of 3.2 suggests that 1,3,5-trioxane has a low
bioaccumulation potential (Bl). The rate of biodegradation of 1,3,5-trioxane is slow to negligible based on the
results of a MITI ready biodegradation test; therefore, it is judged to have high persistence in the environment (P3).

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Table 11). Environmental Fate Characteristics of 1,3,5-Trioxane1

Property

Value

Photodegradation Half-life

25 hours (estimated)2

Biodegradation

2% in 28 days (measured; not readily biodegradable)

Hydrolysis Half-life

780 days at pH 4, 840 days at pH 7, 2000 to 3200 days at
pH 9 (measured)

Bioconcentration

BCF = 3.2 (estimated)2

Direct Photolysis

Not significant

Koc

0.152 (estimated)2

Fugacity

(Level III Model)2

Air = 4.9%

Water = 53.4%
Soil = 41.6%
Sediment = 0.09%

Persistence3

P3 (high)

B io accumul ation3

B1 (low)

http://www.epa.gov/chemrtk/pubs/summaries/triox/trioxtc.htm.

2US EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v3.20. United States
Environmental Protection Agency, Washington, DC, USA. http://www.epa.gov/opptintr/exposure/pubs/episuite.htm
3FR. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64,
Number 213 (November 4, 1999) Page 60194-60204.

Conclusion: 1,3,5-Trioxane is a white, crystalline solid at room temperature with a high vapor pressure and high
water solubility. 1,3,5-Trioxane is expected to partition primarily to soil and water. It is highly mobile in soil and
moderately volatile from water and moist soil surfaces. The rate of hydrolysis of 1,3,5-trioxane is considered
negligible. In the atmosphere, 1,3,5 -trioxane exists primarily in the vapor phase, where it is subject to slow
photooxidation by the hydroxyl radical. It does not undergo direct photolysis. A bioconcentration factor (BCF) of
3.2 was estimated. 1,3,5-Trioxane is expected to have high persistence in the environment (P3) and low
bioaccumulation potential (B1

2. Environmental Effects - Aquatic Toxicity

Acute Toxicity to Fish

Golden orfe (Leuciscus idus) were exposed to 1,3,5-trioxane at nominal concentrations of 0, 1000, 2150, 4640 or
10,000 mg/L under static conditions for 96 hours. Mortality was 100% at the highest concentration at all
observation periods starting at 1 hour.

96-h LCso = 4030 mg/L

Acute Toxicity to Aquatic Invertebrates

Water fleas (Daphnia magna) were exposed to 1,3,5-trioxane at nominal concentrations of 0, 0.1, 1, 10, 100 and
1000 mg/L under static conditions for 48 hours. No immobilization or deaths were seen in the study.

48-h ECso > 1000 mg/L

Toxicity to Aquatic Plants

Green algae (Scenedesmus subspicatus strain SAG 86.81) were exposed to 1,3,5-trioxane at nominal concentrations
of 0, 3.9, 7.8, 15.6, 31.3, 62.5, 125, 250 and 500 mg/L under static conditions for 72 hours.

96-h EC50 (growth) > 500 mg/L

Conclusion: The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants indicates that
the potential acute hazard of 1,3,5-trioxane to aquatic organisms is low.

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3. Human Health Effects
Acute Oral Toxicity

Five male albino rats/group (unspecified strain) were administered 1,3,5-trioxane via gavage at doses of 2520, 5000
and 10,000 mg/kg-bw. Animals were observed for 14 days post-exposure. The numbers of deaths were 0/5, 0/5 and
4/5 for the 2520, 5000 and 10,000 mg/kg-bw dose groups, respectively. There was no observed effect on body
weight at any dose. No information on clinical signs, time of death or target organs was provided.

LD50 = 8190 mg/kg-bw

Acute Dermal Toxicity

1,3,5-Trioxane was applied to skin of four male albino rabbits (two animals had abraded skin) at 3980 mg/kg-bw for
24 hours. No deaths were observed. 1,3,5-Trioxane resulted in slight to moderate erythema, which disappeared by
study termination. Two rabbits had reduced body weights. Necropsy was normal.

LD50 > 3980 mg/kg-bw

Acute Inhalation Toxicity

Charles River CD rats (5/sex/dose) were exposed to 1,3,5-trioxane vapor at concentrations of 8370 or 10,643 ppm
(approximately 30.8 or 39.2 mg/L, respectively) for 4 hours and were observed for 14 days after dosing. No deaths
occurred. Lacrimation, shallow and irregular breathing, reduced activity and nasal discharge were observed at both
doses. Body weights were reduced, but animals gained weight normally during the second week of the observation
period. Although scattered effects were seen at both doses upon necropsy, findings were minor.

LC50 > ~ 39.2 mg/L

Repeated-Dose Toxicity

(1)	Wistar rats (5/sex/dose) were administered 1,3,5-trioxane via gavage 28 times within 29 days at doses of 0, 40,
200 or 1000 mg/kg-bw/day. No clinical signs or changes in body weights or food consumption were seen.
Leukocytes were significantly decreased at 1000 mg/kg -bw/day in males and females (p < 0.05). In the high-dose
females, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT)
activities were increased and protein and glucose levels were decreased significantly (p < 0.05), but no
corresponding histopathologic effects were observed. Absolute (but not relative) spleen weights of high-dose males
were reduced compared with controls (p < 0.05).

LOAEL = 1000 mg/kg-bw/day (based on effects on hematology)

NOAEL = 200 mg/kg-bw/day

(2)	Sprague-Dawley CD rats (5/sex/dose) were exposed to 1,3,5-trioxane for 12 days (5 days/week for 6 hours/day)
via inhalation at vapor concentrations of 0, 103, 984 or 4940 ppm (approximately 0.38, 3.6 or 18 mg/L). Clinical
signs were seen at higher incidences than the controls at different times throughout the study, but the sponsors
suggested that the effects were sporadic at all doses other than at the highest dose; no statistical evaluation was done
for these endpoints. At the high dose, decreased body weights, increased hemoglobin and hematocrit, increased red
blood cells (RBC) (females), decreased RBC (males) and decreased white blood cells (males) were all significantly
different from controls (p < 0.01). Also at the highest dose, clinical chemistry changes (e.g., increases in mean
serum glutamic pyruvic transaminase, total protein and albumin values), but no corresponding histopathologic
effects were observed. Mean absolute and relative spleen weights were decreased at all doses in males and at the
highest two doses in females. Increased relative weights in other organs were considered to be related to decreased
body weights at the high dose. In addition, squamous metaplasia of the anterior nasal cavity mucosa with necrosis
and desquamation and acute rhinitis were observed.

LOAEL (male) = 0.38 mg/L (based on decreased absolute and relative spleen weights)

NOAEL (male) = Not established

LOAEL (female) = 3.6 mg/L (based on decreased absolute and relative spleen weights)

NOAEL (female) = 0.38 mg/L

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Reproductive Toxicity

No data for reproductive toxicity were submitted. Evaluation of effects on fertility, male reproductive organs and
reproduction from two dominant lethal assays and the availability of the developmental toxicity study addressed the
reproductive toxicity endpoint for the purposes of the HPV Challenge Program.

(1) In a dominant lethal study, Wistar rats (10 males/dose) were administered 1,3,5-trioxane via gavage at doses of
0, 850, or 1700 mg/kg-bw/day 5 days/week for 8 weeks and were mated with untreated virgin females. Body weight
gain was 50 and 42% of control at the mid - and high-doses, respectively. Absolute and relative liver, kidney and
spermatic vesicle weights were increased. Histopathology of the testes showed focal necrosis of the seminiferous
epithelium in 1/10 control, 3/10 low-dose and an unspecified number of high-dose males (testicular lesions were
reported to be bilateral in 3/10 high-dose males); severity was reported to be dose-dependent. 1,3,5-Trioxane did
not affect fertility rate, number of implants per female, live fetuses per female or pre -implantation loss per female.
1,3,5-Trioxane affected male reproductive organ histology, but not reproductive performance parameters in
this assay.

(2) In another dominant lethal study, Wistar rats (14 males/dose) were exposed to 1,3,5-trioxane at concentrations
of 0 or 2.5 mg/L, 5 hours/day, 5 days/week for 12 months. At the end of the dosing period, treated males were
mated with untreated virgin females. Although testicular histopathologic effects were similar in the treated and
control groups, it was not stated whether seminiferous tubule pathology was evaluated. Fertility rate, number of
pregnant females, average litter size and average number of implantations, pre-implantation losses and corpora lutea
were similar between controls and treated groups.

1,3,5-Trioxane did not affect male reproductive organ histology or reproductive performance parameters in
this assay.

(3) In a repeated-dose toxicity test conducted to determine the effect on the estrous cycle, female Wistar rats (10 or
12/group) were orally administered doses of 0, 190, 580 or 1160 mg/kg-bw/day 5 days/week for 7 weeks. A 6-week
post-exposure period was also included. Body weights were measured each week and vaginal smears were taken
three times during the study for the first 14 days of exposure, for 14 days during weeks 6 and 7 and for 14 days
during the post-exposure period (weeks 11 and 12). Reduction in body weight gain was observed at all doses.
Changes in behavior and appearance were seen at the highest dose, including ruffled haircoats, squealing when
handled and nasal discharge. Estrous cycle length was increased at 1160 mg/kg-bw/day. All effects returned to
normal after dosing ceased.

LOAEL = 1160 mg/kg-bw/day (based on estrous cycle effects)

NOAEL = 580 mg/kg-bw/day (based on estrous cycle effects)

Developmental Toxicity

Pregnant Wistar rats (20 - 21/dose) were administered 1,3,5-trioxane via gavage at doses of 0, 100, 315 or 1000
mg/kg-bw/day on days 7 - 20 of gestation. Body weight gain and food consumption were decreased in the high-
dose females from day 10 to study termination (statistically significant); food consumption was slightly reduced at
the intermediate group (also statistically significant). (Statistical significance was determined using several tests
with p levels of 0.05 or 0.01; however, the p-level criterion was not always stated in the results tables.) At all doses,
corrected body weight gain (minus gravid uterus weight at day 21) was significantly lower than controls. Gravid
uterus weights were similar among all groups. The high-dose group had five dead fetuses (one per litter)

(statistically significant) and one mid-dose litter had two dead fetuses. One high-dose dam and one low-dose dam
aborted (showing only implantation sites). Litter size was comparable in all groups. At the highest dose,
statistically significant differences included decreased fetal body weights and crown-rump lengths and increased
placental weights. Pre-implantation loss was similar or slightly lower, although no statistical evaluation was
conducted. Early and late intrauterine deaths as percent of implantations (measures of post-implantation loss) were
statistically higher at the highest dose. The number of fetuses as a percent of implantations was statistically
decreased at the intermediate- and high-doses. At the high dose, statistically significant increased 'retarded' fetuses
(showing slow growth, external/visceral effects) were observed. Two high-dose fetuses had aplasia (absence) of the
tail and vertebrae. A variety of other skeletal defects were seen in the high- and intermediate-dose pups.

Exoccipital bone abnormalities were observed in one low-dose and one high-dose fetus; these effects were not dose-

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dependent and were reported to be within historical controls for this rat strain (laboratory and years not stated).
Additional skeletal retardations (non-ossified or weakly-ossified areas) were seen in all dose groups (p < 0.01 for
some measures), with most effects occurring at the highest dose.

LOAEL (maternal toxicity) = 100 mg/kg-bw/day (based on reduced corrected body weight gain)

NOAEL (maternal toxicity) = Not established

LOAEL (developmental toxicity) = 315 mg/kg-bw/day (based on reduced pup weights and skeletal retardations)
NOAEL (developmental toxicity) = 100 mg/kg-bw/day

Genetic Toxicity - Gene Mutation

In vitro

(1) Salmonella typhimurium strains (TA98, TA100, TA1535 and TA1537) were exposed to 1,3,5-trioxane at
concentrations of 20, 100, 500, 2500 and 5000 |ig/plate with and without metabolic activation. Two trials (one with
preincubation and one without preincubation) were conducted and both positive and negative controls were run.
Positive control responses demonstrated the validity of the test. Cytotoxicity was not observed and no dose-
dependent increases in revertants were seen.

1,3,5-Trioxane was not mutagenic in this assay.

(2) Mouse lymphoma L5178Y TK+/- cells were exposed to 1,3,5-trioxane at 0.313, 2.5, 6.25, 12.5 and 15 mg/mL
with and without metabolic activation in the first trial. Concentrations tested in the second trial using metabolic
activation only were 0, 0.156, 0.625, 2.5, 5.0 and 7.5 mg/mL. Triplicate plates were used for counting. Both
positive and negative controls were run. Positive control responses demonstrated the validity of the test. No
cytotoxicity occurred without activation; with activation, cytotoxicity was dose-dependent and was extensive at the
highest concentrations. No dose-dependent increases in mutant numbers were observed in the absence of metabolic
activation, but dose-dependent increases were observed with metabolic activation.

1,3,5-Trioxane was mutagenic in this assay with metabolic activation.

Genetic Toxicity - Chromosomal Aberrations
In vivo

(1) In a micronucleus assay, BALB/c mice (4 males/dose) were administered 1,3,5-trioxane via intraperitoneal
injection at doses of 0, 2125 and 4250 mg/kg-bw. Mitomycin C was used as a positive control. Animals were
sacrificed 5 hours after the second dose. The number of micronuclei per polychromatic erythrocytes was counted (a
range of 2300 - 8000 cells counted depending on substance and dose). The positive control had more than 2 times
the micronuclei of the negative control. There was no increase in the number of micronuclei at any dose.
1,3,5-Trioxane did not induce chromosomal aberrations in the assay.

Genetic Toxicity - Other
In vivo

(1) In the oral dominant lethal study described previously, 1,3,5-trioxane did not affect number of implants per
female, live fetuses per female or pre -implantation loss per female.

1,3,5-Trioxane did not induce dominant lethal effects in this assay.

(2) In the inhalation dominant lethal inhalation study described previously, 1,3,5-trioxane did not result in
differences in number of pregnant females or females mating, average litter size, average number of implantations,
pre-implantation losses or corpora lutea between controls and the treatment groups.

1,3,5-Trioxane did not induce dominant lethal effects in this assay.

(3) 1,3,5-Trioxane was administered to Wistar rats as single exposures at concentrations of 0, 250, 500, 1000, and
2000 mg/kg-bw via gavage. Hepatocytes were harvested 4 and 18 hours after dosing for assessment of cell viability
and DNA repair activity. There were no treatment-related increases in the number of cells under repair.
1,3,5-Trioxane did not induce DNA repair in this assay.

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Conclusion: The acute oral and inhalation toxicity of 1,3,5-trioxane in rats and acute dermal toxicity in rabbits is
low. Repeated-dose studies showed route-specific toxicity. An oral repeated-dose study in rats showed low toxicity
and an inhalation study in rats showed high toxicity. Two dominant lethal studies (one oral and one inhalation),
showed low reproductive toxicity. A separate oral repeated-dose toxicity study, conducted in female rats to evaluate
estrous cycle, showed low toxicity. An oral prenatal developmental study in rats showed low developmental and
maternal toxicity. 1,3,5-Trioxane did not induce gene mutations in bacteria. However, a dose-dependent increase in
mutations was seen in mammalian cells with metabolic activation, but not in the absence of metabolic activation.
1,3,5-Trioxane did not induce chromosomal aberrations in an/'« vivo assay.

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APPENDIX

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

Endpoints

SPONSORED CHEMICAL
1,3,5-Trioxane
(CAS No. 110-88-3)

Structure

.0.
0^0

Summary of Environmental Effects - Aquatic Toxicity Data

Fish

96-h LC50 (mg/L)

4030

Aquatic Invertebrates
48-h EC50 (mg/L)

> 1000

Aquatic Plants
72-h EC50 (mg/L)

(growth)

> 500

Summarv of Human Health Data

Acute Oral Toxicity
LD50 (mg/kg-bw)

8190

Acute Dermal Toxicity
LD50 (mg/kg-bw)

> 3980

Acute Inhalation Toxicity
LC50 (mg/L)

-39.2

Repeated-Dose Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)

NOAEL = 200 (29-d)
LOAEL = 1000 (12-d)

Repeated-Dose Toxicity
NOAEL/LOAEL
Inhalation (mg/L/6-h/day)

(male)
(female)

NOAEL = Not established
LOAEL = 0.38
NOAEL = 0.38
LOAEL = 3.6

Reproductive Toxicity
NOAEL/LOAEL (mg/kg-bw/day)

No data submitted. No effects on mating, fertility or pre- and
post-implantations in two dominant lethal assays.

Developmental Toxicity
NOAEL/LOAEL (mg/kg-bw/day)

Maternal Toxicity

Developmental Toxicity

NOAEL = Not established
LOAEL = 100
NOAEL = 100
LOAEL = 315

Genetic Toxicity - Gene Mutation
In vitro

Negative

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

Endpoints

SPONSORED CHEMICAL
1,3,5-Trioxane
(CAS No. 110-88-3)

Genetic Toxicity - Chromosomal Aberrations
In vivo

Negative

Genetic Toxicity - Other
In vivo
DNA repair

Negative

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Screening Level Exposure Characterization for HPV Challenge

Chemical

1,3,5-Trioxane

CAS # 110-88-3

September 2008

Prepared by

Exposure Assessment Branch
Chemical Engineering Branch
Economics, Exposure and Technology Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001

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Screening Level Exposure Characterization

1,3,5-Trioxane (CAS# 110-88-3)

Non-CBI Executive Summary

Potential Exposures to the General Population and the Environment: EPA identifies, for
purposes of risk-based prioritization, a medium potential that the general population and the
environment might be exposed to 1,3,5-trioxane. There is potential for environmental releases to
water and/or air during manufacturing, processing, and use. Persistence and bioaccumulation
ratings for this chemical are P3 and Bl. These ratings suggest that this chemical is very
persistent in the environment, and is not bioaccumulative.

Potential Exposures to Workers: Based on the information considered, including the HPV
Revised Test Plan and IUR data (both confidential business information (CBI) and non-CBI),
and the Agency's professional judgment, EPA identifies, for the purposes of risk-based
prioritization, a high relative ranking for potential worker exposure. The high relative ranking is
primarily based on the relatively high vapor pressure, which could result in significant worker
exposure to vapor, as well as potential for inhalation exposure to solid material. This chemical
does not have an OSHA Permissible Exposure Limit (PEL).

This exposure characterization was completed using both public, non-confidential sources, and
one or more IUR submissions that were available as of this writing.

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Volume and Use Information

1,3,5-Trioxane has an aggregated production and/or import volume in the United States of 100
million to 500 million pounds.12 Non-confidential information in the IUR indicates that this
chemical is manufactured and/or imported at the following company and site: Ticona/Bishop,
TX. There may be other companies and sites that are claimed confidential. Persons submitting
IUR information for 2005 asserted that some or all of the information was confidential. Data and
information that are confidential have been excluded from this summary.

According to IUR submissions, there are some industrial processing and uses. Table 1 at the end
of this summary provides additional details. There are no reported commercial/consumer uses.

The HP V submission for this chemical stated that it is used primarily as a monomer for
production of high-molecular weight polyacetals and secondarily as a chemical intermediate.13

The HSDB indicates that 1,3,5-trioxane is used as an intermediate to make organic chemicals.14

Exposures to Workers

Based on the information considered, including the HPV Revised Test Plan and IUR data (both
CBI and non-CBI), and the Agency's professional judgment, EPA identifies, for the purposes of
risk-based prioritization, a high relative ranking for potential worker exposure. The high relative
ranking is primarily based on the relatively high vapor pressure, which could result in significant
worker exposure to vapor, as well as potential for inhalation exposure to solid material. This
chemical does not have an OSHA PEL.15

The following is a summary of relevant information affecting occupational exposure.

Summary of Parameters Affecting Worker Exposure

Parameter

Volume*

100 million - 500 million pounds

Physical Form(s)*

liquid, pellets or large crystals, solid

Vapor Pressure

10 mm Hg

Concentration*

up to 100% by weight

Number of Industrial Workers

<1000 (including manufacturing, processing and use)

Uses*

chemical intermediate, organic synthesis, disinfectant, non-
luminous, odorless fuel

Key MSDS Info

hazardous in case of skin contact (irritant), of eye contact
(irritant), of ingestion, of inhalation (lung irritant)

* Only non-CBI IUR information is included.

12 USEPA, 2006. Partial Updating of TSCA Chemical Inventory.

13 Trioxane Manufacturers Consortium, 2001. Robust Summaries for 1,3,5-Trioxane, CAS Number 110-88-3.
http://www.epa.gov/chemrtk/pubs/summaries/triox/cl2863rt.pdf.

14 HSDB, 2008. Hazardous Substances Data Bank. Accessed, 5/14/08. http://toxnet.nlm.nih. gov.

15 NIOSH, 1988. OSHA PEL Project Documentation. Accessed, 5/14/08.
http://www.cdc. gov/niosh/pel88/npelcas.html.

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Based on IUR data, the maximum total number of workers reasonably likely to be exposed to
this chemical during manufacturing and industrial processing and use may be between 100 and
999. This estimate does not include potentially exposed commercial workers. The National
Occupational Exposure Survey (NOES) has no data for the total number of workers potentially
exposed to this chemical under the CAS number 110-88-3.16

Based on IUR data, the chemical is manufactured in liquid form and worker exposure is possible
for this chemical in this form. IUR reporting indicates the chemical is also manufactured as
pellets, large crystals and solids. There may be other physical forms that are claimed
confidential. Also, the non-confidential maximum concentration is up to 100% by weight.

There may be other concentrations that are claimed confidential. This chemical has a vapor
pressure of 10 mm Hg.17 This chemical's vapor pressure could result in worker exposures to
vapors if workers are proximal to the liquid.

This chemical does not have an OSHA PEL.18

Environmental Releases

Environmental releases may impact general population and environmental exposures. Factors
affecting releases include volumes produced, processed and used; numbers of sites; and,
processes of manufacture, processing, and use.

Based on IUR data, the maximum number of sites for manufacturing, processing, or using this
chemical is confidential.

The following release statements are made based on inferences regarding the non-confidential
use information reported in the IUR submissions.

Many chemicals processed as reactants have industrial releases that are a relatively low
percentage of the volume. Lower percentage releases occur when a high percentage of the
chemical reacts without excess loss during its use as an intermediate. The actual percentage and
quantity of release of the reported chemical associated with this processing or use are not known.

Chemicals having industrial uses as "adhesives and binding agents" or "other" can have variable
release percentages during industrial processing and use. The actual percentage and quantity of
release of the reported chemical associated with these uses are not known.

The chemical is not on the Toxics Release Inventory.19 No additional data on releases were
found from other sources.

16 NIOSH, 1983. National Occupational Exposure Survey (NOES, 1981-1983). Accessed, 5/14/08.
http://www.cdc. go v/noes/srch-noes.html.

17 USEPA, 2008. Screening Level Hazard Characterization for 1,3,5-Trioxane (CAS #110-88-3).

18 NIOSH, 1988. OSHA PEL Project Documentation. Accessed, 5/14/08.
http://www.cdc. gov/niosh/pel88/npelcas.html.

19 USEPA, 2006. Toxics Release Inventory. Accessed, 5/14/08. http://www.epa.gov/tri/.

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This chemical's vapor pressure could result in significant air releases. Experience has shown
that air releases due to volatilization may be significant for chemicals with vapor pressures above
0.01 mm Hg.

Exposures to the General Population and the Environment

Based on information indicating the potential for releases, it is likely that there would be some
releases to water and/or air during manufacturing, processing, and use (reactants, chemical
intermediates, "not readily obtainable," adhesives and binding agents, and "other"). A search of
additional relevant databases did not provide any further information on releases of this
chemical. EPA assumes, for the purposes of risk-based prioritization, that environmental release
and subsequent exposure to the general population and the environment are likely. The IUR
ranking for general population and the environment is medium, based on uncertainty that there
will be exposure to this chemical based on the IUR data (reactants, chemical intermediates, "not
readily obtainable," adhesives and binding agents, and "other").

Persistence and bioaccumulation ratings for this chemical are P3 and Bl. These ratings suggest
that this chemical is very persistent in the environment, and is not bioaccumulative. 1,3,5-
Trioxane is expected to partition primarily to soil and water. It is highly mobile in soil and
moderately volatile from water and moist soil surfaces.

Based on the information considered, including environmental fate, known uses, and the
Agency's expert judgment, EPA identifies, for purposes of risk-based prioritization, a medium
potential that the general population and the environment might be exposed to 1,3,5-trioxane.

Exposures to Consumers

There are no consumer uses reported in the IUR data, nor were any found in other data sources.

EPA identifies, for the purposes of risk-based prioritization, a low potential that consumers
might be exposed to 1,3,5-trioxane from products containing this chemical, based on the IUR
data.

Exposures to Children

There are no consumer uses reported in the IUR data, nor were any found in other data sources.

No uses in products specifically intended to be used by children were reported in the IUR, nor
were any found in other data sources. Therefore, EPA identifies a low potential that children
might be exposed to 1,3,5-trioxane.

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Non Confidential IUR Data Summary: 1,3,5-Trioxane (CAS # 110-88-3)

Manufacturing/ Import Information

Production (including import volume):

List of non-CBI companies/sites:*
Maximum number of exposed workers:**

Highest non-CBI maximum concentration:*
Non-CBI physical forms :*

100 million to 500 million pounds

Ticona / Bishop, TX

between 100 and 999 (including those of

manufacturing, industrial processing and use)

up to 100% by weight

pellets or large crystals, solid*** and liquid

* There may be other companies/ sites, concentrations and physical forms that are claimed
confidential.

** There may be additional potentially exposed industrial workers that are not included in this
estimate since not all submitters were required to report on industrial processing and use and/or
there may be at least one use that contains a "Not Readily Obtainable" (NRO) response among
the submissions.

*** It is not certain that it will be supplied in solid form.

1 a hie 1

Industrial Processing and I se Information
Reported in 2006 Il k

Processing Activity ****

Industrial Sector

Function in Industrial Sector

Processing as a reactant

Resin and Synthetic
Rubber Manufacturing

Intermediates

Not Readily Obtainable

Electric Lamp Bulb and Part
Manufacturing

Adhesives and binding agents

Not Readily Obtainable

All Other Chemical Product and
Preparation Manufacturing

Other

Additional line item(s) may be claimed as CBI

**** It is not certain that other uses beyond chemical intermediate will occur.
There are no reported commercial/consumer uses.

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