SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS

SPONSORED CHEMICAL

1,3-Dioxolane (CAS No. 646-06-0)
[9th CI Name: 1,3-Dioxolane]

August 2007

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
1,3-Dioxolane (CAS No. 646-06-0)

Introduction

The sponsor, The Dioxolane Manufacturers Consortium, submitted a Test Plan and Robust Summaries to EPA for
1,3-dioxolane (CAS No. 646-06-0; 9th CI name: 1,3-dioxolane) on November 20, 2000. EPA posted the submission
on the ChemRTK HPV Challenge Website on December 19, 2000

(http://www.epa.gov/chemrtk/pubs/summaries/dioxlne/dioxtc.htm'). EPA comments on the original submission
were posted on April 18, 2001. Public comments were also received and posted to the website. The sponsor
submitted updated/revised documents on June 12, 2001, which were posted to the ChemRTK HPV Challenge
website on April 3, 2002.

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 toxicity is based largely on SIDS endpoints and is described according to
established EPA or OECD effect level definitions and hazard assessment practices.

Sum m an-Conclusion

The lou k indicates that i lie potential of I. ^-dio\olaiie lo hioacciiniiilale is c\pecled lo he low. I. ^-l)io\olaiie is
noi readiK biodegradable, indicating llial il lias ilie potential in persist mi ilie en\ iroiinieiii

The e\ahialioii of a\ailahle aquatic to\icit> dala lor fish. aquatic iii\ eilehiales and aquatic plains indicates llial I lie
poieniial aenie lia/ard of I. ^-dio\olaiie lo aquatic organisms are low

I lie aenie to\icil> lo I. ^-dio\olane lo rals \ ia oral and inhalation ronies is low Repealed e\posiire lo I. ^-dio\olane
\ ia inhalation affeeled w line hlood cells (significant decrease in iinnihen. and spleen and h\ er (decreased weighisi
in rals In male rals e\posed al high eoiieeiiiralioiis. microscopic eviniiiiatioii showed sigmlicaiiik larger
hepaloes les in eeiiinlohiilar regions and more c\ loplasinie eosiiioplnlia ilian controls \i ihe high dose le\ els. I. i-
dio\olaiie affeeled nialing perl on nance of male rals. siiia i\ al of pnps i rediielion in pnps deh\ ered. increase in i he
iiiiniher of siillhorn pnps> and decreased hods weiglii of pnps and dams In ihe I" I h liller. effects seen in hoili
li'cninieiii groups included decreased feeimdils indev decreased parturition indev and lower female lertihtv
l)e\elopnienial effects ineliided eMeriial malformations. septal defects in the heart, and reduced ossification of
\ertchrac I lie weighi-of-e\ idenee. hased on submitted test data, indicates that I. ^-dio\olane does not induce gene
imitation and chromosomal aberrations

I lie potential health lia/ard of I. ^-dio\olane is high hased on repeated-dose. reprodiicli\ e and de\ elopniental

tOMCItS

\o dala gaps were identified under ihe I ll'V Challenge I'rograni

1. Physical-Chemical Properties and Environmental Fate

A summary of physical-chemical properties 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 indictors of bioaccumulation and persistence,
respectively.

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Octanol-Water Partition Coefficient
LogKow: -0.37 (measured)

Biodegradation

In a Closed-Bottle Test using municipal secondary sludge as inoculum, only 3.7% 1,3-dioxolane degraded after 35
days. In another screening level BOD (biological oxygen demand) study using municipal secondary sludge, 12%
degradation was seen in 15 days.

1,3-dioxalane is not readily biodegradable.

Conclusion: The log Kow indicates that the potential for 1,3-dioxolane to bioaccumulate is expected to be low.
1,3-Dioxolane is not readily biodegradable, indicating that it has the potential to persist in the environment.

2. Environmental Effects - Aquatic Toxicity
Acute Toxicity to Fish

Bluegill sunfish (Lepomis macrochirus) were exposed to 1,3-dioxolane at nominal concentration of 100 mg/L under
static conditions for 96 hours with renewal every 24 hours. The mean of the concentration measured at 24, 48, 72
and 96 hours was 95.4 mg/L. No mortality was observed at any concentration.

96-h LCS0 > 95.4 mg/L

Acute Toxicity to Aquatic Invertebrates

Daphnia magna were exposed to 1,3-dioxolane at nominal concentrations of 0, 250, 500 and 1000 mg/L under static
conditions for 48 hours. Measured concentrations were 213, 411, and 772 mg/L.

24-h ECS0 > 764 mg/L
48-h ECS0 > 772 mg/L

Toxicity to Aquatic Plants

Green algae (Pseudokirchneriella subcapitata) were exposed to 1,3-dioxolane at nominal concentrations of 62.5,
125, 250, 500 and 1000 mg/L for 72 hours. Measured concentrations were 37, 81, 163, 280 and 877 mg/L.
72-h EC50 (biomass) > 877 mg/L
72-h EC50 (growth) > 877 mg/L

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

3. Human Health Effects
Acute Oral Toxicity

Male and female rats were administered single doses of 1,3-Dioxolane via gavage at 2500, 3500, 5000, 7100 or
10000 mg/kg-bw and were observed for 14 days. Clinical signs observed include ataxia, decreased respiratory rate,
decreased motor activity, piloerection and hypothermia.

LDS0 = 5200 mg/kg-bw

Acute Inhalation Toxicity

Male and female rats were exposed (whole-body) to 1,3-dioxolane vapors for 4-hours at 0, 37.9,60.6,67.9, 88.4 and
201.9 mg/L (nominal concentrations) and were observed for 14 days. Lacrimation, labored breathing, prostrate, loss of
muscle tone, no response to auditory stimuli and reduced activity were clinical signs of toxicity observed. Lungs

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and liver were the target organs. Deaths were caused by solvent induced narcosis. Surviving animals were normal
by day 14 of the observation period.

4-h LC50 = 68.4 mg/L

Repeated-Dose Toxicity

Male and female rats were exposed (whole body) to 1,3-dioxolane vapor at 0, 298, 1000 or 3010 ppm
(approximately 0.903, 3.030 or 9.121 mg/L/day), 6 hours/day, 5 days/week for 13 weeks. There was a reduction in
white blood cell counts at all concentrations. Although this effect was statistically significant at the medium and
high concentrations, there was a trend showing biological significance at the low concentration. In addition, there
was a decrease in spleen (absolute) and liver (absolute and relative) weights for females at 1000 and 3010 ppm and
males at 3010 ppm; decreased alertness at the end of each exposure duration. Decreased urine specific gravity in
males exposed to highest concentration of 1,3-dioxolane was also observed. Microscopically, in male rats exposed
to 3010 ppm 1,3-dioxolane, slightly larger hepatocytes in centrilobular regions and more cytoplasmic eosinophilia
was seen than controls.

LOAEL = 298 ppm (approximately 0.903 mg/L; based on decrease in WBC count in male rats)

NOAEL = Not established

Reproductive Toxicity

(1)	Male rats were administered 1,3-dioxolane in drinking water at doses of 0.5 or 1.0% (approximately 500 mg/kg-
bw/day), 90 days prior to mating with previously untreated females. Dosing continued for males and females
throughout the mating period and then continued for females throughout gestation, lactation and weaning. Mating
with males pretreated for 90 days with 1,3-dioxolane to produce the Fla litter resulted in treated groups copulating
less frequently, fewer pregnant treated animals delivering litters than controls, a decrease in the number of pups
delivered by the high dose group, an increase in the number of stillborn pups in both groups, reduced survival of
progeny in the high dose group and a decrease in body weight of dams in both dose groups. Mating with proven
breeders to produce the Fib litter showed the following effects in both dose groups: a decrease in the fecundity
index and in the parturition index and a lower female fertility index for the exposed groups.

LOAEL (parental and offspring toxicity) = 0.5% (approximately 500 mg/kg-bw/day)

NOAEL = Not established

(2)	Male rats were exposed to 1,3-dioxolane in drinking water at concentrations of 0.01, 0.03 or 0.1%
(approximately 10, 30 and 100 mg/kg-bw/day, respectively) for 90 days prior to mating with previously untreated
females. Animals were treated during mating and for females, the treatment continued through gestation and
lactation. No treatment-related effects were seen in this study.

LOAEL > 0.1% (approximately 100 mg/kg-bw/day)

NOAEL = 0.1%

Developmental Toxicity

Pregnant female rats were orally dosed at 0, 125, 250, 500 or 1000 mg 1,3-dioxolane/kg-bw/day in corn oil.
Maternal toxicity was evident from statistically significant decreased body weight and food consumption at 500 and
1000 mg/kg/day. Developmental toxicity was evident at the highest dose of 1000 mg/kg-bw/day and was
characterized by significant increases in litter and fetal incidences of externally evident vertebral malformations
associated with tail malformations and septal defects in the heart. One high dose fetus had a cleft palate. Other
adverse effects included reduced ossification of centra in the thoracic vertebrae, the lumbar vertebrae, absent sacral
and caudal vertebrae and rib-vertebral malformations at this dose level.

LOAEL (maternal toxicity) = 500 mg/kg-bw/day (based on decrease in body weight gain)

NOAEL (maternal toxicity) = 250 mg/kg-bw/day

LOAEL (developmental toxicity) = 1000 mg/kg-bw/day (based on reduced fetal body weights and gross external,
soft tissue and skeletal malformations or variations)

NOAEL (developmental toxicity) = 500 mg/kg-bw/day

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Genetic Toxicity - Gene Mutation
In vitro

(1)	An Ames assay was performed using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and
TA1538, with and without metabolic activation, and 1,3-dioxolane concentrations of 0.005-50 |.iL/platc. The test
material did not induce an increase in mutant frequency in tester strains TA98, TA100, TA1537 or TA1538, in the
presence or in the absence of metabolic activation. Appropriate positive and negative controls responses were
observed in the study.

Dioxolane was not mutagenic in this assay.

(2)	In an Ames assay, S. typhimurium TA1535, TA 1537, TA1538 and Saccharomyces cerevisiae strain D4 were
exposed to 1,3-dioxolane, with and without metabolic activation, at concentrations of 0.75 and 1.50% suspension for
S. typhimurium and 2.0 and 5.0% suspension for S. cerevisiae. The test material did not induce an increase in
mutant frequency in tester strains TA 1535, TA1537 or TA1538 or in S. cerevisiae in the presence or in the absence
of metabolic activation. Appropriate positive and negative controls responses were observed in the study.

Dioxolane was not mutagenic in this assay.

(3)	In a forward mutation assay, mouse lymphoma cells (L5 178Y TK+/-) were exposed to 1,3-dioxolane at 0, 750
to 5000 nL/mL with and without metabolic activation. Low dose-dependent cytotoxicty was seen. The results
indicated no dose-dependent increase in the number of mutants in the presence or absence of metabolic activation.
Positive and negative controls responded appropriately.

Dioxolane was not mutagenic in this assay.

Genetic Toxicity - Chromosomal Aberrations
In vitro

Duplicate cultures of Chinese hamster ovary cells were exposed, in vitro, to 1,3-dioxolane at 0, 2.0, 3.0, 4.0, and 5
mg/mL with and without metabolic activation system. A total of 200 metaphases were scored for aberrations.
Cytotoxicity was not observed at any concentration. No increase in the number of aberrations was seen at any
concentration of dioxolane. The positive and negative controls responded appropriately.

Dioxolane did not induce chromosomal aberrations in this assay.

In vivo

(1)	In a micronucleus assay, ICR mice (5/sex/dose) were administered single doses of 1,3-dioxolane via
intraperitoneal injection at 0, 525, 1050 or 2100 mg/kg-bw and were euthanized 72 hours later.

Triethylenemelamine (0.25 mg/kg-bw) was used as a positive control. The number of micronuclei/1000
polychromatic erythrocytes was counted for each animal. The positive control produced a statistically significant
increase in micronuclei, but there was no significant increase in micronuclei for in any of the 1,3-dioxolane treated
groups.

1,3-Dioxolane did not induce chromosomal aberrations or micronuclei in this assay.

(2)	In a dominant lethal assay, male rats were administered 1,3-dioxolane at 0, 580, or 1160 mg/kg-bw 5day/week
for eight weeks and were mated with virgin females. Pregnant females were euthanized and uterine contents were
examined to determine number of implants and live and dead embryos. No evidence of dominant lethal was seen.
1,3-Dioxolane did not induce dominant lethal in the assay.

A test for induction of single strand breaks of DNA in rat hepatocytes showed that 1,3-dioxolane induces single
strand breaks in DNA as evident from significantly higher rates for alkaline elution. The description of this test is in
the test plan only (no robust summary provided) and the sponsor claimed that the results are spurious and may have
been caused by an impurity in the test substance. EPA could not evaluate the adequacy of the data or conclusions
with the information provided.

Conclusion: The acute toxicity to 1,3-dioxolane to rats via oral and inhalation routes is low. Repeated exposure to
1,3-dioxolane via inhalation affected white blood cells (significant decrease in number), and spleen and liver
(decreased weights) in rats. In male rats exposed at high concentrations, microscopic examination showed
significantly larger hepatocytes in centrilobular regions and more cytoplasmic eosinophilia than controls. At the

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high dose levels, 1,3-dioxolane affected mating performance of male rats, survival of pups (reduction in pups
delivered, increase in the number of stillborn pups) and decreased body weight of pups and dams. In the Fib litter,
effects seen in both treatment groups included decreased fecundity index, decreased parturition index, and lower
female fertility. Developmental effects included external malformations, septal defects in the heart, and reduced
ossification of vertebrae. The weight-of-evidence, based on submitted test data, indicates that 1,3-dioxolane does
not induce gene mutation and chromosomal aberrations.

The potential health hazard of 1,3-dioxolane is high based on repeated-dose, reproductive and developmental
toxicity.

4.	Hazard Characterization

The log Kow indicates that the potential of 1,3-dioxolane to bioaccumulate is expected to be low. 1,3-Dioxolane is
not readily biodegradable, indicating that it has the potential to persist in the environment.

The evaluation of available aquatic toxicity data for fish, aquatic invertebrates and aquatic plants indicates that the
potential acute hazard of 1,3-dioxolane to aquatic organisms are low.

The acute toxicity to 1,3-dioxolane to rats via oral and inhalation routes is low. Repeated exposure to 1,3-dioxolane
via inhalation affected white blood cells (significant decrease in number), and spleen and liver (decreased weights)
in rats. In male rats exposed at high concentrations, microscopic examination showed significantly larger
hepatocytes in centrilobular regions and more cytoplasmic eosinophilia than controls. At the high dose levels, 1,3-
dioxolane affected mating performance of male rats, survival of pups (reduction in pups delivered, increase in the
number of stillborn pups) and decreased body weight of pups and dams. In the Fib litter, effects seen in both
treatment groups included decreased fecundity index, decreased parturition index, and lower female fertility.
Developmental effects included external malformations, septal defects in the heart, and reduced ossification of
vertebrae. The weight-of-evidence, based on submitted test data, indicates that 1,3-dioxolane does not induce gene
mutation and chromosomal aberrations.

The potential health hazard of 1,3-dioxolane is high based on repeated-dose, reproductive and developmental
toxicity.

5.	Data Gaps

No data gaps were identified under the HPV Challenge Program.

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Summary Tabic of the Screening Information Data Set
as submitted under the U.S. HPV Challenge Program

Endpoints

SPONSORED CHEMICAL
1,3-Dioxolanc
(646-06-0)

Structure

o

0

Summary of Physical-Chemical Properties and Environmental Fate Data

Melting Point (C)

-95

Boiling Point (C)

78

Vapor Pressure
(hPa at 25C)

93.24 @ 20C

Log Kw

-0.37

Water Solubility
(mg/L at 25C)

Soluble in all proportions

Direct Photodegradation

-

Indirect (OH) Photodegradation
Half-life (t1/2)

11.5 hours (estimated)

Stability in Water (Hydrolysis) (ti/2)

> 1 year @ 25C, pH 4, 7 and 9

Fugacity
(Level III Model)

Water (%)
Sediment (%)
Soil (%)
Air (%)

54
0.1
42
4.1

Biodegradation at 28 days (%)

3.7 (35-days)
12 (15-days)
Not Readily Biodegradable

Summary of Environmental Effects - Aquatic Toxicity Data

Fish

96-h LCS0 (mg/L)

>95.4

Aquatic Invertebrates
48-h ECS0 (mg/L)

>772

Aquatic Plants
72-h ECS0 (mg/L)

(growth)
(biomass)

>877
>877

Summary of Human Health Data

Acute Oral Toxicity
LDS0 (mg/kg-bw)

5200

Acute Inhalation Toxicity

LCS0 (mg/L)

68.4

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Summary Tabic of the Screening Information Data Set
as submitted under the U.S. HPV Challenge Program

Endpoints

SPONSORED CHEMICAL
1,3-Dioxolane
(646-06-0)

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

I.OAF.I. (male) = 0.9
LOAEL (inhalation; female) = 3.03

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

LOAEL ~ 500 (0.5%)
NOAEL = Not established

LOAEL >-100(0.1%)
NOAEL ~ 100 (0.1%)

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

(maternal toxicity)
(developmental toxicity)

LOAEL = 500
NOAEL = 250

LOAEL = 1000
NOAEL = 500

Genetic Toxicity - Gene Mutation
In vitro

Negative

Genetic Toxicity - Gene Mutation
In vitro



Genetic Toxicity - Chromosomal Aberrations
In vitro

Negative

Genetic Toxicity - Chromosomal Aberrations
In vivo

Negative

- indicates endpoint was not addressed for this chemical

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