U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2014
SCREENING-LEVEL HAZARD CHARACTERIZATION
2,5-Dihydrothiophene 1,1-Dioxide
(CASRN 77-79-2)
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 Setl'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.), Science Direct and ECHA4. 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
presented in an international forum that involves review and endorsement by governmental
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.
4	European Chemicals Agency, http://echa.europa.eu.

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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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Chemical Abstract
Service Registry Number	77-79-2
(CASRN)
Chemical Abstract Index
Name	Thiophene, 2,5-dihydro-, 1,1-dioxide
Structural Formula
o
SMILES: 0=S(=0)(CC=C1)C1
Summary
2,5-Dihydrothiophene 1,1-dioxide is a clear, odorous solid possessing high water solubility
and moderate vapor pressure. It is expected to have high mobility in soil. It was not readily
biodegradable using two standard OECD testing methods, but a structural analog was shown
to eventually degrade under typical environmental conditions. Volatilization is expected to be
low. The rate of hydrolysis is considered negligible. The rate of atmospheric photooxidation
is rapid. 2,5-Dihydrothiophene 1,1-dioxide is not readily biodegradable. 2,5-
Dihydrothiophene 1,1-dioxide is expected to have moderate persistence (P2) and low (Bl)
bioaccumulation potential.
The acute oral toxicity of 2,5-Dihydrothiophene 1,1-dioxide is low in rats. The acute
inhalation toxicity of 2,5-Dihydrothiophene 1,1-dioxide in rats was not determined because the
concentration of saturation was not reported; however, no mortalities occurred at the saturated
concentration. In an oral gavage combined repeated-dose/reproductive/developmental
screening test in rats, 2,5-dihydrothiophene 1,1-dioxide showed an increase in male
neuropathy at 150 mg/kg-day; the NOAEL for systemic toxicity is 75 mg/kg-day. No
treatment-related effects were observed in the functional observational battery (FOB);
however, significant increases were noted in total and ambulatory activity in males at 150
mg/kg-day. No treatment-related effects were observed on reproductive parameters; the
NOAEL for reproductive toxicity is 150 mg/kg-day; highest dose tested. In the same study, a
decrease in mean body weight in dams and mean pup weight was observed at 75 mg/kg-day;
the NOAEL for maternal and developmental toxicity is 25 mg/kg-day. 2,5-Dihydrothiophene
1,1-dioxide was not mutagenic in bacteria or mammalian cells in vitro. 2,5-Dihydrothiophene
1,1-dioxide did not induce chromosomal aberrations or sister chromatid exchange in vitro.
2,5-Dihydrothiophene 1,1-dioxide is irritating to the rabbit eye but not rabbit skin. 2,5-
Dihydrothiophene 1,1-dioxide did not increase the incidence of tumors in rats and mice.
For 2,5-Dihydrothiophene 1,1-dioxide, the 96-h LCso for fish is 940 mg/L, the 48-h ECso for
aquatic invertebrates is 800 mg/L and the 96-h ECso aquatic plant growth rate is > 1000 mg/L.
No data gaps were identified under the HPV Challenge Program.	
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The sponsor, Chevron Phillips Chemical Company, LP, submitted a Test Plan and Robust
Summaries to EPA for 2,5-dihydrothiophene 1,1-dioxide (CASRN 77-79-2; CA Index name:
thiophene, 2,5-dihydro-,l,l-dioxide) on April 6, 2004. EPA posted the Submission on the
ChemRTK HPV Challenge website on April 19, 2004
(http://www.epa.gov/oppt/chemrtk/pubs/summaries/25disulf/cl5167tc.htm). EPA comments on
the original submission were posted to the website on July, 20, 2005. Public comments were
also received and posted to the website. The sponsor submitted updated/revised documents on
November 14, 2006, which were posted to the ChemRTK website on January 10, 2007.
1. Chemical Identity
1.1	Identification and Purity
The robust summary states a purity of 92-99% for particular studies in this hazard
characterization, where indicated. The sponsor states in its 2006 Test Plan that 2,5-
dihydrothiophene 1,1-dioxide is a clear, solid, odorous organosulfur compound (C4H602S)
used as a specialty solvent in petroleum refining and as a chemical intermediate in the
production of tetrahydrothiophene 1,1-dioxide (Sulfolane). The National Toxicology Program
(NTP) states that Sulfolene is an intermediate in the production of sulfolane, which is used in the
petroleum, plastics, and textile industries, and in the synthesis of one or more fungicides or
additional chemicals. The substance can also be used as a catalyst. The purity of this substance
in the conducting of NTP studies was not specified.
1.2	Physical-Chemical Properties
The physical-chemical properties of 2,5-dihydrothiophene 1,1-dioxide are summarized in Table
1.
2,5-Dihydrothiophene 1,1-dioxide is a clear, odorous solid at room temperature. It has high
water solubility and moderate vapor pressure. It is used as an industrial solvent and isolated
intermediate for the production of 2,5-dihydrothiophene 1,1-dioxide (sulfolane, CASRN 126-33-
0). It is also used as a chemical intermediate in the production of transmission fluids.
Table 1. Physical-Chemical Properties of 2,5-Dihydrothiophene 1,1-Dioxide1
Property
Value
CASRN
77-79-2
Molecular Weight
118.15
Physical State
Solid at room temperature
Melting Point
63-65.5°C (measured)
Boiling Point
Decomposes before boiling
Vapor Pressure
9.75><10"3 mm Hg at 25°C (measured)
Dissociation Constant
(pK)
Not applicable
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Table 1. Physical-Chemical Properties of 2,5-Dihydrothiophene 1,1-Dioxide1
Property
Value
Henry's Law Constant
2.6x 10"8 atm-m3/mole (estimated)2
Water Solubility
-59,000 mg/L at 25°C (measured)
Log Kow
<1 (measured);
-0.45 (estimated)
'Chevron Phillips. 2006. Revised Robust Summary and Test Plan for 2,5-dihydrothiophene 1,1-dioxide (Sulfolene). U.S. High
Production Volume (HPV) Chemical Challenge Program. Available online at
http://www.epa.gov/chemrtk/pubs/summaries/25disulf/cl5167tc.htm as of July 23,2012.
2U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental Protection
Agency, Washington, DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of July 26,
2012.
2. General Information on Exposure
2.1	Production Volume and Use Pattern
2,5-Dihydrothiophene 1,1-dioxide had an aggregated production and/or import volume in the
United States between 1 to 10 million pounds during calendar year 2005.
Industrial processing and uses for the chemical were claimed confidential. No commercial and
consumer uses were reported for the chemical.
2.2	Environmental Exposure and Fate
The environmental fate properties are provided in Table 2.
2,5-Dihydrothiophene 1,1-dioxide is expected to have high mobility in soil. 2,5-
Dihydrothiophene 1,1-dioxide achieved 0% of its theoretical biochemical oxygen demand
(BOD) after 28 days using an activated sludge inoculum and the closed bottle (OECD 301D)
test. It was degraded 2% as measured by CO2 evolution after 28 days using the modified Sturm
(OECD 301B) test. A structural analog, thiophene, tetrahydro-, 1,1-dioxide, was also not readily
biodegradable using the MITI (OECD 301C) test; however, it did biodegrade under aerobic
conditions within a few days using aquifer slurries obtained from ground water and sediment
from a sour gas plant following a 10-day acclimation period. Data from other microcosm and
field studies indicate that, under typical groundwater conditions (aerobic or anaerobic but very
low in nutrients, particularly phosphate), 2,5-dihydrothiophene 1,1-dioxide degradation may be
very slow or nonexistent. However, under conditions typical of surface water (aerobic, sufficient
nutrients), it has been shown that 2,5-dihydrothiophene 1,1-dioxide degradation can be relatively
rapid. This suggests that 2,5-dihydrothiophene 1,1-dioxide will have similar biodegradation
rates under similar environmental conditions. The rate of volatilization for 2,5-dihydrothiophene
1,1-dioxide is considered low based on the Henry's Law constant for this substance. The rate of
hydrolysis is considered negligible. The rate of atmospheric photooxidation is rapid. 2,5-
Dihydrothiophene 1,1-dioxide is expected to have moderate persistence (P2) and low (Bl)
bioaccumulation potential.
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Table 2. Environmental Fate Properties of 2,5-Dihydrothiophene 1,1-dioxide1
Property
Value
CASRN
77-79-2
Photodegradation Half-life
1.4-1.9 hours (estimated)2
Hydrolysis Half-life
Stable
Biodegradation
2% at 28 days (not readily biodegradable, OECD 301B);
0% at 28 days (not readily biodegradable, OECD 301D)
Bioaccumulation Factor
BAF = 0.91 (estimated)2
Log Koc
0.9 (estimated)2
Fugacity
(Level III Model)2
Air (%)
0.1
Water (%)
38.4
Soil (%)
61.5
Sediment (%)
<0.1
Persistence3
P2 (moderate)
Bi oaccumul ati on3
Bl (low)
'Chevron Phillips. 2006. Revised Robust Summary and Test Plan for 2,5-dihydrothiophene 1,1-dioxide (Sulfolene). U.S. High
Production Volume (HPV) Chemical Challenge Program. Available online at
http://www.epa.gov/chemrtk/pubs/summaries/25disulf/cl5167tc.htm as of July 23,2012.
2U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental Protection
Agency, Washington, DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of July 26,
2012.
3Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64,
Number 213 (November 4, 1999) pp. 60194-60204.
Conclusions: 2,5-Dihydrothiophene 1,1-dioxide is a clear, odorous solid possessing high water
solubility and moderate vapor pressure. It is expected to have high mobility in soil. It was not
readily biodegradable using two standard OECD testing methods, but a structural analog was
shown to eventually degrade under typical environmental conditions. Volatilization is expected
to be low. The rate of hydrolysis is considered negligible. The rate of atmospheric
photooxidation is rapid. 2,5-Dihydrothiophene 1,1-dioxide is expected to have moderate
persistence (P2) and low (Bl) bioaccumulation potential.
3. Human Health Hazard
A summary of the human health toxicity data submitted for SIDS endpoint is provided in
Table 3.
Acute Oral Toxicity
Sprague-Dawley rats (five/sex/dose) were administered 2,5-dihydrothiophene 1,1-dioxide (purity
not specified) via gavage at 1000, 2000, 2500 (females only), 3000, 4000 or 5000 mg/kg and
observed for up to 14 days following dosing. Mortality was observed at > 2500 mg/kg in
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females and at > 3000 mg/kg in males. Specific mortalities were identified at 2500 (3F), 3000
(2M, 5F), 4000 (5M, 4F) and 5000 (all animals died for both sexes).
LDso = 2876 mg/kg (combined)
Acute Inhalation Toxicity
Wistar rats (10/sex/control, 5/sex/treatment) were administered a saturated concentration of 2,5-
dihydrothiophene 1,1 -dioxide 99% pure mixed with isopropyl alcohol via vapor inhalation for 4
hours and observed for 14 days. The saturation concentration was not quantified. No mortalities
occurred during the study. Additional information was included from OTS0533768.
LD50 > Saturated concentration of 2,5-dihydrothiophene 1,1-dioxide in air at 25°C
Repeated-Dose Toxicity
In a modified combined repeated-dose/reproductive/developmental toxicity screening test,
CrL:CD(SD) rats (12/sex/dose, 18/sex in the control and high-dose groups) were administered
2,5-dihydrothiophene 1,1-dioxide (98.9% pure) via gavage in corn oil at 10, 25 or 75 mg/kg-day
for females and 25, 75 or 150 mg/kg-day for males. Control animals received corn oil only.
Males were dosed for 28 days (premating through 1 day prior to scheduled sacrifice) and females
were dosed for 40 to 44 days (14 days premating through lactation day 3). Females with no
evidence of mating were dosed through the day prior to sacrifice for a total of 52 doses. At the
end of the study, 6/sex in the control and high-dose groups remained on study for 14 days of
recovery. Mortality was observed in 1/12 dams at 75 mg/kg-day during lactation day 4. Mid-
and high-dose males and high-dose females exhibited statistically significant (p < 0.01)
decreased mean body-weight gains and decreased food consumption during study days 0 - 7. A
statistically significantly (p < 0.01) decrease in mean body weight gains and food consumption
was observed in high-dose males during the remainder of the premating and treatment periods
and in high-dose females during the entire pre-mating period. No treatment-related effects were
observed on functional observational battery (FOB); however, total and ambulatory activity was
statistically significant (p=0.007) in males at 150 mg/kg-day. Increases in motor activity were
noted in females at 75 mg/kg-day. Treatment-related effects were observed in the hematology
and urinalysis endpoints, but were considered not toxicologically significant because these
values either had slight difference in or were within normal control values. The total volumes of
urine for recovery phase males in the high-dose group were increased by more than 2-fold
compared to the control group, but the increase was not statistically significant. Statistically
significant (p < 0.01) increases in relative liver and kidney weights were observed in high-dose
males. Histopathology revealed increased incidences of centrilobular hepatocellular hypertrophy
and eosinophilic kidney tubules in high-dose males and increased incidences of hyaline droplets
in kidney proximal tubular epithelial cells of mid- and high-dose males. Brain and heart weights
were statistically significantly (p < 0.05) increased among certain test groups, but these
differences were considered to be a result of the 2,5-dihydrothiophene 1,1-dioxide-related effects
on final body weight. No consistent treatment-related effects were found for the functional
observational battery (FOB), locomotor activity patterns, hematology, serum chemistry or
findings at necropsy. No additional treatment-related effects were found on organ weights
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(adrenal glands, brain, epididymides, heart, ovaries and oviducts, spleen, testes, thymus gland
and thyroids with parathyroid) or histology (comprehensive set of tissues evaluated for the
reproduction phase in the control, high-dose males and females and from females that died or
failed to deliver and liver and kidneys from low-dose, mid-dose and recovery-phase males).
LOAEL (systemic toxicity) = 150 mg/kg-day (based on male nephropathy)5
NOAEL (systemic toxicity) = 75 mg/kg-day
Reproductive Toxicity
In a combined repeated-dose/reproductive/developmental toxicity screening test in CrL:CD(SD)
rats previously mentioned, no treatment-related effects were evident for reproductive
performance, gestation and lactation, food consumption, pup sex ratios, pup survival, pup
external examinations, gestation length or litter size to postnatal day (PND) 4. No treatment-
related effects on mating or fertility were observed in males or females at any dosage level.
Mating indices were 100.0%, 100.0%, 100.0%) and 91.7% each in the control, 25, 75 and 150
mg/kg-day groups (males) and control, 10, 25 and 75 mg/kg-day groups (females), respectively.
Fertility indices were 91.7%, 100.0%), 100.0%) and 91.7%, and male copulation and female
copulation indices were 91.7%, 100.0%), 100.0%) and 100.0%) in the same respective groups. The
mean numbers of days between pairing and coitus in the test article-treated groups were similar
to the control group value. None of these differences were statistically significant and none were
attributed to the test article.
LOAEL (maternal toxicity) = 75 mg/kg-day (based on decreased mean body weight in dams
on lactation days 1 and 4)
NOAEL (maternal toxicity) = 25 mg/kg-day
NOAEL (reproductive toxicity) = 150 mg/kg-day (highest dose tested)
Developmental Toxicity
In a combined oral gavage repeated-dose/reproductive/developmental toxicity screening test,
CrL:CD(SD) rats previously mentioned(12/sex/dose, 18/sex in the control and high-dose groups)
were administered 2,5-dihydrothiophene 1,1-dioxide via gavage in corn oil at 10, 25 or 75
mg/kg-day for females and 25, 75 or 150 mg/kg-day for males. Control animals received corn
oil. Males were dosed for 28 days (14 days premating through 1 day prior to scheduled
euthanasia) and females were dosed for 40 - 44 days (14 days premating through lactation day
3). Females with no evidence of mating were dosed through the day prior to euthanasia for a
total of 52 doses. At the end of the study, six animals/sex in the control and high-dose groups
remained on study for 14 days without treatment. On PND 1 and 4, mean body weights of dams
5 The presence of nephropathy in association with the hyaline droplet accumulation in male rats suggests that the nephropathy in
the males is occurring by an alpha2U-globulin-mediated mechanism, which appears to be unique to male rats and the response is
probably not relevant to humans for purposes of risk assessment. EPA's Risk Assessment Forum has outlined the key events and
the data that are necessary to demonstrate this mode of action (Alpha2U-Globulin: Association with Chemically Induced Renal
Toxicity and Neoplasia in the Rat, EPA/625/3-91/019F). Although the protocol for this study on sulfolene indicated that
immunohisto-chemical staining was to be used to evaluate alpha2U-globulin in kidney tissue sections from control and high-dose
males, the result section did not describe the findings from such a study. Therefore, one of the key events, alpha 2u-globulin
accumulation, has not been demonstrated and the nephropathy is assumed to be relevant to human health.
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were 8.6 and 6.9% respectively at 75 mg/kg-day. A decrease in mean male (11%) and female
(10.4%) pup body weights was observed at 75 mg/kg-day. At the same dose, mean pup body-
weights on PND 4 remained lower than values in historical controls. No additional treatment-
related effects were found for organ weights (adrenal glands, brain, epididymides, heart, ovaries
and oviducts, spleen, testes, thymus gland and thyroids with parathyroid) or histology
(comprehensive set of tissues evaluated for the reproduction phase in the control, high-dose
males and females and from females that died or failed to deliver and liver and kidneys from
low-dose, mid-dose and recovery-phase males).
LOAEL (maternal and developmental toxicity) = 75 mg/kg-day (based on decreased mean
body weight in dams on lactation days 1 and 4 and decrease mean male and female pup weights
on PND 1 and 4)
NOAEL (maternal and developmental toxicity) = 25 mg/kg-day
Genetic Toxicity — Gene Mutation
In vitro
(1)	Mouse lymphoma L5178Y TK+/- cells were exposed to 2,5-dihydrothiophene 1,1-dioxide
(purity not specified) at concentrations of 0, 61, 90, 135, 202, 301, 449, 670 or 1000 |j,g/mL in
the presence and absence of metabolic activation. Positive controls were used and produced
appropriate responses. Based on percent survival, the highest test concentration was not
cytotoxic.
2,5-Dihydrothiophene 1,1-dioxide was not mutagenic in this assay.
(2)	In an NTP study, Mouse lymphoma cells were exposed to 2,5-dihydrothiophene 1,1-dioxide
(purity not specified) at concentrations of 0, 312.5, 625, 1250, 2500 and 5000 |j,g/mL or 0, 1000,
2000, 3000, 4000, or 5000 |j,g/mL in the absence of metabolic activation or at concentrations of
0, 1000, 2000, 3000, 4000 or 5000 |j,g/mL in two trials in the presence of metabolic activation.
Positive controls were used and produced appropriate responses. There was no indication of
cytotoxicity in the absence or presence of metabolic activity. Trial two in the absence of
metabolic activity was inconclusive. Study ID # 964398
2,5-Dihydrothiophene 1,1-dioxide was not mutagenic in this assay.
(3)	Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed
to 2,5-dihydrothiophene 1,1-dioxide (purity not specified) at concentrations of 0, 123.5, 370.4,
1111.1, 3333.3 or 10,000 |j,g/plate in the presence and absence of metabolic activation. Positive
controls were used and produced appropriate responses. The cytotoxic concentration was not
provided.
2,5-Dihydrothiophene 1,1-dioxide was not mutagenic in this assay.
(4)	In an NTP study, Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 were
exposed to 2,5-dihydrothiophene 1,1-dioxide (purity not specified) at concentrations of 0, 100,
3333, 1000, 3333 or 10,000 |j,g/plate in the presence and absence of metabolic activation.
Positive controls were used and produced appropriate responses. The cytotoxic concentration
was not provided. Study ID #430543
2,5-Dihydrothiophene 1,1-dioxide was not mutagenic in this assay.
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Genetic Toxicity - Chromosomal Aberrations
In vitro
(1)	In a Sister Chromatid Exchange (SCE) study, Chinese Hamster Ovary (CHO) cells, CCL 61
were exposed to 2,5-dihydrothiophene 1,1-dioxide (purity not specified) at concentrations of 0,
10, 34, 100, 334 or 1000 |j,g/mL in the presence and absence of metabolic activation. Positive
controls were used and produced appropriate responses. No increase in the number of SCEs per
chromosome was seen at any dose level in the presence or absence of metabolic activation. The
cytotoxic concentration was not provided.
2,5-Dihydrothiophene 1,1-dioxide did not induce SCE in this assay.
(2)	In two NTP studies, CHO cells were exposed to 2,5-dihydrothiophene 1,1-dioxide (purity
not specified) at concentrations of 0, 368, 1110 or 3680 |j,g/mL (Study 067203) and at 0, 1600, or
3000 |ig/mL (Study #080941) in the presence and absence of metabolic activation. Positive
controls were used and produced appropriate responses. The cytotoxic concentration was not
provided.
2,5-Dihydrothiophene 1,1-dioxide did not induce chromosomal aberrations in these assays.
(3)	In two studies conducted by NTP for the induction of sister chromatid exchange (SCE),
mammalian (CHO) cells were exposed to 2,5-Dihydrothiophene 1,1-dioxide (purity not
specified) at 0, 379, 1140 or 3790 |ig/mL (Study #067203) and concentrations of 0, 160, 500, or
1600, or 5000 |ig/mL (Study #080941) in the presence and absence of metabolic activation.
Positive controls were used and produced appropriate responses. The cytotoxic concentration
was not provided.
2,5-Dihydrothiophene 1,1-dioxide did not induce SCE in these assays.
Additional Information
Eye Irritation
(1)	New Zealand White/Dutchland rabbits (6, sex not specified) were administered 2,5-
Dihydrothiophene 1,1-dioxide (0.1 mL, purity not specified) in a "normal saline slurry" into the
left eye of each rabbit. Treated eyes were held closed for 1 second and not washed. Ocular
reactions were evaluated at 1, 24, 48 and 72 hours and at 4 and 7 days after treatment. Corneal
opacity, iritis, conjunctival redness, conjunctival chemosis, phonation, ocular irritation and
conjunctival discharge were observed. Total scores were 16.8, 35.7, 36.3, 29.2, 25.5, and 11.8 at
1, 24, 48, 72 hours, 4 and 7 days.
2,5-Dihydrothiophene 1,1-dioxide was irritating to rabbit eyes in this study.
(2)	New Zealand White/Dutchland rabbits (6, sex not specified) were administered 2,5-
Dihydrothiophene 1,1-dioxide (0.1 mL, purity not specified) in a "normal saline slurry" into the
left eye of each rabbit. Treated eyes were held closed for 1 second and washed with 40 mL of
tap water. Ocular reactions were evaluated at 1, 24, 48 and 72 hours and at 4 and 7 days after
treatment. Corneal opacity, iritis, conjunctival redness, conjunctival chemosis, phonation, ocular
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irritation and conjunctival discharge were observed. Total scores were 34.2, 13.5, 15.0, 8.8, 7.5
and 4.3 at 1, 24, 48, 72 hours and 4 and 7 days.
2,5-Dihydrothiophene 1,1-dioxide was irritating to rabbit eyes in this study.
Skin Irritation
New Zealand White/Dutchland rabbits (3/sex) were treated with undiluted 2,5-dihydrothiophene
1,1-dioxide (0.5 g, purity not specified) to clipped, abraded and unabraded skin under occluded
conditions for 24, then wiped clean. Animals were evaluated at 24 and 72 hours after exposure.
No erythema or edema was observed.
2,5-Dihydrothiophene 1,1-dioxide was not irritating to rabbit skin in this study.
Carcinogenicity
(1)	In an NTP study, Osborne-Mendel rats (20/sex/controls; 50/sex/dose) were exposed to 2,5-
dihydrothiophene 1,1-dioxide via gavage at 0 (corn oil), 197 or 372 mg/kg-bw/day in males and
0 (corn oil), 120 or 240 mg/kg-bw/day in females 5 days/week for 78 weeks. A significant (p <
0.002) positive association between dosage and mortality was found in treated males and females
compared to the vehicle controls. The last high-dose male died at week 60. Incidences of
neoplasms in treated animals were within or below spontaneous incidences observed in this rat
strain.
2,5-Dihydrothiophene 1,1-dioxide did not shown to induce tumors in this study.
(2)	In a NTP study, B6C3F1 mice (20/sex/controls; 50/sex/dose) were exposed to 2,5-
dihydrothiophene 1,1-dioxide via gavage at 0 (corn oil), 311 or 622 mg/kg-bw/day in males and
0 (corn oil), 384 or 768 mg/kg-bw/day in females 5 days/week for 78 weeks. A significant (p <
0.001) positive association between dosage and mortality was found in treated males and females
when compared to control. Although the Cochran-Armitage statistical test indicated that a
significant (p = 0.040) positive association between dose and incidence of hepatocellular
carcinomas, the Fisher exact test was not significant. Therefore, there was no evidence for
carcinogenicity.
2,5-Dihydrothiophene 1,1-dioxide did not induce the incidence of tumors in this study.
Conclusion: The acute oral toxicity of 2,5-Dihydrothiophene 1,1-dioxide is low in rats. The
acute inhalation toxicity of 2,5-Dihydrothiophene 1,1-dioxide in rats was not determined because
the concentration of saturation was not reported; however, no mortalities occurred at the
saturated concentration. In an oral gavage combined repeated-dose/reproductive/developmental
screening test in rats, 2,5-dihydrothiophene 1,1-dioxide showed an increase in male neuropathy
at 150 mg/kg-day; the NOAEL for systemic toxicity is 75 mg/kg-day. No treatment-related
effects were observed in the functional observational battery (FOB); however, significant
increases were noted in total and ambulatory activity in males at 150 mg/kg-day. No treatment-
related effects were observed on reproductive parameters; the NOAEL for reproductive toxicity
is 150 mg/kg-day; highest dose tested. In the same study, a decrease in mean body weight in
dams and mean pup weight was observed at 75 mg/kg-day; the NOAEL for maternal and
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developmental toxicity is 25 mg/kg-day. 2,5-Dihydrothiophene 1,1-dioxide was not mutagenic in
bacteria or mammalian cells in vitro. 2,5-Dihydrothiophene 1,1-dioxide did not induce
chromosomal aberrations or sister chromatid exchange in vitro. 2,5-Dihydrothiophene 1,1-
dioxide is irritating to the rabbit eye but not rabbit skin. 2,5-Dihydrothiophene 1,1-dioxide did
not increase the incidence of tumors in rats and mice.
Table 3. Summary Table of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program -
Human Health Data
Endpoint
2,5-Dihydrothiophene 1,1 -Dioxide
(77-79-2)
Acute Oral Toxicity
LDso (mg/kg)
2876
Acute Inhalation Toxicity
LC50 (mg/L)
>Saturated concentration in air at 25°C
(not quantified)
Repeated-Dose Toxicity
NOAEL/LOAEL
Oral (mg/kg-day)
(rat)
LOAEL = 150
NOAEL = 75
Reproductive Toxicity
NOAEL/LOAEL
Oral (mg/kg-day)
Reproductive Toxicity
NOAEL = 150
(highest dose tested)
Developmental Toxicity
NOAEL/LOAEL
Oral (mg/kg-day)
Maternal Toxicity
Developmental Toxicity
(rat)
LOAEL = 75
NOAEL = 25
LOAEL = 75
NOAEL = 25
Genetic Toxicity - Gene Mutation
In vitro
Negative
Genetic Toxicity - Chromosomal
Aberrations
In vitro
Negative
Genetic Toxicity - Other
SCE
Negative
Additional Information
Carcinogenicity
Eye Irritation
Skin Irritation
Negative (rats and mice)
Irritating
Not Irritating
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4. Hazard to the Environment
A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 4.
Acute Toxicity to Fish
Rainbow trout (Oncorhynchus myki.s.s, 10/concentration) were exposed to 2,5-dihydrothiophene
1,1-dioxide at nominal concentrations of 0, 100, 200, 500 or 1000 mg/L under static renewal
conditions for 96 hours. Measured concentrations were not provided. At 96 hours, 60 %
mortality was observed at the highest concentration and 0 % mortality was observed at all other
concentrations.
96-h LCso = 940 mg/L
Acute Toxicity to Aquatic Invertebrates
Water fleas (Daphnia magna, 10/replicate, three replicates/concentration) were exposed to 2,5-
dihydrothiophene 1,1-dioxide at nominal concentrations of 50, 100, 200, 500 or 1000 mg/L
under static conditions for 48 hours. Measured concentrations were not provided.
Immobilization was observed at 1000 mg/L at 24 hours and at 500 and 1000 mg/L at 48 hours.
48-h ECso = 800 mg/L
Toxicity to Aquatic Plants
Green algae (Pseudokirchneriella subcapitata) were exposed to 2,5-dihydrothiophene 1,1-
dioxide at nominal concentrations of 10, 20, 50, 100, 200, 500 or 1000 mg/L for 96 hours.
Measured concentrations were not provided. Cell concentrations at 96 hours were 0.76, 0.60,
0.61, 0.46, 0.72, 0.76 and 0.73 x 106 for the 10, 20, 50, 100, 200, 500 and 1000 mg/L groups,
respectively.
96-h ECso (growth rate) > 1000 mg/L
Conclusion: For 2,5-Dihydrothiophene 1,1-dioxide, the 96-h LC50 for fish is 940 mg/L, the
48-h EC50 for aquatic invertebrates is 800 mg/L and the 96-h EC50 value for aquatic plant growth
rate is > 1000 mg/L.
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Table 4. Summary Table of the Screening Information Data Set as Submitted under
the U.S. HPV Challenge Program - Aquatic Toxicity Data
Endpoint
2,5-Dihydrothiophene 1,1-Dioxide
(77-79-2)
Fish
96-h LCso (mg/L)
940
Aquatic Invertebrates
48-h ECso (mg/L)
800
Aquatic Plants
72-h ECso (mg/L; growth rate)
> 1000
Bold = experimental data (i.e. derived from testing)
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