United States
Environmental Protection
1=1 m m Agency
EPA/690/R-07/033F
Final
8-30-2007
Provisional Peer Reviewed Toxicity Values for
T etrahy drothiophene
(CASRN 110-01-0)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw
body weight
cc
cubic centimeters
CD
Caesarean Delivered
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
LOAEL
lowest-observed-adverse-effect level
LOAEL(ADJ)
LOAEL adjusted to continuous exposure duration
LOAEL(HEC)
LOAEL adjusted for dosimetric differences across species to a human
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
1

-------
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
11

-------
8-30-2007
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
TETRAHYDROTHIOPHENE (CASRN 110-01-0)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
1

-------
8-30-2007
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Computer searches of the following databases were conducted to 2007 to identify studies
regarding the oral toxicity of tetrahydrothiophene: TOXLINE, TOXLINE65, RTECS, TSCATS,
DART, ETIC and GENETOX. Other sources of information that were consulted include the
CARA data base (U.S. EPA, 1991, 1994), IRIS (U.S. EPA, 2007), the HEAST (U.S. EPA, 1997)
and the Drinking Water Regulations and Health Advisories list (U.S. EPA, 2006), the updated
National Toxicology Program Status Reports (NTP, 2007), the Merck Index (Merck and
Company, 1989) and Sax's Dangerous Properties of Industrial Materials (Sax, 1984). No
ATSDR Toxicological Profile for this compound was available (2007).
Occupational exposure limits for tetrahydrothiophene were not adopted by ACGIH
(2007), OSHA (2007) orNIOSH (2005).
REVIEW OF PERTINENT DATA
Human Studies
No toxicity or epidemiology data in humans were identified.
2

-------
8-30-2007
Animal Studies
Atochem North America, Inc. (1992) reported a skin irritation study in rabbits, in which
0.5 mL of tetrahydrothiophene was applied to an occluded, 1-square-inch area of the skin of six
rabbits for 4 hours, produced tissue destruction at the application site (necrosis and eschar
formation) in four of the six rabbits within 7 days of exposure. RTECS (1994) listed a mouse
inhalation LC50 of 27 g/m3 from a Czechoslovakian report.
The German Deutsche Forschungsgemeinschaft (DFG, 2005) reported an 8-hour time-
weighted-average workplace airborne exposure limit (MAK) of 180 mg/m3. However, at this
writing, the basis for this value was unavailable.
The International Toxicology Estimates of Risk (ITER) database (TERA, 2007) and
Vermeire, 1993 noted that unpublished data from a German language report (Glaser, 1990)
served as the basis for a Dutch tolerable concentration in air (TCA) of 0.65 mg/m3 (Vermeire,
1991). Berg, 1997 reported that the Dutch oral tolerable daily intake (TDI) of 0.18 mg/kg-day
was based on the TDI for tetrahydrofuran. However, Baars et al. (2001) corrected this by noting
that the TDI was based on extrapolation from the inhalation data.
In a 12-week inhalation study, Glaser (1990) identified a 6-hour/day, 5-day/week
NOAEL of 3660 mg/m3 for adrenal effects in rats. Vermeire (1991) adjusted this value for
duration of exposure, as follows:
3660 mg/m3 x
6 hr I day f 5 days / wk
24 hr / day J I 7 days / wk
= 654 mg/m3
to determine a point of departure. Uncertainty factors of ten each were applied to account for
inter- and intraspecies variability and for the apparent species differences in severity of effects
on the central nervous system following inhalation exposure to the primary metabolite sulfolane,
for which monkeys were more sensitive than dogs and dogs more sensitive than rodents
(Andersen et al., 1977). No attempt to calculate a human effective concentration (HEC) was
reported. TERA (2007) reported no other study details, including other dose levels, numbers of
animals, specific adrenal effects observed, or frequency of effects.
The European Commission (EC), 2000 compiled toxicology data for tetrahydrothiophene
in its IUCLID dataset. Of special interest were two industry reports, apparently in English, from
the Pennwalt Corporation (1988a,b). EC (2000) noted that both studies followed good
laboratory practices (GLP). However, the dataset also noted that data reported in IUCLID
datasets have not undergone evaluation by the EC.
In Pennwalt, 1988a, Sprague-Dawley rats were exposed via inhalation, 6 hours/day, 5
days/week for 90 days, to tetrahydrothiophene, at concentrations of 50, 275, and 1500 ppm.
These airborne concentrations are equivalent to exposures at approximately 180, 1000, and 5400
mg/m3. The NOAEL reported was 180 mg/ m3 for mild irritation. The EC (2000) reported that
no other significant toxic effects were observed.
3

-------
8-30-2007
In Pennwalt 1988b, pregnant Sprague-Dawley rats were exposed 6 hours per day via
inhalation to 250, 750, and 2000 ppm tetrahydrothiophene, on days 6 through 15 of gestation.
These concentrations were equivalent to approximately 900, 2700, and 7200 mg/ m3. The
NOAEL for unspecified maternal effects was 900 mg/m3. EC (2000) reported that no
teratogenic or embryogenic effects were observed.
Tetrahydrothiophene is structurally similar to tetrahydrofuran (S replaces O in the furan
ring), a compound for which there was considerable toxicological information (ACGIH, 2001b).
However, there was insufficient information regarding the behavior of tetrahydrothiophene in
biological systems to conclude that the toxicity of these compounds may be similar.
DERIVATION OF PROVISIONAL RfDs FOR TETRAHYDROTHIOPHENE
The absence of oral toxicity data precluded derivation of p-RfDs for tetrahydrothiophene.
DERIVATION OF PROVISIONAL RfCs FOR TETRAHYDROTHIOPHENE
EC (2000) reported that Pennwalt, 1988a identified a 90-day inhalation NOAEL of 180
mg/m3 for irritation in rats and that Pennwalt, 1988b identified a 20-day inhalation NOAEL of
900 mg/m3 for maternal toxicity. It also reported that Pennwalt, 1988b identified a
developmental NOAEL of >900 mg/m3, although the EC (2000) description implied that no
effects were seen in developing pups when dams were exposed to concentrations as high as 7200
mg/m3. Although EC (2000) reported that both of these Pennwalt studies followed GLP, the
original data were not available to the author of this PPRTV document. In addition, the EC
(2000) secondary source for these data indicated that the studies had not been peer reviewed and
provided few study details. For these reasons, the PPRTV author deemed these data to be
insufficient for deriving inhalation toxicity values.
In its ITER database, TERA (2007) reported that unpublished data from Glaser (1990)
was used by the Netherland National Institute of Public Health & Environmental Protection
(RIVM) to derive an inhalation tolerable concentration in air (TCA) of 0.65 mg/m3, based on a
duration-adjusted NOAEL of 650 mg/m3 for unspecified adrenal effects. Although it seems
likely that RIVM peer-reviewed the Glaser (1990) study report before selecting it as the basis for
its TCA, we could not verify this because the original RIVM derivation paper (Vermeire, 1991),
in Dutch or a translation, was not available to the author of this PPRTV document. Because the
Glaser (1990) data were available only in a tertiary source, the PPRTV author deemed these data
to be insufficient for deriving inhalation toxicity values.
The authors of this PPRTV report will continue attempts to obtain the Glaser (1990) and
Pennwalt (1988a,b) reports. If they become available, derivation of p-RfCs will be reconsidered.
4

-------
8-30-2007
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
TETRAHYDROTHIOPHENE
A cancer classification of "Inadequate Information to Assess Carcinogenic Potential'
was appropriate, since no data pertinent to the possible carcinogenicity of the compound were
available.
In the absence of tumor data, derivation of p-OSF or p-IUR values for carcinogenicity
was precluded.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Tetrahydrofuran.
In: Documentation of Threshold Limit Values and Biological Exposure Indices for Chemical
Substances in the Workroom Air, 7th ed., Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hygienists). 2007. Threshold Limit
Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH,
Cincinnati, OH.
Andersen ME, Jones RA, Mehl RG, Hill TA, Kurlansik L, Jenkins LJ: The inhalation toxicity of
sulfolane (tetrahydrothiophene-1,1-dioxide). Toxicol Appl Pharmacol 40: 463-472, 1977. Cited
inVermeire, 1991.
Atochem North America, Inc. 1992. Primary Dermal Irritation Study in Rabbits. Report
submitted to U.S. EPA under TSCA Section 8(e). OTS Fiche No. 0540567.
ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Profile
Information. Accessed August 14, 2007 Online http://www.atsdr.cdc. gov/toxpro2.html.
Baars AJ, RMC Theelen, PJCM Jansen, JM Hesse, ME van Apeldoorn, MCM Meijerink, L
Verdam, MJ Zeilmaker. 2001. Re-evaluation of human-toxicological maximum permissible risk
levels. RIVM report no. 711701025, National Institute of Public Health and the Environment,
Bilthoven, The Netherlands, March 2001, p 277. Online:
http://www.rivm.nl/bibliotheek/rapporten/711701025.pdf.
DFG (Deutsche Forschungsgemeinschaft). 2005. List of MAK and BAT Values. Report No. 38.
Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area.
Wiley-VCH, Weinheim, Germany. Online
http://www.mrw.interscience.wilev.com/makbat/db/articles/mbell001/frame.html
EC (European Commission). 2000. IUCLID Dataset for Tetrahydrothiophene. European
Chemicals Bureau. February 18, 2000. Accessed August 14, 2007. Online:
http://ecb.irc.it/IUCLID-Data-Sheet/110010.pdf
5

-------
8-30-2007
Glaser U. 1990. Prufung der subakuten inhalativen Toxicitat von Tetrahydrothiophen (THT) an
Ratten. Fraunhofer-Institut fur Umweltchemie und Okotoxicologie in opdracht van de
Berufsgenossenschaft der Chemische Industrie. Projekt: 217280/88. (Cited in Vermeire et al.,
1991.)
Merck and Company. 1989. The Merck Index. An Encyclopedia of Chemicals, Drugs and
Biologicals. Eleventh Edition. S. Budavari, Ed. Merck and Company. Rahway, NJ. p. 9286.
NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to
Chemical Hazards. Accessed on August 16, 2007. Online:
http://www.cdc.gov/niosh/npg/npgd0267.html
NTP (National Toxicology Program). 2007a. Chemical Status Reports. Accessed August 14,
2007. Online http://ntp.niehs.nih.gov:8080/index.html?col=010stat
OSHA (Occupational Safety and Health Administration). 1989. 29 CFR 1910. Air
Contaminants; Final Rule. Federal Register. 54(12): 2332-2983.
OSHA (Occupational Safety and Health Administration). 2007. 29 CFR 1910. Air
Contaminants; Rule. Federal Register. 58(124): 35338-35351.
Pennwalt Corporation. 1998a. Tetrahydrothiophene - 90-day inhalation. Huntingdon Research
Centre. Report PWT 50/871158. June 1988.
Pennwalt Corporation. 1998b. Effect of Tetrahydrothiophene on pregnancy of the rat. Report
PWT 52-R/8849. May 1988.
RTECS (Registry of Toxic Effects of Chemical Substances). 1994. On-line. U.S. DHHS, PHS,
CDC, NIOSH, Cincinnati, OH.
Sax, N.I. 1984. Dangerous Properties of Industrial Materials. Sixth Edition. VanNostrand
Reinhold Company, New York.
TERA (Toxicology Excellence for Risk Assessment). 2007. Tetrahydrothiophene. In the
International Toxicity Estimates for Risk (ITER) database. Accessed August 16, 2007. On-line
http://iter.ctcnet.net/publicurl/pub view list.cfm?crn=l 10%2D01%2D0
U.S. EPA. 1991. Office of Health and Environmental Assessment Chemical Assessments and
Related Activities. Office of Health and Environmental Assessment, Washington, DC. April
1991. OHEA-I-127.
U.S. EPA. 1994. Office of Health and Environmental Assessment Chemical Assessments and
Related Activities. Availability: NTIS. Office of Health and Environmental Assessment,
Washington, DC. December, 1994. OHEA-I-127.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. Annual FY-1997. Office of
Research and Development, Office of Solid Waste and Emergency Response, Washington, DC.
NTIS No. PB95-921199. Accessed August 14, 2007.
6

-------
8-30-2007
U.S. EPA. 2006. Drinking Water Regulations and Health Advisories. Office of Water,
Washington, DC. May 1994. Online
http://www.epa.gov/waterscience/criteria/drinking/dwstandards.pdf
U.S. EPA. 2007. Integrated Risk Information System (IRIS). Online. Office of Health and
Environmental Assessment, National Center for Environmental Assessment, Cincinnati, OH.
Accessed August 16, 2007, Online http://www.epa.gov/iris/
van den Berg R. 1997. Verantwoording van gegevans en proedures voor de le tranche
interventiewaarden: van RIVM-rapporten naar de Notitie interventie-waarden bodemsanering.
(In Dutch). RIVM report no.715810012. National Institute of Public Health and the
Environment, Bilthoven, The Netherlands, pp. 14, 16, 24, 37, 57, 64, and 70. Online
http://www.rivm.nl/bibliotheek/rapporten/715810012.pdf
Vermeire, TG, ME van Apeldoorn, JC de Fouw and PJCM Janssen. 1991. Voorstel voor de
humaan-toxicologische onderbouwing van C-(toetsings)warden (In Dutch). RIVM report no.
725201005. National Institute of Public Health and the Environment, Bilthoven, The
Netherlands, February 1991, p 170. (Cited in TERA, 2007 and Vermeire, 1993.)
Vermeire, TG. 1993. Voorstel voor de humaan-toxicologische onderbouwing van C-
(toetsings)warden. Betreft addendum op rapport 725201005 (In Dutch). RIVM report no.
715801001. National Institute of Public Health and the Environment, Bilthoven, The
Netherlands, May 1993, p. 27-28. Online
http://www.rivm.n1/bibliotheek/rapporten/715801001 .pdf
7

-------