United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-04/002F
Final
11-23-2004
Provisional Peer Reviewed Toxicity Values for
Benzothiazole
(CASRN 95-16-9)
Derivation of Subchronic and Chronic Oral RfDs
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
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
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
1

-------
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-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-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
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

-------
11-23-2004
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
BENZOTHIAZOLE (CASRN 95-16-9)
Derivation of a Subchronic or Chronic Oral RfD
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 science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. 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.
1

-------
11-23-2004
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
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
A subchronic or chronic RfD for benzothiazole is not available on IRIS (U.S. EPA,
2002a), the HEAST (U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories
list (U.S. EPA, 2002b). No relevant documents were located in the CARA list (U.S. EPA, 1991,
1994). The Office of Drinking Water produced a Toxicological Profile for benzothiazole (U.S.
EPA, 1989) that provided a synopsis of toxicological information for the chemical, but no risk
assessment. Neither ATSDR (2002), NTP (2002), IARC (2002), nor WHO (2002) have
produced documents regarding benzothiazole. Literature searches of the following databases
were conducted from 1965 through May 2004 in order to locate relevant studies: TOXLINE,
CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK,
EMIC/EMICBACK, RTECS and TSCATS.
2

-------
11-23-2004
REVIEW OF PERTINENT DATA
Human Studies
No data regarding the toxicity of benzothiazole to humans following chronic or
subchronic oral exposure were located.
Animal Studies
No data regarding the toxicity of benzothiazole to animals following chronic or
subchronic oral exposure were located. The only data found were acute animal studies.
Investigators reported oral LD50 values of 380-492 mg/kg for benzothiazole in male and female
Fischer 344 (Mayhew and Muni, 1986) and Sprague-Dawley (Younger Laboratories, 1964, 1976)
rats, and an oral LD50 of 375 mg/kg in male rats of an unspecified strain (Lorke, 1983). A dermal
LD50 of 126-200 mg/kg was found for male and female New Zealand Albino rabbits (Younger
Laboratories, 1976). Benzothiazole was a mild to moderate skin irritant and a severe eye irritant
in rabbits (Younger Laboratories, 1964, 1976).
FEASIBILITY OF DERIVING A PROVISIONAL SUBCHRONIC OR CHRONIC
RfD FOR BENZOTHIAZOLE
The lack of chronic or subchronic oral toxicity data for humans or animals precludes
derivation of a subchronic or chronic p-RfD for benzothiazole. It was considered that systemic
toxicity values might be obtained by analogy to 2-mercaptobenzothiazole (MBT), which has
toxicity and carcinogenicity information. However, the pharmacokinetic data on MBT (Colucci
and Buyske, 1965; El Dareer et al., 1989; Larsen et al., 1988; Nagamatsu et al., 1979) do not
suggest that biotransformation to benzothiazole would occur, and no obvious pathways for
biotransformation of benzothiazole to MBT were identified. In addition, there is some evidence
that the sulfur-containing mercapto group is involved in MBT carcinogenicity (NTP, 1988) and
other aspects of MBT toxicity (Feinman, 1987).
REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Profile
Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html
Colucci, D.F. and D.A. Buyske. 1965. The biotransformation of a sulfonamide to a mercaptan
and to mercapturic acid and glucuronide conjugates. Biochem. Pharmacol. 14: 457-466.
3

-------
11-23-2004
El Dareer, S.M., J.R. Kalin, K.F. Tillery et al. 1989. Disposition of 2-mercaptobenzothiazole
and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally and topically and in
guinea-pigs dosed topically. J. Toxicol. Environ. Health. 27(1): 65-84.
Feinman, S.E. 1987. Sensitivity to rubber chemicals. J. Toxicol.-Cut. Ocular Toxicol. 6(2):
117-153.
I ARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Larsen, G.L., J.E. Bakke, V.J. Feil and J.K. Huwe. 1988. In vitro metabolism of the methylthio
group of 2-methylthiobenzothiazole by rat liver. Xenobiotica. 18(3): 313-322.
Lorke, D. 1983. A new approach to practical acute toxicity testing. Arch. Toxicol. 54(4): 275-
288.
Mayhew, D.A. and I.A. Muni. 1986. Dermal, eye and oral toxicological evaluations. Phase II
report. Acute oral LD50 determinations of benzothiazole, dithiane, and oxathiane. Report
submitted by American Biogenics Corp. to U.S. Army Medical Research and Development
Command. NTIS AD-A172647.
Nagamatsu, K., Y. Kido, G. Urakubo et al. 1979. Absorption, distribution, excretion and
metabolism of 2-mercaptobenzothiazole in guinea pig. Eisei Kagaku. 25:59-65. (Cited in NTP,
1988)
NTP (National Toxicology Program). 1988. Technical Report on the Toxicology and
Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and
B6C3F1 Mice. National Toxicology Program, Research Triangle Park, NC. NTP TR 332. NTIS
PB 88245154. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html
NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
U.S. EPA. 1989. Toxicological Profile for Benzothiazole. Criteria and Standards Division,
Office of Drinking Water, Washington, DC. NTIS PB95-182655.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
4

-------
11-23-2004
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS 97-921199.
U.S. EPA. 2002a. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa.gov/iris/
U.S. EPA. 2002b. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-02-038. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria
Series. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Younger Laboratories. 1964. Toxicological investigation with benzothiazole in rats and rabbits.
Initial submission with cover letter dated 8/19/92. Submitted by Monsanto Co. to U.S. EPA.
OTS 0545424.
Younger Laboratories. 1976. Toxicologic investigation of benzothiazole (Final report). Initial
submission with cover letter dated 11/26/91. Submitted by Monsanto Co. to U.S. EPA. OTS
0534825.
5

-------
11-23-2004
Provisional Peer Reviewed Toxicity Values for
Benzothiazole
(CASRN 95-16-9)
Derivation of Subchronic and Chronic Inhalation RfCs
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
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
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
1

-------
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-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-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
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

-------
11-23-2004
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
BENZOTHIAZOLE (CASRN 95-16-9)
Derivation of a Subchronic or Chronic Inhalation RfC
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 science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. 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.
1

-------
11-23-2004
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
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
A subchronic or chronic RfC for benzothiazole is not available on IRIS (U.S. EPA, 2002)
or in the HEAST (U.S. EPA, 1997). No relevant documents were located in the CARA list (U.S.
EPA, 1991, 1994). The Office of Drinking Water produced a Toxicological Profile for
benzothiazole (U.S. EPA, 1989) that provided a synopsis of toxicological information for the
chemical, but no risk assessment. ACGIH (2001), NIOSH (2002) and OSHA (2002) have not
recommended occupational exposure limits for benzothiazole. ATSDR (2002), NTP (2002),
IARC (2002), and WHO (2002) have not produced documents for this chemical. Literature
searches of the following databases were conducted from 1965 through May 2004 in order to
locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB,
DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS.
2

-------
11-23-2004
REVIEW OF THE PERTINENT DATA
Human Studies
No data regarding the toxicity of benzothiazole to humans following chronic or
subchronic inhalation exposure were located.
Animal Studies
No data regarding the toxicity of benzothiazole to animals following chronic or
subchronic inhalation exposure were located. An acute inhalation study was conducted in which
four male Sprague-Dawley rats survived a 6-hour exposure to a concentrated vapor of
benzothiazole (Younger Laboratories, 1964). The exposure concentration was not estimated.
FEASIBILITY OF DERIVING A PROVISIONAL SUBCHRONIC OR CHRONIC
RfC FOR BENZOTHIAZOLE
The lack of chronic or subchronic inhalation data for humans or animals precludes
derivation of a subchronic or chronic p-RfC for benzothiazole. It was considered that systemic
toxicity values might be obtained by analogy to 2-mercaptobenzothiazole (MBT), which has
toxicity and carcinogenicity information. However, the pharmacokinetic data on MBT (Colucci
and Buyske, 1965; El Dareer et al., 1989; Larsen et al., 1988; Nagamatsu et al., 1979) do not
suggest that biotransformation to benzothiazole would occur, and no obvious pathways for
biotransformation of benzothiazole to MBT were identified. In addition, there is some evidence
that the sulfur-containing mercapto group is involved in MBT carcinogenicity (NTP, 1988) and
other aspects of MBT toxicity (Feinman, 1987).
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2001. 2001 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Profile
Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html
Colucci, D.F. and D.A. Buyske. 1965. The biotransformation of a sulfonamide to a mercaptan
and to mercapturic acid and glucuronide conjugates. Biochem. Pharmacol. 14: 457-466.
3

-------
11-23-2004
El Dareer, S.M., J.R. Kalin, K.F. Tillery et al. 1989. Disposition of 2-mercaptobenzothiazole
and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally and topically and in
guinea-pigs dosed topically. J. Toxicol. Environ. Health. 27(1): 65-84.
Feinman, S.E. 1987. Sensitivity to rubber chemicals. J. Toxicol.-Cut. Ocular Toxicol. 6(2):
117-153.
I ARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Larsen, G.L., J.E. Bakke, V.J. Feil and J.K. Huwe. 1988. In vitro metabolism of the methylthio
group of 2-methylthiobenzothiazole by rat liver. Xenobiotica. 18(3): 313-322.
Nagamatsu, K., Y. Kido, G. Urakubo et al. 1979. Absorption, distribution, excretion and
metabolism of 2-mercaptobenzothiazole in guinea pig. Eisei Kagaku. 25: 59-65. (Cited in NTP,
1988)
NIOSH (National Institute for Occupational Safety and Health). 2002. NIOSH Pocket Guide to
Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/.html
NTP (National Toxicology Program). 1988. Technical Report on the Toxicology and
Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and
B6C3F1 Mice. National Toxicology Program, Research Triangle Park, NC. NTP TR 332. NTIS
PB 88245154. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/A [J. SRCH/iH ATI, SRCH Frames.html
NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
OSHA (Occupational Safety and Health Administration). 2002. OSHA Standard 1910.1000
TableZ-1. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html
U.S. EPA. 1989. Toxicological Profile for Benzothiazole. Criteria and Standards Division,
Office of Drinking Water, Washington, DC. NTIS PB95-182655.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
4

-------
11-23-2004
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS 97-921199.
U.S. EPA. 2002. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http ://www. epa. gov/ iris/
WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria
Series. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Younger Laboratories. 1964. Toxicological investigation with benzothiazole in rats and rabbits.
Initial submission with cover letter dated 8/19/92. Submitted by Monsanto Co. to U.S. EPA.
OTS 0545424.
5

-------
11-23-2004
Provisional Peer Reviewed Toxicity Values for
Benzothiazole
(CASRN 95-16-9)
Derivation of a Carcinogenicity Assessment
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
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
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
1

-------
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-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-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
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
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
BENZOTHIAZOLE (CASRN 95-16-9)
Derivation of a Carcinogenicity Assessment
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 science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. 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.
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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
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
A carcinogenicity assessment of benzothiazole is not available on IRIS (U.S. EPA,
2002a), the HEAST (U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories
list (U.S. EPA, 2002b). No relevant documents were located in the CARA list (U.S. EPA, 1991,
1994). A toxicological profile on benzothiazole prepared by the Office of Drinking Water (U.S.
EPA, 1989) did not locate carcinogenic study data for benzothiazole in humans or animals, but
did include mutagenicity assay results in bacteria (Sano and Korte, 1985). Neither ATSDR
(2002), NTP (2002), IARC (2002), nor WHO (2002) have produced documents regarding
benzothiazole. Literature searches of the following databases were conducted from 1965 through
May 2004 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS,
GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS.
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REVIEW OF THE PERTINENT DATA
Human Studies
No data regarding the possible carcinogenicity of benzothiazole in humans were located.
Animal Studies
No reports of animal studies examining the carcinogenicity of benzothiazole by any route
of exposure were located.
Supporting Studies
Data regarding the genotoxicity of benzothiazole are limited to two reports of testing in
the Ames assay. Benzothiazole did not induce an increase in revertant colony counts with or
without an S-9 metabolic activation system in Salmonella typhimurium tester strains TA98,
TA100, TA1535, TA1537, and TA1538 exposed to concentrations ranging from 3.2 x 10"4 to 1
jj.l/plate (Sano and Korte, 1985). In another study, benzothiazole was reported to have induced
reverse mutations in strain TA1537 in the presence of an S-9 metabolic activation system, but the
study was presented in an abstract that did not include any experimental details (Kinae et al.,
1981).
PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION
There are no data on the carcinogenicity of benzothiazole in humans or animals and only
limited genotoxicity data. It was considered that cancer toxicity values might be obtained by
analogy to 2-mercaptobenzothiazole (MBT), which has toxicity and carcinogenicity information.
However, the pharmacokinetic data on MBT (Colucci and Buyske, 1965; El Dareer et al., 1989;
Larsen et al, 1988; Nagamatsu et al., 1979) do not suggest that biotransformation to
benzothiazole would occur, and no obvious pathways for biotransformation of benzothiazole to
MBT were identified. In addition, there is some evidence that the sulfur-containing mercapto
group is involved in MBT carcinogenicity (NTP, 1988) and other aspects of MBT toxicity
(Feinman, 1987). Under the proposed U.S. EPA (1999) cancer guidelines, the available data are
inadequate for an assessment of human carcinogenic potential.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Derivation of quantitative estimates of cancer risk for benzothiazole is precluded by the
lack of data demonstrating carcinogenicity associated with benzothiazole exposure.
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REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Profile
Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html
Colucci, D.F. and D.A. Buyske. 1965. The biotransformation of a sulfonamide to a mercaptan
and to mercapturic acid and glucuronide conjugates. Biochem. Pharmacol. 14: 457-466.
El Dareer, S.M., J.R. Kalin, K.F. Tillery et al. 1989. Disposition of 2-mercaptobenzothiazole
and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally and topically and in
guinea-pigs dosed topically. J. Toxicol. Environ. Health. 27(1): 65-84.
Feinman, S.E. 1987. Sensitivity to rubber chemicals. J. Toxicol.-Cut. Ocular Toxicol. 6(2):
117-153.
I ARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Kinae, N., H. Kawashima, R. Kawane et al. 1981. Detection and isolation of mutagenic
substances from sea water. J. Pharmacobio-Dyn. 4: S-63. (Abstract)
Larsen, G.L., J.E. Bakke, V.J. Feil and J.K. Huwe. 1988. In vitro metabolism of the methylthio
group of 2-methylthiobenzothiazole by rat liver. Xenobiotica. 18(3): 313-322.
Nagamatsu, K., Y. Kido, G. Urakubo et al. 1979. Absorption, distribution, excretion and
metabolism of 2-mercaptobenzothiazole in guinea pig. Eisei Kagaku. 25:59-65. (Cited in NTP,
1988)
NTP (National Toxicology Program). 1988. Technical Report on the Toxicology and
Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and
B6C3F1 Mice. National Toxicology Program, Research Triangle Park, NC. NTP TR 332. NTIS
PB 88245154. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html
NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
Sano, S.K. and D.W. Korte, Jr. 1985. Mutagenic Potential of Benzothiazole. Institute Report
No. 205. U.S. Army Medical Research and Development Command, Letterman Army Institute
of Research, Presidio of San Francisco, CA. NTIS ADA-164696.
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U.S. EPA. 1989. Toxicological Profile for Benzothiazole. Criteria and Standards Division,
Office of Drinking Water, Washington, DC. NTIS PB95-182655.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS 97-921199.
U.S. EPA. 1999. Guidelines for Carcinogen Risk Assessment. Review Draft. Risk Assessment
Forum, Washington, DC. July.
U.S. EPA. 2002a. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa.gov/iris/
U.S. EPA. 2002b. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-02-038. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria
Series. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
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