United States
Environmental Protection
1=1 m m Agency
EPA/690/R-04/01OF
Final
12-20-2004
Provisional Peer Reviewed Toxicity Values for
Methyl Mercaptan
(CASRN 74-93-1)
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

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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

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12-20-04
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
METHYL MERCAPTAN (CASRN 74-93-1)
Derivation of Subchronic and Chronic Oral RfDs
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

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12-20-04
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 to OSRTI.
INTRODUCTION
A subchronic or chronic RfD for methyl mercaptan is not available on IRIS (U.S. EPA,
2003), the HEAST (U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories
list (U.S. EPA, 2002). No relevant documents were located in the CARA list (U.S. EPA, 1991,
1994). NTP (2003), IARC (2003), and WHO (2003) have not produced documents for this
chemical. ATSDR (1992) produced a toxicological profile for methyl mercaptan, but did not
derive oral MRL values for any exposure duration. Review documents by Shertzer (2001) and
Santodonato (1985) were consulted. Literature searches of the following databases were
conducted from 1965 through June 2003 in order to locate relevant studies: TOXLINE
(supplemented with BIOSIS and NTIS updates), CANCERLIT, MEDLINE, CCRIS, GENETOX,
HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. Additional literature
2

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12-20-04
searches from June 2003 through October 2004 were conducted by NCEA-Cincinnati using
MEDLINE, TOXLINE, Chemical and Biological Abstracts databases.
Methyl mercaptan occurs in foods (onion, garlic, meat, bread, fish), sometimes as a result
of microbial activity (Shertzer, 2001; Sinki and Schlegel, 1990; Budavari, 2001). It is approved
for use as a food additive (synthetic flavoring agent) by the FDA [21 CFR 172.515] (U.S. FDA,
2003).
Methyl mercaptan is produced endogenously in mammals during metabolism of
methionine and related substances (Blom et al., 1988, 1989; A1 Mardini et al., 1984; Shertzer,
2001), and by bacteria in the mammalian gut and mouth (Budavari, 2001; De Boever et al., 1994;
Hiele et al., 1991; Yaegaki and Sanada, 1992a,b). High levels of methyl mercaptan have been
detected in the breath and urine of some patients with advanced liver disease (Shertzer, 2001;
Tangerman et al, 1994). A number of studies and reviews explored the possibility that methyl
mercaptan may play a role in the pathogenesis of encephalopathy resulting from hepatic failure
(Al Mardini et al., 1984; Blom et al., 1988, 1989; Zieve, 1981; Zieve et al., 1974, 1984). These
authors concluded that methyl mercaptan may interact (mechanism unknown) with ammonia and
fatty acids to possibly exacerbate the encephalopathy in human hepatic failure.
REVIEW OF PERTINENT DATA
Human Studies
No data regarding the toxicity of methyl mercaptan to humans following oral exposure
were located.
Animal Studies
No data regarding the toxicity of methyl mercaptan to animals following oral exposure
were located.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfDs FOR METHYL MERCAPTAN
The lack of subchronic or chronic oral toxicity data for humans or animals precludes
derivation of a subchronic or chronic p-RfD for methyl mercaptan.
3

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12-20-04
REFERENCES
A1 Mardini, H., K. Bartlett and C.O. Record. 1984. Blood and brain concentrations of
mercaptans in hepatic and methanethiol induced coma. Gut. 25(3): 284-290.
ATSDR (Agency for Toxic Substances and Disease Registry). 1992. Toxicological Profile for
Methyl Mercaptan. U.S. Department of Health and Human Services, Public Health Service.
Atlanta, GA. PB93/110799/AS. Online, http://www.atsdr.cdc.gov/toxprofiles/tpl39.html
Blom, H.J., J.P. van den Elzen, S.H. Yap and A. Tangerman. 1988. Methanethiol and
dimethylsulfide formation from 3-methylthiopropionate in human and rat hepatocytes. Biochim.
Biophys. Acta. 972(2): 131-136.
Blom, H.J., G.H. Boers, J.P. van den Elzen et al. 1989. Transamination of methionine in
humans. Clin. Sci. 76(1): 43-49.
Budavari, S. 2001. The Merck Index. Thirteenth edition. Merck & Co. Inc., Whitehouse
Station, NJ. p. 1091.
De Boever, E.H., M. De Uzeda and W.J. Loesche. 1994. Relationship between volatile sulfur
compounds, BANA-hydrolyzing bacteria and gingival health in patients with and without
complaints of oral malodor. J. Clin. Dent. 4(4): 114-119.
Hiele, M., Y. Ghoos, P. Rutgeerts et al. 1991. Influence of nutritional substrates on the
formation of volatiles by the fecal flora. Gastroenterology. 100(6): 1597-1602.
I ARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary
Evaluations. Online, http://www-cie.iarc.fr/
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/
Shertzer, H.G. 2001. Organic Sulfur Compounds. Methyl Mercaptan. In: Patty's Toxicology,
Fifth edition. Vol.7. E. Bingham, B. Cohrssen and C.H. Powell, Ed. John Wiley & Sons, NY.
p. 687-690.
Santodonato, J., S. Bosch, W. Meylan et al. 1985. Monograph on human exposure to chemicals
in the workplace: Mercaptans. Center for Chemical Hazard Assessment, Syracuse Research
Corporation, Syracuse, New York. SRC-TR-85-187.
4

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12-20-04
Sinki, G.S. and W.A. Schlegel. 1990. Flavoring Agents. In: Food Science and Technology,
Vol. 35, Food Additives, A.L. Branen, P.M. Davidson, and S. Salminen, Ed. Marcel Dekker,
New York. p. 195-258.
Tangerman, A., M.T. Meuwese-Arends and J.B. Jansen. 1994. Cause and composition of foetor
hepaticus [letter]. Lancet. 343(8895): 483.
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 PB97-921199.
U.S. EPA. 2002. 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
U.S. EPA. 2003. 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. FDA. 2003. Code of Federal Regulations. Title 21 Food and Drugs. 21 CFR172.515.
Department of Health and Human Services, Washington, DC. Online.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?FR=172.515
WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm
Yaegaki, K. and K. Sanada. 1992a. Volatile sulfur compounds in mouth air from clinically
healthy subjects and patients with periodontal disease. J. Period. Res. 27(4 Pt 1): 233-238.
Yaegaki, K. and K. Sanada. 1992b. Biochemical and clinical factors influencing oral malodor in
periodontal patients. J. Periodont. 63(9): 783-789.
5

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Zieve, L., W.M. Doizaki and F J. Zieve. 1974. Synergism between mercaptans and ammonia or
fatty acids in the production of coma: A possible role for mercaptans in the pathogenesis of
hepatic coma. J. Lab. Clin. Med. 83: 16-28.
Zieve, L. 1981. The mechanism of hepatic coma. Hepatology. 1:360-365.
Zieve, L., W.M. Doizaki and C. Hyftogt. 1984. Brain methanethiol and ammonia concentrations
in experimental hepatid coma and coma induced by injections of various combinations of these
substances. J. Lab. Clin. Med. 104(5): 655-664.
6

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Provisional Peer Reviewed Toxicity Values for
Methyl Mercaptan
(CASRN 74-93-1)
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

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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

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12-20-04
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
METHYL MERCAPTAN (CASRN 74-93-1)
Derivation of Subchronic and Chronic Inhalation RfCs
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

-------
12-20-04
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 to OSRTI.
INTRODUCTION
A subchronic or chronic RfC for methyl mercaptan is not available on IRIS (U.S. EPA,
2003) or in the HEAST (U.S. EPA, 1997). No relevant documents were located in the CARA
list (U.S. EPA, 1991, 1994a). NTP (2003), IARC (2003), and WHO (2003) have not produced
documents for this chemical. ATSDR (1992) produced a toxicological profile for methyl
mercaptan, but did not derive inhalation MRL values for any duration. Recommended
occupational exposure limits for methyl mercaptan, to protect against acute sensory irritation,
headache, nausea, and the strong unpleasant odor, include a TLV-TWA of 0.5 ppm (1 mg/m3)
(ACGIH, 2003); a REL for 15-minute ceiling limit of 0.5 ppm (NIOSH, 2003); and a PEL of 10
ppm (20 mg/m3) (OSHA, 2003). Review documents by Shertzer (2001) and Santodonato (1985)
were consulted. Literature searches of the following databases were conducted from 1965
through June 2003 in order to locate relevant studies: TOXLINE (supplemented with BIOSIS and
2

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12-20-04
NTIS updates), CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK,
EMIC/EMICBACK, RTECS and TSCATS. Additional literature searches from June 2003
through October 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE,
Chemical and Biological Abstracts databases.
Methyl mercaptan (CH3SH, MW = 48.11) is a gas with a strong unpleasant odor of
rotting cabbage (Budavari, 2001). Natural sources of methyl mercaptan include vegetation,
animal waste, microbial degradation, crude oils containing sulfur, and the "sour" natural gas of
West Texas (ATSDR, 1992; Budavari, 2001; Rose, 1983; Santodonato et al., 1985). Industrial
sources include wood pulp, oil shale, petroleum processing plants, and sewage treatment plants
(ATSDR, 1992). Although some other mercaptans are used as odorants in natural and liquified
petroleum gas or in commercial, industrial, and residential natural gas, methyl mercaptan is not
used for this purpose (ATSDR, 1992; Cain and Turk, 1985; Shertzer, 2001; Santodonato et al.,
1985).
Methyl mercaptan occurs in foods (onion, garlic, meat, bread, fish), sometimes as a result
of microbial activity (Shertzer, 2001; Sinki and Schlegel, 1990; Budavari, 2001). It is approved
for use as a food additive (synthetic flavoring agent) by the FDA [21 CFR 172.515] (U.S. FDA,
2003).
Methyl mercaptan is produced endogenously in mammals during metabolism of
methionine and related substances (Blom et al., 1988, 1989; Al Mardini et al., 1984, Shertzer,
2001), and by bacteria in the mammalian gut and mouth (Budavari, 2001; De Boever et al., 1994;
Hiele et al., 1991; Yaegaki and Sanada, 1992a,b). High levels of methyl mercaptan have been
detected in the breath and urine of some patients with advanced liver disease
(Shertzer, 2001; Tangerman et al., 1994). A number of studies and reviews explored the
possibility that methyl mercaptan may play a role in the pathogenesis of encephalopathy resulting
from hepatic failure (Al Mardini et al., 1984; Blom et al., 1988, 1989; Zieve, 1981; Zieve et al.,
1974, 1984). These authors concluded that methyl mercaptan may interact (mechanism
unknown) with ammonia and fatty acids to possibly exacerbate the encephalopathy in human
hepatic failure.
REVIEW OF THE PERTINENT DATA
Human Studies
Low-level ambient air concentrations of methyl mercaptan have been reported to produce
symptoms in exposed workers that include: eye and mucous membrane irritation, dizziness,
staggering gait, nausea, and vomiting. Respiratory tract irritation can progress to pulmonary
edema, and hepatic and renal damage have been reported (Key et al., 1977). Sources of
3

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12-20-04
information regarding the toxicity of methyl mercaptan to humans are limited to a few case
reports of acute inhalation exposures and several epidemiological studies involving a mixture of
chemical exposures. Estimates of exposure levels for the accidental case reports and the
epidemiological studies were not available.
Shults et al. (1970) reported the case of a 53-year old black man who was found
unconscious after exposure to volatilized methyl mercaptan while emptying metal gas cylinders
containing methyl mercaptan. A vaporizing liquid was observed on asphalt pavement near him.
Upon medical examination, he exhibited tachycardia, elevated blood pressure, persistent coma,
and methemoglobinemia. He developed severe acute hemolytic anemia. A deficiency in
glucose-6-phosphate dehydrogenase (G6PD) was suspected as the mechanism of the hemolytic
episode due to the oxidant effect of methyl mercaptan. Despite medical intervention, the
patient's condition deteriorated and he died 28 days after accidental exposure. Autopsy
determined the cause of death was due to a massive embolus which occluded both main
pulmonary arteries. Bilateral polycystic kidneys were found. No gross or microscopic
abnormalities were seen in the brain.
A Romanian refinery worker inhaled an unknown amount of methyl mercaptan that
rendered him unconscious for 9 hours (Cristescu, 1941). The worker was not reported dyspneic,
but was cyanotic and experienced convulsions. Hemoglobin value and red cell count were
normal, but a determination for methemoglobin was not indicated in this report. Ten days later,
the patient was hospitalized for a lung abscess from which he recovered.
Mixed exposures to methyl mercaptan and other sulfur compounds, including ethyl
mercaptan, dimethyl sulfide and acrylonitrile, have occurred in industrial accidents (Allied
Chemical Corp., 1978; Syntex Corp., 1979). In two separate accidents, a total of four workers
were found unconscious after exposure to such a mixture occurred in the work area of a chemical
plant. In one accident, a worker was found unconscious and later died after a gas mixture
containing in excess of 10,000 ppm of methyl mercaptan was emitted from a pipe into his work
area (Syntex Corp., 1979). Autopsy indicated that the immediate cause of death was acute
congestive heart failure (this worker had a pre-existing heart condition). In a second accident,
three workers recovered after being found unconscious, although one developed pulmonary
edema (Allied Chemical Corp., 1978). The workers in the second accident did not report any
odor and did not experience symptoms of eye, nose, or throat irritation (they were wearing
goggles that may have protected against eye irritation).
Garrettson and Warren (1990) described the adverse effects of exposure to intermittent
high levels of methyl mercaptan in a 59-year-old plumber's helper who had pumped 3 school
kitchen grease traps daily for 3 weeks, 3 times a year, for 15 years via septic tank pumping rig
and manual stirring, without using respiratory protection. Symptoms while on the job included a
throbbing headache that intensified over that work day and waned over the following 3-4 day
4

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12-20-04
period, nausea and vomiting, eye irritation, tightness in chest, wheezing, dizziness and double
vision to the extent that it impaired his ability to drive and delayed him 1 to 2 hours prior to
driving to the next site. After 10 years, the worker developed a limited pulmonary reserve and
productive cough. His FVC and FEVj presumably after 15 years, were 72% and 77% of
predicted. The pump exhaust discharged near the cab was found to contain high levels of a
substance "comparable with" methyl mercaptan. High concentrations of methyl mercaptan and
lower levels of ethyl mercaptan were identified by GC-CS analysis of material from the traps at
several sites.
The information that can be obtained for epidemiological studies regarding methyl
mercaptan yield only limited information. This is due to the fact that under most situations,
exposure occured to a mixture of chemicals. No good exposure assessments were available and
information on potentially adverse health effects relied mostly on self-reported symptoms. Most
of the studies focused on workers in the paper pulp industry or on populations located near pulp
mills, exposed to several sulfur compounds, including hydrogen sulfide, methyl mercaptan,
dimethyl sulfide, dimethyl disulfide, and sulfur dioxide. Increases in headaches in workers
(Kangas et al., 1984), changes in heme synthesis or iron metabolism in workers (Klingberg et al.,
1988; Tenhunen et al., 1983), and eye and respiratory symptoms reported by residents of
communities located near the paper pulp mills (Jaakkola et al., 1990; Martillaet al., 1995; Partti-
Pellinen et al., 1996) were attributed to exposure to the sulfur compound mixtures (described
above). An increase in respiratory infections was reported in children exposed to sulfur
compounds from pulp plants and to oxides of nitrogen released from a chemical plant (Jaakkola
et al., 1991). Studies of respiratory endpoints in pulp mill workers, however, found decrements
only in the workers exposed to chlorine during the bleach process of production (Enarson and
Yeung, 1985; Kennedy et al., 1991).
Animal Studies
No chronic inhalation studies for methyl mercaptan were located. Two subchronic
studies are available; one continuous inhalation study examining the effects of methyl mercaptan
exposure in monkeys, rats, and mice and one intermittent exposure toxicity study in rats. Several
acute inhalation exposure studies are also available.
An LC50 of 675 ppm (1328 mg/m3) for methyl mercaptan was determined in male and
female Sprague-Dawley rats exposed for 4 hours (Tansy et al., 1980, 1981). Rats that survived
the first 24 hours post-exposure survived the full 14-day observation period. There was no
evidence of bleeding from any orifice of exposed animals; no other endpoints were indicated. An
LC50 of 1680 ppm was reported for a 1-hour exposure in rats (ELF Atochem, 1977). Mice appear
to be somewhat less sensitive to methyl mercaptan lethality than rats. A 4-hour LC50 of 1664
ppm was reported in this species (Horiguchi, 1960).
5

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Other acute inhalation studies examined endpoints in addition to lethality. Zieve et al.
(1974) reported that rats (3-5/group) exposed to 2000 ppm of methyl mercaptan became
comatose, but coma was not induced in any of the rats exposed to 1200 ppm for up to 15
minutes. Ljunggren andNorberg (1943) exposed rats (1 female per group) to levels of methyl
mercaptan ranging from 500 to 10,000 ppm for 30-35 minutes, followed by a 24-hour
observation period. No overt effects were seen at 500 ppm, signs of fatigue were observed at 700
ppm, prostration and trembling were observed at 1500 ppm, and death occurred at 10,000 ppm
after 14 minutes. Microscopic examination revealed pulmonary edema in the rats exposed to
1500 and 10,000 ppm. Male rats exposed to methyl mercaptan at 250 to 500 ppm for 4-hour
periods exhibited clinical signs of irritation of the eyes and nose and at autopsy showed
pulmonary congestion and edema (Haskell Laboratory, n.d.). In subacute inhalation studies, ten
6-hour exposures at 100 ppm were not lethal, but similar exposure to 200 ppm resulted in death
to 1 of 4 rats in each of two experiments. At necropsy, rats that had died during the exposure or
were killed at the end of the study were found to have pneumonia, but there were no controls
with which to compare. The authors concluded that the pathological changes were suggestive of
an irritant effect of methyl mercaptan, which could have predisposed the animals to a pneumonia
infection (Haskell Laboratory, n.d.).
A 2-month intermittent inhalation exposure study of a relatively high concentration of
methyl mercaptan was conducted in mice by Horiguchi (1960). In this study, 11 male white mice
were exposed to 300 ppm of methyl mercaptan for 2 hours/day, 3 days/week, for up to 2 months.
Six mice died after 15 exposures, and all the remaining mice were dead after 25 exposures.
Additional details were not available.
A 3-month intermittent inhalation study of methyl mercaptan in young adult male Charles
River Sprague-Dawley rats was conducted by Tansy and coworkers (Tansy et al., 1980, 1981).
Groups of 31 rats were exposed to 0, 2, 17 or 57 ppm (0, 4, 33 or 112 mg/m3) ofmethyl
mercaptan, 7 hours/day, 5 days/week for 3 months. The rats from the 0 and 57 ppm exposure
groups were selected from a different shipment of rats than the rats from the 2 or 17 ppm
exposure groups. Observations made on all animals included: oxygen consumption, blood
clinical chemistry, organ weights, and complete histopathological liver examinations. Ten
rats/group were observed for metabolic performance and systolic blood pressure, and 5 rats/group
were subjected to histopathological examination of the heart, lungs, small intestine, and kidneys.
Little evidence of toxicity was seen in the study (Tansy et al., 1980, 1981). No deaths
occurred. During the exposures to 57 ppm, the rats huddled in small groups toward the periphery
of the chamber with noses pointed outward. This behavior did not occur in the sham exposures:
it is unclear whether and to what extent it may have occurred in the 2 or 17 ppm groups. Time
courses of weight-normalized metabolic parameters were analyzed by regression analysis.
Results indicate that rates of change in food intake and in wet and dry fecal weight increases
were not affected. Other metabolic performance parameters were statistically significantly
6

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different in the 2 and 17 ppm groups, but not the 57 ppm exposure group, as compared to
controls (i.e., fecal pellet count increases and water intake rate increases were lower and urine
output increases were higher in the 2 and 17 ppm groups). There were no significant differences
in intestinal transit parameters. The mean terminal body weights of the exposed groups were
depressed; the weights were statistically significantly different from controls at the 57 ppm level
(-15% lower) and showed a statistically significant dose-related trend. Similar results were seen
for the average rates of body weight gain for the subset groups, as determined by regression
analysis. Some statistically significant (but small) differences in mean organ weights were seen,
but there was no dose-related trend and the investigators suggested that the precision of organ
removal was such that these differences may not have been biologically significant. No
consistent patterns were found for systolic blood pressure and no consistent statistically
significant differences were found for oxygen consumption (data not provided). Some
statistically significant differences between treated and control groups were seen in the clinical
chemistry findings, but none of these demonstrated a statistically significant dose-related trend.
Total serum proteins were similar in all three exposed groups and significantly higher than in
controls. Serum albumin levels were similar in the three exposed groups and significantly lower
than in controls. Lactate dehydrogenase (LDH) activities were lower in the exposed groups than
in the control groups. Increases in serum bilirubin were seen in the 2 and 17 ppm groups, but not
the 57 ppm group, as compared to controls. Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) activities were similar in all groups.
Histological evidence of liver involvement was reported, but the report does not explicitly
describe the liver histology of controls (Tansy et al., 1980, 1981). The investigators stated that
the pathologist could not predict whether a liver sample was from an exposed or control rat on a
blind basis, indicating that differences between liver histology in exposed and control rats were
negligible. Hyperplastic nodules were found in livers of a few rats from the control-, 2-, and 57-
ppm-groups and a hepatic carcinoma was found in a liver from a 17-ppm rat; these findings,
while not associated with exposure, were unexpected in rats of this age. Evidence of pneumonia,
emphysematic changes, and occasional fibrosis were seen in the lungs of rats from all groups,
including the control group. Actual incidences of histopathological effects were not reported.
The results of the study by Tansy et al. (1980, 1981) suggest that 7 ppm (33 mg/m3) is a
NOAEL and 57 ppm (112 mg/m3) is a LOAEL for body-weight-depression in male rats exposed
subchronically to methyl mercaptan for 7 hours/day, 5 days/week.
In a continuous inhalation exposure study, 10 male rhesus monkeys, 50 male Sprague-
Dawley rats, and 100 male Porten-Woods mice were exposed to methyl mercaptan at 50 ppm (98
mg/m3) (as part of a mixture of indole, skatole, hydrogen sulfide, and methyl mercaptan) while
housed in cages located in a large exposure chamber for 90 days (Sandage, 1961). Controls were
housed in the room that contained the exposure chamber. Endpoints included: hematology,
blood chemistry and urinalysis in all species, liver function tests in monkeys, stress tests
7

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(swimming) in 50% of the surviving animals, and necropsy and histopathological examinations
of major organs in all monkeys and in 25% of the surviving rats and mice.
Although the experimental protocol and the findings of the study are described only in
very broad terms, it appears that some of the rats and mice that died during the exposure period
were necropsied and examined histopathologically (Sandage, 1961). This study included groups
exposed to three other chemicals or to a mixture. The reporting of the data was relatively
nonspecific, with little tabulation of the numerical data, so that meaningful comparisons between
methyl mercaptan-exposed and control animals are possible only for mortality. For example, the
pathology data were reported in a summary table as per cent of necropsied animals having any
gross or microscopic pathology findings in each organ examined (heart, lung, liver, kidneys,
brain), with no indication of the specific lesions or their incidences. Some sporadic discussion of
specific findings is presented in the text, but the discussion by the author is frequently
inconsistent with the comments of the pathologist, which are included in the report.
For methyl mercap tan, the data presentation (in Sandage, 1961) is insufficient to support
any independent conclusions. Terminal body weights were lower in monkeys and unaffected in
rats and mice compared statistically to those in controls (data not presented). Increased mortality
was seen in the exposed groups (4/10 monkeys, 5/50 rats, 43/100 mice) as compared to controls
(0/9 monkeys, 2/50 rats, 16/100 mice), and was significantly different from controls in the
monkeys and mice. According to the author, the above tests and examinations did not reveal a
probable cause for the mortality in monkeys exposed to methyl mercaptan. Rather, the results
were said to be similar to those for a group of monkeys exposed to hydrogen sulfide (20 ppm), in
which there were no deaths. The pathologist's comments mention a mild-to-moderate edema in
the lungs of 12 of the 14 monkeys that died during the exposure to any of the tested chemicals or
the mixture, but do not specifically discuss findings for methyl mercaptan. In addition, the
pathologist mentions that many of the surviving monkeys had recent mild inflammation of the
lungs, probably resulting from the swimming test (i.e., not chemical-related). The pathology data
table does not differentiate between these conditions, and shows a 40% occurrence of lung
pathology in control monkeys, all of which survived.
The author ascribed the increased mortality in methyl mercaptan-exposed mice to
hepatitis, whereas the pathologist's comments (included in the report) stated that "most of the
mice and rats were normal, except for the persistent hepatitis in mice," a statement that does not
seem to ascribe that lethality was significantly associated with hepatitis (Sandage, 1961). In
addition, the pathologist noted that there was "some hepatitis" in the controls. The author stated
that, in rats, methyl mercaptan perhaps was associated with lung damage: 16% in exposed versus
0% in controls. These incidences are unlikely to be statistically significantly different, because
the number of exposed rats examined histopathologically is approximately 16 (5 that died during
exposure plus 25% of the surviving 45), so the number with lung effects may have been only 2 or
3; similarly, the number of controls examined was probably approximately 14. In addition, the
8

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12-20-04
pathologist's comments do not include any mention of adverse lung effects in the rats exposed to
methyl mercaptan.
The hematological tests revealed some statistically significant differences in red cell
parameters in rats and mice exposed to methyl mercaptan, but the actual data were not presented
(Sandage, 1961). The author considered the results indicative of an adverse effect in these
species. Performance of the methyl mercaptan-exposed groups in the swim test was better in
monkeys, not different in rats, and worse in mice, as compared statistically with performance in
controls (data not shown).
The deficiencies in experimental design and the reporting of results in the study by
Sandage (1961) compromise a quality assessment for inhalation toxicity of methyl mercaptan in
the exposed animals. It appears that the animals tested were exposed to a mixture of gases, from
which severity of effects could not be attributed exclusively to methyl mercaptan. Although the
reported results seem to indicate that rats maybe less sensitive than monkeys or mice to
continuous exposure at 50 ppm methyl mercaptan, confidence in this study is very low, and the
results from a single exposure level are not necessarily predictive of a dose-response at lower
exposure levels.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfCs FOR METHYL MERCAPTAN
The inhalation data base for methyl mercaptan is inadequate for p-RfC derivation. Two
subchronic inhalation studies are available, but were of inadequate design for use in derivation of
provisional toxicity values. The minimal database requirement for derivation of an RfC is a
well-conducted subchronic inhalation bioassay that evaluated a comprehensive array of
endpoints, including adequate evaluation of the respiratory tract, and established an unequivocal
NOAEL and LOAEL (U.S. EPA, 1994b).
The 90-day continuous inhalation exposure study (Sandage, 1961) exposed monkeys,
mice, and rats to a mixture that included methyl mercaptan; determination of adverse effects by a
single chemical component was not possible.
The subchronic inhalation study in rats by Tansy et al. (1980, 1981) resulted in body
weight depression in male rats exposed to methyl mercaptan 7 hours/day, 5 days/week, for 3
months. No clear evidence of other adverse effects was observed in this study. The study has
several limitations that preclude its use as a basis for RfC derivation. Histopathological
examinations were performed on a limited number of organs in a small subset of the animals;
reporting of these results was not comprehensive. Evidence of pneumonia, emphysematic
changes, and occasional fibrosis were seen in the lungs in the subset of rats examined from all
9

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12-20-04
groups, including the control group. The upper respiratory tract of the exposed animals was not
evaluated and actual incidences of histopathological effects were not reported. Animals in two of
the exposure groups were from a different shipment than animals from the other exposure
groups, lowering confidence in the overall experimental design and results.
In conclusion, the lack of adequate chronic or subchronic inhalation data for humans or
animals precludes derivation of a subchronic or chronic p-RfC for methyl mercaptan.
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Cristescu, V. 1941. A case of poisoning with mercaptan. Med. Bull. Standard Oil Co., N.J. 5:
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Garrettson, L.K. and D.A. Warren. 1990. Chronic methanethiol poisoning. American
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Haskell Laboratory, n.d. Toxicity of methyl mercaptan. Medical Research Project No. MR-287.
Submitted by Dupont Chemical in 1992 to EPA under TSCA 8E. OTS Fiche #: OTS0571484.
Hiele, M., Y. Ghoos, P. Rutgeerts et al. 1991. Influence of nutritional substrates on the
formation of volatiles by the fecal flora. Gastroenterology. 100(6): 1597-1602.
Horiguchi, M.J. 1960. [An experimental study on the toxicity of methylmercaptan in
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Am. Rev. Respir. Dis. 142(6 Pt 1): 1344-1350.
Jaakkola, J.J., M. Paunio, M. Virtanen and O.P. Heinonen. 1991. Low-level air pollution and
upper respiratory infections in children. Am. J. Pub. Health. 81(8): 1060-1063.
Kangas, J., P. Jappinen and H. Savolainen. 1984. Exposure to hydrogen sulfide, mercaptans and
sulfur dioxide in pulp industry. Am. Ind. Hyg. Assoc. J. 45(12): 787-790.
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Kennedy, S.M., D.A. Enarson, R.G. Janssen and M. Chan-Yeung. 1991. Lung health
consequences of reported accidental chlorine gas exposures among pulpmill workers. Am. Rev.
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Key, M.M., A.F. Henschel, J. Butler et al. 1977. Occupational diseases: A guide to their
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Klingberg, J., A. Beviz, C-G. Ohlson and R. Tenhunen. 1988. Disturbed iron metabolism
among workers exposed to organic sulfides in a pulp plant. Scan. J. Work Environ. Health.
14(1): 17-20.
Ljunggren, G. and B. Norberg. 1943. On the effect and toxicity of dimethyl sulfide, dimethyl
disulfide, and methyl mercaptan. Acta Physiol. Scand. 5:248-255.
Martilla, O., J. Jaakkola, K. Partti-Pellinen et al. 1995. South Karelia air pollution study: Daily
symptom intensity in relation to exposure levels of malodorous sulfur compounds from pulp
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NIOSH (National Institute for Occupational Safety and Health). 2003. NIOSH Pocket Guide to
Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/npgd0000.html#F
NTP (National Toxicology Program). 2003. Management Status Report. Online.
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OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910.1000
TableZ-1. Part Z, Toxic and Hazardous Substances. Online.
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Partti-Pellinen, K, O. Marttila, V. Vilkka et al. 1996. The South Karelia air pollution study:
Effects of low-level exposure to malodorous sulfur compounds on symptoms. Arch. Environ.
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Rose, V.E. 1983. Thiols. Encyclopedia of Occupational Health and Safety. 2:2172-2173.
Sandage, C. 1961. Tolerance criteria for continuous inhalation exposure to toxic material. II.
Effects on animals of 90-day exposure to phenol, CC14, and a mixture of indole, skatole, H2S, and
methyl mercaptan. ASD Technical Report 61-519 (II), Biomedical Laboratory, Wright-Patterson
Air Force Base, OH. NTIS AD-287-797.
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Shertzer, H.G. 2001. Organic Sulfur Compounds. Methyl Mercaptan. In: Patty's Toxicology,
Fifth edition. Vol. 7. E. Bingham, B. Cohrssen and C.H. Powell, Ed. John Wiley & Sons, NY.
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Santodonato, J., S. Bosch, W. Meylan et al. 1985. Monograph on human exposure to chemicals
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Sinki, G.S. and W.A. Schlegel. 1990. Flavoring agents. In: Food Science and Technology, Vol.
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York. p. 195-258.
Shults, W.T., E.N. Fountain and E.C. Lynch. 1970. Methanethiol poisoning: Irreversible coma
and hemolytic anemia following inhalation. J. Am. Med. Assoc. 211: 2153-2154.
Syntex Corporation. 1979. Summary of accident report on methyl mercap tan fatality with cover
letter. Produced 05/15/79. U.S. EPA OPTS Fiche #: OTS0000032-0. Doc#:FYI-AX-0579-
0032.
Tangerman, A., M.T. Meuwese-Arends and J.B. Jansen. 1994. Cause and composition of foetor
hepaticus (letter). Lancet. 343(8895): 483.
Tansy, M.F., R.M. Kendall, J. Fantasia et al. 1980. Acute and subchronic toxicity studies of rats
exposed to vapors of methyl mercap tan and other reduced sulfur compounds. RYO Submission
FYI-OTS-0680-0080 by the American Paper Institute. OTS Fiche # OTS000080-0.
Tansy, M.F., F.M. Kendall, J. Fantasia et al. 1981. Acute and subchronic toxicity studies of rats
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Environ. Health. 8(1-2): 71-88.
Tenhunen, R., H. Savolainen and P. Jappinen. 1983. Changes in haem synthesis associated with
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Environmental Assessment, Washington, DC. April.
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Environmental Assessment, Washington, DC. December.
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U.S. EPA. 1994b. Methods of Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry. Office of Research and Development, Washington, DC.
October 1994. EPA/600/8-90/066F.
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Zieve, L., W.M. Doizaki and F.J. Zieve. 1974. Synergism between mercaptans and ammonia or
fatty acids in the production of coma: A possible role for mercaptans in the pathogenesis of
hepatic coma. J. Lab. Clin. Med. 83: 16-28.
Zieve, L. 1981. The mechanism of hepatic coma. Hepatology. 1:360-365.
Zieve, L., W.M. Doizaki and C. Hyftogt. 1984. Brain methanethiol and ammonia concentrations
in experimental hepatid coma and coma induced by injections of various combinations of these
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Provisional Peer Reviewed Toxicity Values for
Methyl Mercaptan
(CASRN 74-93-1)
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

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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

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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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12-20-04
PROVISIONAL PEER REVIEWED TOXICITY VALUE FOR
METHYL MERCAPTAN (CASRN 74-93-1)
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 to OSRTI.
INTRODUCTION
A carcinogenicity assessment for methyl mercaptan is not available on IRIS (U.S. EPA,
2003), the HEAST (U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories
list (U.S. EPA, 2002). No relevant documents were located in the CARA list (U.S. EPA, 1991,
1994). NTP (2003), IARC (2003), and WHO (2003) have not produced documents for this
chemical. Review documents by ATSDR (1992), Shertzer (2001), and Santodonato (1985) were
consulted. Literature searches of the following databases were conducted from 1965 through
June 2003 in order to locate relevant studies: TOXLINE (supplemented with BIO SIS and NTIS
updates), CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK,
EMIC/EMICBACK, RTECS and TSCATS. Additional literature searches from June 2003
through October 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE,
Chemical and Biological Abstracts databases.
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Methyl mercaptan (CH3SH, MW = 48.11) is a gas with a strong unpleasant odor of
rotting cabbage (Budavari, 2001). Natural sources of methyl mercaptan include vegetation,
animal waste, microbial degradation, crude oils containing sulfur, and the "sour" natural gas of
West Texas (ATSDR, 1992; Budavari, 2001; Rose, 1983; Santodonato et al., 1985). Industrial
sources include wood pulp, oil shale, petroleum processing plants, and sewage treatment plants
(ATSDR, 1992). Although some other mercaptans are used as odorants in natural and liquified
petroleum gas or in commercial, industrial, and residential natural gas; methyl mercaptan is not
used for this purpose (ATSDR, 1992; Cain and Turk, 1985; Shertzer, 2001; Santodonato et al.,
1985).
Methyl mercaptan occurs in foods (onion, garlic, meat, bread, fish), sometimes as a result
of microbial activity (Shertzer, 2001; Sinki and Schlegel, 1990; Budavari, 2001). It is approved
for use as a food additive (synthetic flavoring agent) by the FDA [21 CFR 172.515] (U.S. FDA,
2003).
Methyl mercaptan is produced endogenously in mammals during metabolism of
methionine and related substances (Blom et al., 1988, 1989; Al Mardini et al., 1984; Shertzer,
2001), and by bacteria in the mammalian gut and mouth (Budavari, 2001; De Boever et al., 1994;
Hiele et al., 1991; Yaegaki and Suetaka, 1992a,b). High levels of methyl mercaptan have been
detected in the breath and urine of some patients with advanced liver disease (Shertzer, 2001;
Tangerman et al, 1994). A number of studies and reviews explored the possibility that methyl
mercaptan may play a role in the pathogenesis of encephalopathy resulting from hepatic failure
(Al Mardini et al., 1984; Blom et al., 1988, 1989; Zieve, 1981; Zieve et al., 1974, 1984). These
authors concluded that methyl mercaptan may interact (mechanism unknown) with ammonia and
fatty acids to possibly exacerbate the encephalopathy in human hepatic failure.
REVIEW OF THE PERTINENT DATA
Human Studies
No data regarding the possible carcinogenicity of methyl mercaptan in humans were
located.
Animal Studies
No animal studies examining the carcinogenicity of methyl mercaptan by any route of
exposure were located.
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Other Studies
Methyl mercaptan was mutagenic in an in vivo assay in Drosophila melanogaster (Garrett
and Fuerst, 1974) and elicited a weak positive response in a bone marrow micronucleus assay
conducted by inhalation exposure in mice (ELF Atochem, 1996, 1997).
PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION
No studies examining the carcinogenic potential of methyl mercaptan in humans or
animals were located. Available genotoxicity data are positive, but limited to only two assays.
The available data are insufficient to assess carcinogenic potential in animals or humans as
specified by the proposed U.S. EPA (1999) Guidelines for Carcinogen Risk Assessment.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Derivation of quantitative estimates of cancer risk for methyl mercaptan is precluded by
the lack of data to assess carcinogenicity associated with methyl mercaptan exposure.
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mercaptans in hepatic and methanethiol induced coma. Gut. 25(3): 284-290.
ATSDR (Agency for Toxic Substances and Disease Registry). 1992. Toxicological Profile for
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Atlanta, GA. PB93/110799/AS. Online, http://www.atsdr.cdc.gov/toxprofiles/tpl39.html
Blom, H.J., J.P. van den Elzen, S.H. Yap, and A. Tangerman. 1988. Methanethiol and
dimethylsulfide formation from 3-methylthiopropionate in human and rat hepatocytes. Biochim.
Biophys. Acta. 972(2): 131-136.
Blom, H.J., G.H. Boers, J.P. van den Elzen et al. 1989. Transamination of methionine in
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Budavari, S. 2001. The Merck Index. Thirteenth Edition. Merck & Co. Inc., Whitehouse
Station, NJ. p. 1091.
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Cain, W.S. and A. Turk. 1985. Smell of danger: An analysis of LP-gas odorization. Am. Ind.
Hyg. Assoc. J. 46 (3): 115-126.
De Boever, E.H., M. De Uzeda, and W.J. Loesche. 1994. Relationship between volatile sulfur
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Female Swiss-Webster Mice Following Acute Nose-Only Inhalation Exposure to Methyl
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Garrett, S. and R. Fuerst. 1974. Sex-linked mutations in Drosophila after exposure to various
mixtures of gas atmospheres. Environ. Res. 7:286-93.
Hiele, M., Y. Ghoos, P. Rutgeerts et al. 1991. Influence of nutritional substrates on the
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Rose, V.E. 1983. Thiols. Encyclo. Occup. Health Saf. 2:2172-2173.
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Santodonato, J., S. Bosch, W. Meylan et al. 1985. Monograph on human exposure to chemicals
in the workplace: Mercaptans. Center for Chemical Hazard Assessment, Syracuse Research
Corporation, Syracuse, New York. SRC-TR-85-187.
Sinki, G.S. and W.A. Schlegel. 1990. Flavoring agents. In: Food Science and Technology, Vol.
35, Food Additives, A.L. Branen, P.M. Davidson, and S. Salminen, Ed. Marcel Dekker, New
York. p. 195-258.
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Tangerman, A., M.T. Meuwese-Arends and J.B. Jansen. 1994. Cause and composition of foetor
hepaticus (letter). Lancet. 343(8895): 483.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
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U.S. EPA. 1999. Proposed Guidelines for Cancer Risk Assessment. July 1999. Office of
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U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
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http://www.epa. gov/waterscience/drinking/ standards/dwstandards .pdf
U.S. EPA. 2003. 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. FDA. 2003. Code of Federal Regulations. Title 21 Food and Drugs. 21 CFR.172.515.
Department of Health and Human Services, Washington, DC. Online.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?FR=172.515
WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria
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Yaegaki, K. and K. Sanada. 1992a. Volatile sulfur compounds in mouth air from clinically
healthy subjects and patients with periodontal disease. J. Period. Res. 27(4 Pt 1): 233-238.
Yaegaki, K. and K. Sanada. 1992b. Biochemical and clinical factors influencing oral malodor in
periodontal patients. J. Periodont. 63(9): 783-789.
Zieve, L., W.M. Doizaki, and F.J. Zieve. 1974. Synergism between mercaptans and ammonia or
fatty acids in the production of coma: A possible role for mercaptans in the pathogenesis of
hepatic coma. J. Lab. Clin. Med. 83: 16-28.
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Zieve, L. 1981. The mechanism of hepatic coma. Hepatology. 1:360-365.
Zieve, L., W.M. Doizaki, and C. Hyftogt. 1984. Brain methanethiol and ammonia
concentrations in experimental hepatid coma and coma induced by injections of various
combinations of these substances. J. Lab. Clin. Med. 104(5): 655-664.
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