CARBON DISULFIDE
CAS number: 75-15-0
Synonyms: Carbon disulphide, Carbon bisulfide, Carbon bisulphide, Carbon bisulfur,
Dithiocarbonic anhydride, Carbon sulfide, Sulphocarbonic anhydride,
Weeviltox®
Molecular formula: CS2
RECOMMENDED BEI®
Determinant Sampling Time
2-Thioxothiazolidine-4-carboxylic End of shift
acid (TTCA) in urine
Basis for the Biological Exposure Index
The adverse health effect observed in occu-
pationally exposed workers is a reduction in
conduction velocity in the motor and sensory nerves
above carbon disulfide concentrations of 1 ppm
(3.13 mg/m3). The recommended BEI® of 0.5 mg
TTCA/g creatinine is based on the adopted TLV® of
1 ppm carbon disulfide. The TLV is intended to
protect workers from observed adverse health
effects caused by carbon disulfide exposure. The
TLV is based primarily on neurological endpoints,
but all other organ systems, including cardio-
vascular, reproductive, ophthalmologic, and renal,
would also be protected from adverse effects
caused by carbon disulfide exposure. Dithio-
carbamates are the metabolites of carbon disulfide
formed after reaction with amino acids, and these
metabolites contribute, in part, to the neurotoxic
effects of carbon disulfide. A satisfactory correlation
between airborne carbon disulfide exposure and an
end of shift urinary 2-thioxothiazolidine-4-carboxylic
acid (TTCA) concentration has been observed.
Urinary excretion of TTCA has been observed to be
biphasic (with half-lives of about 6 h and 68 h) at
mean airborne carbon disulfide concentration of 3
ppm, and moderate accumulation may occur
towards the end of the workweek with repeated
exposure. The observed average background level
of 0.09 mg TTCA/g creatinine in non-occupationally
exposed individuals is about 20% of the proposed
BEI value of 0.5 mg TTCA/g creatinine. Therefore,
exposure from non-occupational sources (e.g., diet)
may have an impact, and the BEI has been
assigned a “B” notation. Exposure to substances,
which can be metabolized to carbon disulfide (e.g.,
pesticide Captan, the anti-alcoholic drug disulfiram
(antabuse, tetraethylthiuram disulfide), some rubber
accelerators, and dithiocarbamates, may result in
the appearance of carbon disulfide and its
ACGIH® © 2009
BEI® Notation
0.5 mg/g Ns, B
creatinine
metabolites in the body and excreta. Therefore,
TTCA is not a specific indicator of carbon disulfide
exposure and an “Ns” or “nonspecific” notation is
assigned.
Conversion Factors
Carbon disulfide
1 mg/L = 0.013 mmol/L; 1 mmol/L = 76.1 mg/L
2-Thioxothiazolidine-4-carboxylic acid (TTCA)
1 mg/g creatinine = 0.70 mmol/mol creatinine
1 mmol/mol creatinine = 1.4 mg/g creatinine
1 mg/L = 6 μmol/L
1 mmol/L = 163 mg/L
Uses and Properties
Carbon disulfide is a clear, colorless to yellow
liquid at room temperature. Pure carbon disulfide
has a sweet odor resembling chloroform, while
technical grade has a strong, unpleasant hydrogen
sulfide odor (ATSDR, 1996). The saturated vapor
pressure is 297 torr at 20°C (39.6 kPa) (ATSDR,
1996). It is highly soluble in blood and fat and
moderately soluble in water (2.3 g/L at 22°C)
(ATSDR, 1996). Its blood/gas partition coefficient is
2.4 (Ghittori et al., 1998) and the octanol/water
partition coefficient (log Pow) is approximately 2
(range 1.84–2.16) (ATSDR, 1996).
Worldwide production of carbon disulfide is
estimated to be one million tons (Newhook and
Meek, 2002). The principal industrial uses of carbon
disulfide are the manufacture of viscose rayon,
cellophane film, carbon tetrachloride, xantho-
genates, sodium sulfite, mercaptans, thioureas,
mineral flotation agents, rubber chemicals, dyes,
and pesticides as well as to solubilize waxes and
oils, resins, rubbers, phosphorous, sulfur mono-
Carbon disulfide BEI® – 1
chloride, selenium, bromine, and iodine (ATSDR,
1996; Newhook and Meek, 2002). Carbon disulfide
is also used in preservation of fresh fruit, in adhesive
composition for food packaging, in solvent extraction
of growth inhibitors, and as a soil fumigant against
insects and nematodes (ATSDR, 1996; NSC, 2007).
NIOSH has estimated that approximately 46,000
workers are exposed to carbon disulfide in the U.S.
(NIOSH, 2007). However, the actual number may be
significantly higher, since the survey did not include
worker exposures to chemicals that may contain
carbon disulfide.
Possible Non-occupational Exposure
Ambient air is the major source for exposure in
general population. Carbon disulfide is produced
and released to the environment from natural
sources (e.g., soil and sediment microorganisms,
vegetation, forest and grass fires, and volcanoes)
and has been detected in air, water, sediment, and
soil (Newhook and Meek, 2002). It is also produced
during metabolism of some pesticides, such as
dithiocarbamates in plants and soil. Carbon disulfide
is released into the environment in cigarette smoke
(Horton and Guerin, 1974). Between 2002 and 2004,
an average 27 million pounds per year of carbon
disulfide were released into the environment as point
source air emissions from manufacturing and
processing facilities in the U.S. (U.S. EPA, 2006).
The highest ambient air concentrations (up to 156
μg/m3) have been measured near industrial sources,
particularly near natural gas processing plants and
sites with sulfur-containing natural gas flares (Legge
et al., 1990a, b). Outdoor concentrations of carbon
disulfide have been measured up to 1.1 μg/m3 and
1.2 μg/m3 in the U.S. and Europe, respectively
(ATSDR, 1996; Maroulis and Bandy, 1980; Phillips,
1992; Sandalls and Penkett, 1977).
In air, carbon disulfide has a half-life of 1–2
weeks and it is removed from air primarily by
reaction with hydroxy radicals (Wine et al., 1981). It
is rapidly metabolized by organisms and does not
bioconcentrate or biomagnify (Beauchamp et al.,
1983). Exposure to substances that can be
metabolized to carbon disulfide, such as the
pesticide Captan (Krieger and Thongsinthusak,
1993; van Welie et al., 1991), the anti-alcoholic drug
disulfiram (antabuse), some rubber accelerators,
and dithiocarbamates (e.g., Thiram [tetramethyl-
thiuram disulfide]) may result in the appearance of
carbon disulfide and its metabolites in the body and
excreta (van Doorn et al., 1982).
Simon and colleagues observed an average
background level of 0.09 mg TTCA/g creatinine in
non-occupationally exposed individuals (Simon et
al., 1994). This value is about 20% of the proposed
BEI value of 0.5 mg TTCA/g creatinine. Therefore,
interpretation of the measurement of urinary TTCA in
workers occupationally exposed to carbon disulfide
may be confounded by other exposure sources.
2 — Carbon Disulfide BEI®
Absorption
Carbon disulfide is extensively absorbed via
inhalation, dermal, and oral routes. Absorbed carbon
disulfide is distributed throughout the body, particu-
larly into lipophilic tissues and organs, such as liver
and brain. Carbon disulfide is readily soluble in lipids
and also has affinity for amino acids and proteins.
Thus, it has a potential to accumulate in the body.
Pulmonary
A rapid and extensive absorption of inhaled
carbon disulfide has been observed in humans.
Pulmonary retention at the start of exposure is about
80% and declines steadily, reaching a plateau of
about 45% of the inhaled concentration within one
hour (Beauchamp et al., 1983; Harashima and
Masuda, 1962; Petrovic and Duric, 1966; WHO,
1979).
Dermal
Carbon disulfide is readily absorbed through
human skin. The penetration rate measured in
volunteers immersing a hand for one hour in an
aqueous solution containing 0.33–1.67 g of carbon
disulfide per liter varied between 0.23 and 0.79
mg/cm2/h (Dutkiewicz and Baranowska, 1967).
Higher absorption was indicated in earlier invest-
igations (Baranowska, 1965). The physical and
chemical properties also predict a significant dermal
absorption (penetration rate 0.89 mg/cm2/h) (see
Dermal Absorption in the “Introduction to the
BEIs®”). Extensive dermal absorption of vapor and
liquid carbon disulfide was observed in experimental
animal studies (Cohen et al., 1958; Izmerov, 1983).
Available evidence suggests that percutaneous
absorption may add to the adverse effects induced
by inhalation exposure (Grandjean, 1990).
Gastrointestinal
No human studies were found regarding oral
exposure to carbon disulfide. However, based on a
study of intragastric administration of 10 mg/kg 14C-
carbon disulfide in rats (De Matteis and Seawright,
1973), gastrointestinal absorption is expected to be
rapid.
Elimination
Lungs are the primary excretory pathway of
unmetabolized carbon disulfide, whereas filtration in
the kidneys is the primary route of excretion of the
metabolites. Of the total uptake of carbon disulfide,
5–30% is eliminated unchanged in the breath
(Djuric, 1967; Petrovic and Duric, 1966; WHO, 1979)
and less than 1% is excreted unchanged in urine
(Djuric, 1967; Harashima and Masuda, 1962), while
70–90% is excreted as metabolites (Djuric, 1967;
Riihimäki et al., 1992). About 3% of the amount
absorbed via skin was found in breath of volunteers
exposing their hands to aqueous solutions of carbon
ACGIH® © 2009
disulfide (Dutkiewicz and Baranowska, 1967).
Pulmonary elimination of carbon disulfide was
observed to be fast with a half-life of about 10
minutes (Harashima and Masuda, 1962). A biphasic
elimination with half-lives of 1 minute and 110
minutes has also been observed (Rosier et al.,
1987). However, carbon disulfide was found in the
breath of workers 16 hours after the end of high
exposure, but the breath carbon disulfide
concentrations did not correlate with blood carbon
disulfide levels (Campbell et al., 1985). Small
amounts of carbon disulfide are excreted in saliva
and sweat and through the skin of exposed
individuals (Merlevede and Casier, 1961). Excretion
in feces is negligible (< 1%) (Harashima and
Masuda, 1962).
Carbon disulfide is present in blood in both a
free and bound form (Bartonicek, 1959; Soucek and
Pavelkova, 1953; WHO, 1979). Free carbon disulfide
(> 90%) in blood resides in erythrocytes (Bartonicek,
1959; Lam and DiStefano, 1983, 1986; Lam et al.,
1986). Free carbon disulfide in rat blood was
eliminated within one day, while bound carbon
disulfide was eliminated over two to three days (Lam
and DiStefano, 1982, 1983, 1986; Lam et al., 1986).
Acid-labile carbon disulfide was also found in the
blood of workers in a viscose rayon plant (Campbell
et al., 1985). The observed second, slow elimination
phase of carbon disulfide and moderate accumu-
lation over the workweek may be associated with
binding to amino acids or biological macromolecules
(Campbell et al., 1985; Lam and DiStefano, 1986).
Metabolic Pathways and Biochemical
Interactions
Carbon disulfide is extensively metabolized in
the body by two primary pathways: (1) nonenzymatic
reaction with free amino groups or (2) conjugation
mediated by glutathione-S-transferase (Beauchamp
et al., 1983). Metabolites are primarily excreted
through kidneys into urine. Three metabolites have
been identified in the urine of exposed workers:
thiocarbamide, 2-mercapto-2-thiazolinone-5, and
TTCA (Pergal et al., 1972a, b; van Doorn et al.,
1981a, b, 1982). TTCA has been shown to represent
about 6% of the carbon disulfide absorbed during
occupational exposure to ambient concentration of
approximately 10 ppm (31 mg/m3) (Campbell et al.,
1985; Rosier et al., 1987). Brugnone and colleagues
observed that glutathione conjugates of carbon
disulfide after an enzymatic degradation and ring-
closure reaction were excreted in urine as TTCA
(Brugnone et al., 1992). TTCA concentration in urine
was observed to be quantitatively related to the
uptake of carbon disulfide in rats (Cox et al., 1996).
In addition to TTCA, 2-thioxothiazolidin-4-
ylcarbonylglycine (TTCG) has been identified in the
urine of carbon disulfide-exposed workers
(Amarnath et al., 2001). Carbon disulfide can bind to
albumin and amino acids in blood (Erve et al.,
ACGIH® © 2009
1998a, b; Pergal et al., 1972a, b; Soucek, 1957;
Valentine et al., 1998). Figure 1 shows the likely
metabolic pathways of carbon disulfide in humans
(adapted from Amarnath et al., 2001).
Summary of Toxicology
Associations between occupational exposure to
carbon disulfide and neurological and cardiovascular
effects have been observed (reviewed in Newhook
and Meek, 2002). The most common finding has
been a reduction in conduction velocity in the motor
and sensory nerves at average carbon disulfide
concentrations between 1–66 ppm (3–200 mg/m3)
and, generally, this has been most pronounced in
the distal portions of the peripheral nervous system
(Gilioli et al., 1978; Johnson et al., 1983; Reinhardt
et al., 1997a, b; Ruijten et al., 1993; Sandrini et al.,
1983; Seppäläinen and Tolonen, 1974; Vanhoorne
et al., 1995; Vasilescu and Florescu, 1980). In
addition, impaired performance on
neuropsychological testing, most often in
psychomotor tests of motor speed or dexterity, has
been reported (De Fruyt et al., 1998; Hänninen
1971, Hänninen et al.,1978; Putz-Anderson et al.,
1983). Furthermore, an association between carbon
disulfide exposure and hyperintense spots on MRI of
the brain has been observed in rayon manufacturing
workers (Nishiwaki et al., 2004). Huang and
colleagues observed brain lesions and debilitating
neurological symptoms resembling Parkinson’s
disease after long-term occupational exposure to
carbon disulfide (Huang et al., 2004). Excess
mortality from coronary heart disease, as well as
clinical changes associated with the increased risk
for coronary heart disease, including increased
blood pressure and serum levels of total cholesterol;
low-density lipoprotein cholesterol; and decreased
high-density lipoprotein cholesterol have been
reported (Egeland et al., 1992; Hernberg et al.,
1976; Price et al., 1997; Stanosz et al., 1994a, b;
Takebayashi et al., 2004; Vanhoorne et al., 1992). In
two other studies, no evidence of these clinical
changes was found (Cirla and Graziano, 1981;
Drexler et al., 1995b). An increased risk for
ophthalmological illness has been observed (De
Rouck et al., 1986). The biological plausibility of the
association between carbon disulfide exposure and
neurological and cardiovascular effects is supported
by a number of animal studies (reviewed in the TLV®
Documentation) (ACGIH®, 2006).
Carbon disulfide was not observed to induce
endocrine dysfunction at the ambient average level
of 5.02 ± 1.84 ppm and mean TTCA concentration of
1.61 ± 1.91 mg/g creatinine (Takebayashi et al.,
2003). However, increased incidence of ischaemic
findings (OR 2.1; 95% CI 1.1–4.0), a significant
increase in blood pressure, and increase in retinal
microaneurysms in the highest exposed workers
were observed (average air concentration 8.7 ppm
and average TTCA concentration of 3.6 mg/g
Carbon disulfide BEI® – 3
creatinine in urine) (Takebayashi et al., 2004).
No clear evidence of effects on human
reproduction and development has been observed
(Cirla and Graziano, 1981; Cirla et al., 1978;
Vanhoorne et al., 1994; Wägar et al., 1981). There
are limited data to assess the irritancy and
sensitization potential of carbon disulfide on
humans. Carbon disulfide has been observed to be
irritating to the eyes, skin, and the mucous
membranes including those of the respiratory
system. Chou and colleagues observed skin lesions
and dermatitis among rayon workers who had
frequent contact with carbon disulfide (Chou et al.,
2004). However, a concomitant exposure to
hydrogen sulfide and sulfuric acid in the viscose
rayon industry may have confounded these
observations. The literature on carbon disulfide
toxicity in humans has been reviewed in the TLV®
Documentation (ACGIH®, 2006).
TLV–TWA
TLV–TWA of 1 ppm (3.13 mg/m3), with a skin
notation, is based on prevention of neurological
effects, but all other organ systems, including
cardiovascular, reproductive, ophthalmologic, and
renal, would also be protected from adverse effects
caused by carbon disulfide exposure.

Exhaled

NH2 NH R
Amino acids
H2N C S C S S C

S
Carbon disulfide SH

Thiocarbamide GSH Dithiocarbamates

HS SG
C

S S
O S

O
H2C NH

HNH2CO2CH C
2-Mercapto-2-thiazolidinone-5

HN S

S
2-Thioxothiazolidin-4-ylcarbonylglycine (TTCG)

HO C

CH CH2

NH S
C

2-Thioxothiazolidine-4-carboxylic acid (TTCA)

Figure 1. Metabolic pathways of carbon disulfide in humans (adapted from Amarnath et al., 2001).

4 — Carbon Disulfide BEI® ACGIH® © 2009

 2-THIOXOTHIAZOLIDINE-4-
CARBOXYLIC ACID (TTCA)
IN URINE INDEX
Analytical Methods
High-performance liquid chromatography
(HPLC) with ultraviolet detection at 271 – 273 nm is
a specific and quantitative method for the
determination of TTCA in urine (Amarnath et al.,
2001; Chang et al., 2002; Daemen et al., 1999; Jian,
2002; Lee et al., 1995; Ogata and Taguchi, 1989;
Rosier et al., 1982). Acidification and solid phase
extraction improves purification, and the use of an
internal standard tetrahydro-2-thioxo-2H-1,3-
thiazine-4-carboxylic acid (T3CA) improves
quantification with HPLC (Amarnath et al., 2001).
The limit of detection for TTCA is 40 pmol/mL (6.5
μg/L) and the detection is linear over at least three
orders of magnitude (Amarnath et al., 2001).
A gas chromatography-mass spectrometry
analysis can also be used for quantitative
determination of TTCA in urine (Weiss et al., 1999).
TTCA is separated from the urinary matrix using
liquid-liquid extraction after which the analyte is
converted into its diethyl derivative. 4-(4-Chloro-2-
methylphenoxy)butanoic acid (MCPBA) is used as
an internal standard. The detection limit is 0.7 μg/L
in urine.
Determination of creatinine in the urine is
required. Drexler and colleagues observed a
significant creatinine dependence of the TTCA
excretion and a correlation between creatinine
corrected TTCA concentration in end of shift urine
samples and the personal air levels (r = 0.84)
(Drexler et al., 1994). Chang and colleagues
observed that creatinine adjustment provided more
consistent and reliable results than volume
adjustment (r = 0.8 versus r = 0.64) (Chang et al.,
2002).
Sampling and Storage
Urine samples should be collected at the end of
the work shift into polyethylene or polycarbonate
containers. Although stability studies have shown
that TTCA in refrigerated urine is stable for 40 hours,
freezing of the urine is recommended (Campbell et
al., 1985; Rosier et al., 1982, 1984). TTCA was
observed to degrade 10–15% when stored at 4°C for
three weeks (Lee et al., 1995). Stabilization of urine
samples is recommended by acidification prior to
storage at –20°C; otherwise, immediate extraction
and analysis should be performed (Lee et al., 1995).
Sample contamination is not likely.
ACGIH® © 2009
Biological Levels Without Occupational
Exposure
TTCA has been found in the urine of individuals
without occupational exposure to carbon disulfide
(Jian, 2002; Simon et al., 1994). Excretion of TTCA
has been observed after consumption of brassica
(cruciferous) vegetables (e.g., cabbage, broccoli,
turnip, lettuce) (Kikuchi et al., 2002; Simon et al.,
1994). Simon and colleagues observed urinary
TTCA levels of 0.25–1.55 mg/g creatinine four hours
after consumption of 100 g crude cabbages while
levels without ingestion of cabbage were < 0.05–
0.20 mg/g creatinine (Simon et al., 1994). Kivistö
also confirmed that many cruciferous vegetables
contain endogenous TTCA, which is excreted
unchanged in the urine (Kivistö, 2000). TTCA levels
were significantly correlated with and increased
three hours after alcohol consumption (Jian, 2002).
The drug disulfiram, which is used in the treatment
of chronic alcoholism, is metabolized to carbon
disulfide and TTCA (van Doorn et al., 1982).
Humans treated with 250 mg of disulfiram excreted
up to 0.49 mg TTCA/g creatinine 10 hours after
dosing. Exposures to other dithiocarbamates, such
as Thiram and rubber accelerators metabolized to
carbon disulfide, may also result in the excretion of
TTCA (Amarnath et al., 2001). In experimental
animals, TTCA has been identified as a metabolic
product of Captan (Krieger and Thongsinthusak,
1993; van Welie et al., 1991). Simon and colleagues
observed an average background level of 0.09 mg
TTCA/g creatinine in non-occupationally exposed
individuals (Simon et al., 1994). In summary,
measurement of urinary TTCA in workers
occupationally exposed to carbon disulfide may be
confounded by diet and drinking of alcoholic
beverages in large quantities.
Kinetics
Data from six volunteers exposed to carbon
disulfide concentrations of 10 ppm or 20 ppm for 50
minutes indicated that TTCA appears in urine shortly
after the start of exposure. The concentration
peaked at the end of exposure and then declined
with a half-life of about two hours (Rosier et al.,
1987). A similar excretion rate was observed in
workers with occupational exposure to carbon
disulfide (Campbell et al., 1985; Rosier et al., 1982;
van Doorn et al., 1981a). Riihimäki and colleagues
observed half-lives of 6 and 68 hours for urinary
TTCA at a mean airborne carbon disulfide concen-
tration of 3 ppm (range 0.1–8.5 ppm) among 20
viscose rayon factory workers (Riihimäki et al.,
1992). The authors concluded that the slow
elimination is compatible with a high lipid solubility
and reversible protein binding of carbon disulfide.
Chang and colleagues investigated the kinetics of
urinary TTCA in 10 workers exposed to carbon
disulfide and observed a half-life of 7.96 ± 2.15
Carbon disulfide BEI® – 5
hours at an average airborne carbon disulfide
concentration of 10.1 ± 2.8 ppm (Chang et al.,
2002).
Factors Affecting Interpretation of
Measurements
Analytical Procedure and Sampling
The HPLC with ultraviolet detection is a specific
and sensitive method to detect occupational
exposure to carbon disulfide. Urinary excretion of
TTCA has been observed to be biphasic with half-
lives of approximately 6 hours and 68 hours (van
Doorn et al., 1981a; Campbell et al., 1985; Riihimäki
et al., 1992; Chang et al., 2002) and to increase
towards the end of the workweek (van Doorn et al.,
1981a; van Pouckel et al., 1990; Campbell et al.,
1985; Shih et al., 2003). Therefore, the sampling
time is critical to correct interpretation of results.
Exposure
Exposures to disulfiram and other dithio-
carbamates, such as Thiram, rubber accelerators,
and Captan, which are metabolized to carbon
disulfide, may result in the excretion of TTCA and an
overestimation of an occupational carbon disulfide
exposure.
Measurement of TTCA in urine may reflect not
only the exposure to carbon disulfide during the day
of sampling but also exposure on previous days due
to moderate accumulation over the workweek.
Exposure to substances that can be metabolized to
carbon disulfide (e.g., pesticide Captan, the anti-
alcoholic drug disulfiram [antabuse, tetrae-
thylthiuram disulfide], some rubber accelerators, and
dithiocarbamates) may result in the appearance of
carbon disulfide and its metabolites in the body and
excreta. Consumption of cruciferous vegetables and
alcohol positively interfere with the measurements of
TTCA in urine (Jian, 2002; Kikuchi et al., 2002;
Kivistö, 2000; Simon et al., 1994).
Population
Workers undergoing treatment for alcohol abuse
with disulfiram should not participate in biological
monitoring of occupational exposure to carbon
disulfide.
Justification
Both controlled laboratory and field studies are
available to relate the BEI to the TLV–TWA for
inhalation exposure. These studies are briefly
summarized below. For consistency, all TTCA
concentrations reported as mmol/mol creatinine
(Rosier et al., 1987; Meuling et al., 1990; Riihimäki
et al., 1992; van Doorn et al., 1981a; Rosier et al.,
1982; Campbell et al., 1985) have been converted to
mg/g creatinine.
6 — Carbon Disulfide BEI®
Toxicokinetic Studies
Rosier and colleagues exposed six volunteers to
carbon disulfide concentrations of 3 ppm at 50 W
workload, 10 ppm at rest or at 50 W workload, or 20
ppm at rest for 50 minutes with a 10-minute break
between each period (Rosier et al., 1987). Urine
samples were collected pre-exposure and 30, 60,
120, 180, and 240 minutes after exposure. TTCA
appeared in urine shortly after the start of exposure
and the concentration peaked at the end of
exposure, and then declined with a half-life of about
two hours. A small fraction (0.7–2.2%) of the
absorbed carbon disulfide was transformed to TTCA.
Carbon disulfide exposure correlated the best with
the excretion rate of TTCA (r = 0.70) followed by
urinary concentration (r = 0.66) and creatinine
correction (r = 0.64).
Chang and colleagues investigated the kinetics
of urinary TTCA in 10 workers exposed to carbon
disulfide and observed a half-life of 7.96 ± 2.15
hours at average airborne carbon disulfide
concentration of 10.1 ± 2.8 ppm (Chang et al.,
2002). They also observed a better correlation for
creatinine-adjusted (r = 0.80) than for volume-
adjusted (r = 0.64) TTCA values. Based on the first-
order kinetics, they estimated that 10 ppm TWA
carbon disulfide concentration corresponds to TTCA
concentration of 3.0 mg/g creatinine.
Field Studies
Meuling and colleagues investigated the
relationship between exposure to carbon disulfide
and urinary TTCA concentration in 29 workers
involved in the production of viscose rayon fibers
(Meuling et al., 1990). Urine samples were collected
immediately after waking up, prior to the start of
exposure, and during the last four hours of
exposure. The TWA carbon disulfide concentration
was 4 ppm (< 0.3–21) and the corresponding
average TTCA concentration was 0.1 mg/g
creatinine. The relationship between carbon disulfide
concentration in air and TTCA concentration in the
urine was described by the function log (TTCA
mmol/mol creatinine) = 0.84 log (CS2 mg/m3) – 1.10.
Based on this equation, current TLV of 1 ppm for
carbon disulfide results in urinary excretion of
approximately 0.3 mg TTCA/g creatinine.
Riihimäki and colleagues measured personal
carbon disulfide and TTCA concentrations in the end
of shift urine over a four-day workweek among 20
viscose rayon factory workers (Riihimäki et al.,
1992). The TWA carbon disulfide concentrations
varied from 0.1–8.5 ppm with a mean of 3 ppm. The
estimated TTCA concentration at the current TLV of
1 ppm is approximately 0.2 mg TTCA/g creatinine.
Drexler and colleagues investigated the carbon
disulfide exposure in 362 rayon factory workers
using personal air sampling (median concentration 4
ppm; range < 0.20–65.7 ppm) and measurements of
TTCA in urine (median 1.63 mg/g creatinine; range
ACGIH® © 2009
< 0.16–11.57 mg/g creatinine) (Drexler et al., 1994,
1995a). The investigators observed a significant
creatinine dependence of the TTCA excretion and a
correlation between creatinine corrected TTCA
concentration in end of shift urine samples and the
personal air levels. This relationship is described by
the function TTCA mg/g creatinine = 0.59 + 0.315 ×
CS2 ppm (r = 084). According to this equation, the
TTCA level corresponding to the current TLV of 1
ppm for carbon disulfide is 0.9 mg/g creatinine.
Shih and colleagues measured personal
breathing-zone carbon disulfide and pre- and post-
shift urinary TTCA concentrations over a period of
one week for five workers working eight-hour shifts
and seven workers working 12-hour shifts (Shih et
al., 2003). The TWA air concentration for workers
working 8-hour shifts was 2 ± 0.2 ppm and for
workers working 12-hour shifts was 3.6 ± 0.5 ppm
while the corresponding average TTCA levels were
3.24 ± 1.21 mg/g creatinine and 5.88 ± 2.04 mg/g
creatinine, respectively. They concluded that the
TTCA accumulation was dependent on exposure
magnitude only for workers working 12-hour shifts
but no accumulation was observed for workers
working eight-hour shifts. When the daily average
carbon disulfide and TTCA concentrations for the
five workers are plotted, a linear relationship
between urinary TTCA and airborne carbon disulfide
concentration can be derived as TTCA mg/g
creatinine = –0.17 + 0.54 × CS2 ppm (r = 0.95).
According to this equation, the TTCA level
corresponding to the current TLV of 1 ppm for
carbon disulfide is 0.4 mg/g creatinine.
The eight studies in which the measured carbon
disulfide exposures were above 1 ppm indicate great
variability when urinary excretion levels were
extrapolated from these data to the current TLV of 1
ppm. van Doorn and colleagues observed a mean
TTCA concentration of 12.5 ± 0.98 mg/g of
creatinine in urine at TWA concentration of 32 ppm
of carbon disulfide in 22 viscose rayon process
workers (van Doorn et al., 1981a). Extrapolation of
these data to exposure at the current TLV of 1 ppm
for carbon disulfide results in urinary excretion of
approximately 1 mg TTCA/g creatinine. In the
studies by Rosier and colleagues, the carbon
disulfide concentration in a viscose rayon process
varied between 2.4 and 51 ppm (Rosier et al., 1982,
1984). Although there was a significant dose-
response relationship between average carbon
disulfide concentration in air and the increase of
TTCA concentration in urine during the workday,
estimation of the TTCA concentration at airborne
concentration of 1 ppm of carbon disulfide was not
feasible from this data because the measured
exposure levels were substantially above 1 ppm.
Campbell and colleagues monitored 23 workers, 13
exposed to carbon disulfide and 10 controls, in a
viscose rayon plant by personal sampling on day
one and day five of a workweek (Campbell et al.,
1985). Inhalation exposure averaged 11 ppm on day
ACGIH® © 2009
one and 3 ppm on day five. In post-shift urine
specimens, TTCA levels averaged 6.9 mg/g of
creatinine on day one and 3.9 mg/g of creatinine on
day five. All urine specimens collected from control
subjects were below the limit of detection, 0.5
μmol/L. van Pouckel and colleagues measured
average TTCA concentrations of 7.6 mg/g creatinine
(n = 25) and 0.1 mg/g creatinine (n = 14) in viscose
factory workers exposed to TWA carbon disulfide
concentrations of 38 ppm (range 37–47 ppm) and
1.8 ppm (range 1.3–2.3 ppm), respectively (van
Pouckel et al., 1990). Tan and colleagues measured
geometric mean TTCA concentration of 1.18 mg/g
creatinine in staple viscose hall workers (N = 74)
exposed to geometric mean carbon disulfide
concentration of 4.4 ppm, while the filament spinning
hall workers’ (N = 61) geometric mean carbon
disulfide concentration was 6.4 ppm and geometric
mean TTCA concentration was 1.07 mg/g creatinine
(Tan et al., 2000). Chang and colleagues
investigated the kinetics of urinary TTCA in 10
workers and estimated that 10 ppm TWA carbon
disulfide concentration corresponds to TTCA
concentration of 3.0 mg/g creatinine (Chang et al.,
2002). Takebayashi and colleagues measured
personal breathing-zone carbon disulfide concen-
trations and collected end of shift urine samples
simultaneously twice a year over a six-year study
period for 432 male rayon workers (Takebayashi et
al., 2004). Geometric mean carbon disulfide and
TTCA levels were 5.02 ppm and 1.61 mg/g
creatinine for all workers, 6.11 ppm and 1.94 mg/g
creatinine for spinning and refining workers, and
3.08 ppm and 0.98 mg/g creatinine for other
workers, respectively.
In summary, the review of the published
literature indicates a clear correlation between
airborne carbon disulfide exposure in viscose rayon
plants and urinary TTCA concentration. In eight of
the studies, the measured carbon disulfide
exposures were substantially above the TLV of 1
ppm (3.13 mg/m3) and, thus, it was not feasible to
ascertain the relationship between the TTCA
concentration and airborne carbon disulfide
exposure at or below 1 ppm from these studies.
However, from four studies, the correlation between
personal airborne carbon disulfide exposure at the
current TLV of 1 ppm and urinary TTCA concen-
tration could be ascertained (Meuling et al., 1990;
Riihimäki et al., 1992; Drexler et al., 1994; Shih et
al., 2003). In these studies, the mean TTCA
concentration at mean TLV of 1 ppm varied from 0.2
to 0.9 mg/g creatinine. Based on these data, an
average urinary excretion of 0.5 mg TTCA/g
creatinine is estimated at 1 ppm of carbon disulfide
exposure.
Laboratory Studies
Rosier and colleagues studied the excretion of
TTCA in six human volunteers in a laboratory
Carbon disulfide BEI® – 7
chamber by exposing them to 3 ppm of carbon
disulfide at 50 W workload, 10 ppm at rest or at 50
W workload, or 20 ppm at rest for four consecutive
periods of 50 minutes with a 10-minute break
between each period (Rosier et al., 1987). Carbon
disulfide was excreted as TTCA representing 0.7–
2.2% of the absorbed dose, with a half-life of two
hours. Carbon disulfide exposure correlated best
with the excretion rate of TTCA (r = 0.70) followed
by urinary concentration (r = 0.66) and creatinine
corrected urinary concentration (r = 0.64). The
average TTCA concentration at 3 ppm carbon
disulfide exposure level was 1.08 ± 0.71 mg/g
creatinine (0.77 ± 0.51 mmol/mol creatinine).
Current Database Available
A sufficient database is available to recommend
a BEI for TTCA as an indicator of carbon disulfide
exposure. The measurement of TTCA in urine
collected at the end of the shift, end of workweek is
suitable for monitoring exposure to carbon disulfide.
The excretion is a good indicator of exposure on the
sampling day. The TTCA measurement is a non-
specific indicator of exposure to carbon disulfide.
TTCA may be excreted in the urine following
exposure to some medications, industrial chemicals,
and consumption of large quantities of cruciferous
vegetables (e.g., cabbage, broccoli, turnip, lettuce)
or possibly alcoholic beverages. The iodine-azide
test, used widely to assess carbon disulfide
exposure in the past, is not recommended because
of the lack of sensitivity at the current TLV.
Recommendation
ACGIH® recommends monitoring TTCA in urine
collected at the end of the work shift as an indicator
of current exposure to carbon disulfide. The
recommended BEI of 0.5 mg TTCA/g creatinine
corresponds to an eight-hour exposure at the current
carbon disulfide TLV of 1 ppm. Dermal exposure to
liquid carbon disulfide may alter the relationship
between concentrations of carbon disulfide in air and
TTCA in urine. The sampling time is critical. Sample
contamination is unlikely. The recommended BEI is
equivalent in the International System of Units (SI) to
0.35 mmol/mol of creatinine.
Other Reference Values
The German Commission for the Investigation of
Health Hazards of Chemical Compounds in the
Work Area recommends 4 mg TTCA/g creatinine,
with a skin notation, for a sample collected at the
8 — Carbon Disulfide BEI®
end of exposure or end of shift as the Biological
Tolerance Value (BAT) (DFG, 2006). The BAT value
is based on the relationship between TTCA in urine
and health effects.
The Finnish Ministry of Social Affairs and Health
recommends 2 mmol TTCA/mol creatinine (2.9 mg
TTCA/g creatinine) for a sample collected at the
end-of-shift, end of workweek, or end of exposure
period as the Biological Limit Value (Finnish Ministry
of Social Affairs and Health, 2005).
Other Indicators of Exposure
The widely used iodine-azide test, first described
by Vasak et al. (1963), was used extensively in the
past (Djuric, 1967; Djuric et al., 1965; Lauwerys,
1983; NIOSH, 1977; Rosensteel et al., 1974; Rosier
et al., 1984). However, the test is not sensitive
enough to detect exposures equivalent to the current
TLV (Campbell et al., 1985; WHO, 1979), and the
BEI Committee does not recommend this
determinant.
The measurement of carbon disulfide in urine
and blood collected immediately after exposure has
been suggested (Herber, 1976; Teisinger and
Soucek, 1949). Lam and DiStefano exposed rats to
carbon disulfide and observed that blood-bound
carbon disulfide increased linearly for four hours and
thereafter showed a curvilinear rise for at least 32
hours (Lam and DiStefano, 1982). Elimination was
observed to be biexponential with a half-life of two
hours and 43 hours. Acid-labile carbon disulfide in
blood (Campbell et al., 1985) and toluene-3,4-dithiol
(free and protein bound) analysis of plasma and
hemolysate (Johnson et al., 1983; Valentine et al.,
1999) may also be useful in assessing carbon
disulfide exposure. The BEI Committee does not
recommend these determinants because of the lack
of reliable data in humans.
Breath analysis for exposure monitoring has
only been reported in one study (Campbell et al.,
1985). Due to the limited data, ACGIH® does not
recommend this determinant.
Djuric and others have recommended the
administration of disulfiram to workers and
measurement of diethylthiocarbamates in urine as
an exposure test for carbon disulfide (Djuric, 1967;
WHO, 1979, 1981). This test is not recommended by
ACGIH®.
BEI® Chronology
See Table 1.
ACGIH® © 2009
Table 1. BEI® Chronology
Date Action Determinant
1986 Proposed 2-Thioxothiazolidine-4-carboxylic
acid (TTCA) in urine
1988 Adopted 2-Thioxothiazolidine-4-carboxylic
acid (TTCA) in urine
2009 Proposed 2-Thioxothiazolidine-4-carboxylic
acid (TTCA) in urine
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