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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 BEI® Notation
2-Thioxothiazolidine-4-carboxylic End of shift 0.5 mg/g Ns, B
acid (TTCA) in urine creatinine

Basis for the Biological Exposure Index metabolites in the body and excreta. Therefore,
TTCA is not a specific indicator of carbon disulfide
The adverse health effect observed in occu- exposure and an “Ns” or “nonspecific” notation is
pationally exposed workers is a reduction in assigned.
conduction velocity in the motor and sensory nerves
above carbon disulfide concentrations of 1 ppm
Conversion Factors
(3.13 mg/m3). The recommended BEI® of 0.5 mg
TTCA/g creatinine is based on the adopted TLV® of Carbon disulfide
1 ppm carbon disulfide. The TLV is intended to
protect workers from observed adverse health 1 mg/L = 0.013 mmol/L; 1 mmol/L = 76.1 mg/L
effects caused by carbon disulfide exposure. The 2-Thioxothiazolidine-4-carboxylic acid (TTCA)
TLV is based primarily on neurological endpoints,
but all other organ systems, including cardio- 1 mg/g creatinine = 0.70 mmol/mol creatinine
vascular, reproductive, ophthalmologic, and renal, 1 mmol/mol creatinine = 1.4 mg/g creatinine
would also be protected from adverse effects 1 mg/L = 6 μmol/L
caused by carbon disulfide exposure. Dithio- 1 mmol/L = 163 mg/L
carbamates are the metabolites of carbon disulfide
formed after reaction with amino acids, and these Uses and Properties
metabolites contribute, in part, to the neurotoxic
Carbon disulfide is a clear, colorless to yellow
effects of carbon disulfide. A satisfactory correlation
liquid at room temperature. Pure carbon disulfide
between airborne carbon disulfide exposure and an
has a sweet odor resembling chloroform, while
end of shift urinary 2-thioxothiazolidine-4-carboxylic
technical grade has a strong, unpleasant hydrogen
acid (TTCA) concentration has been observed.
sulfide odor (ATSDR, 1996). The saturated vapor
Urinary excretion of TTCA has been observed to be
biphasic (with half-lives of about 6 h and 68 h) at pressure is 297 torr at 20°C (39.6 kPa) (ATSDR,
mean airborne carbon disulfide concentration of 3 1996). It is highly soluble in blood and fat and
ppm, and moderate accumulation may occur moderately soluble in water (2.3 g/L at 22°C)
towards the end of the workweek with repeated (ATSDR, 1996). Its blood/gas partition coefficient is
exposure. The observed average background level 2.4 (Ghittori et al., 1998) and the octanol/water
of 0.09 mg TTCA/g creatinine in non-occupationally partition coefficient (log Pow) is approximately 2
exposed individuals is about 20% of the proposed (range 1.84–2.16) (ATSDR, 1996).
BEI value of 0.5 mg TTCA/g creatinine. Therefore, Worldwide production of carbon disulfide is
exposure from non-occupational sources (e.g., diet) estimated to be one million tons (Newhook and
may have an impact, and the BEI has been Meek, 2002). The principal industrial uses of carbon
assigned a “B” notation. Exposure to substances, disulfide are the manufacture of viscose rayon,
which can be metabolized to carbon disulfide (e.g., cellophane film, carbon tetrachloride, xantho-
pesticide Captan, the anti-alcoholic drug disulfiram genates, sodium sulfite, mercaptans, thioureas,
(antabuse, tetraethylthiuram disulfide), some rubber mineral flotation agents, rubber chemicals, dyes,
accelerators, and dithiocarbamates, may result in and pesticides as well as to solubilize waxes and
the appearance of carbon disulfide and its oils, resins, rubbers, phosphorous, sulfur mono-

ACGIH® © 2009 Carbon disulfide BEI® – 1


chloride, selenium, bromine, and iodine (ATSDR, Absorption
1996; Newhook and Meek, 2002). Carbon disulfide
is also used in preservation of fresh fruit, in adhesive Carbon disulfide is extensively absorbed via
composition for food packaging, in solvent extraction inhalation, dermal, and oral routes. Absorbed carbon
of growth inhibitors, and as a soil fumigant against disulfide is distributed throughout the body, particu-
insects and nematodes (ATSDR, 1996; NSC, 2007). larly into lipophilic tissues and organs, such as liver
NIOSH has estimated that approximately 46,000 and brain. Carbon disulfide is readily soluble in lipids
workers are exposed to carbon disulfide in the U.S. and also has affinity for amino acids and proteins.
(NIOSH, 2007). However, the actual number may be Thus, it has a potential to accumulate in the body.
significantly higher, since the survey did not include Pulmonary
worker exposures to chemicals that may contain
carbon disulfide. A rapid and extensive absorption of inhaled
carbon disulfide has been observed in humans.
Possible Non-occupational Exposure Pulmonary retention at the start of exposure is about
80% and declines steadily, reaching a plateau of
Ambient air is the major source for exposure in about 45% of the inhaled concentration within one
general population. Carbon disulfide is produced hour (Beauchamp et al., 1983; Harashima and
and released to the environment from natural Masuda, 1962; Petrovic and Duric, 1966; WHO,
sources (e.g., soil and sediment microorganisms, 1979).
vegetation, forest and grass fires, and volcanoes)
and has been detected in air, water, sediment, and Dermal
soil (Newhook and Meek, 2002). It is also produced Carbon disulfide is readily absorbed through
during metabolism of some pesticides, such as human skin. The penetration rate measured in
dithiocarbamates in plants and soil. Carbon disulfide volunteers immersing a hand for one hour in an
is released into the environment in cigarette smoke aqueous solution containing 0.33–1.67 g of carbon
(Horton and Guerin, 1974). Between 2002 and 2004, disulfide per liter varied between 0.23 and 0.79
an average 27 million pounds per year of carbon mg/cm2/h (Dutkiewicz and Baranowska, 1967).
disulfide were released into the environment as point Higher absorption was indicated in earlier invest-
source air emissions from manufacturing and igations (Baranowska, 1965). The physical and
processing facilities in the U.S. (U.S. EPA, 2006). chemical properties also predict a significant dermal
The highest ambient air concentrations (up to 156 absorption (penetration rate 0.89 mg/cm2/h) (see
μg/m3) have been measured near industrial sources, Dermal Absorption in the “Introduction to the
particularly near natural gas processing plants and BEIs®”). Extensive dermal absorption of vapor and
sites with sulfur-containing natural gas flares (Legge liquid carbon disulfide was observed in experimental
et al., 1990a, b). Outdoor concentrations of carbon animal studies (Cohen et al., 1958; Izmerov, 1983).
disulfide have been measured up to 1.1 μg/m3 and Available evidence suggests that percutaneous
1.2 μg/m3 in the U.S. and Europe, respectively absorption may add to the adverse effects induced
(ATSDR, 1996; Maroulis and Bandy, 1980; Phillips, by inhalation exposure (Grandjean, 1990).
1992; Sandalls and Penkett, 1977).
In air, carbon disulfide has a half-life of 1–2 Gastrointestinal
weeks and it is removed from air primarily by No human studies were found regarding oral
reaction with hydroxy radicals (Wine et al., 1981). It exposure to carbon disulfide. However, based on a
is rapidly metabolized by organisms and does not study of intragastric administration of 10 mg/kg 14C-
bioconcentrate or biomagnify (Beauchamp et al., carbon disulfide in rats (De Matteis and Seawright,
1983). Exposure to substances that can be 1973), gastrointestinal absorption is expected to be
metabolized to carbon disulfide, such as the rapid.
pesticide Captan (Krieger and Thongsinthusak,
1993; van Welie et al., 1991), the anti-alcoholic drug Elimination
disulfiram (antabuse), some rubber accelerators,
and dithiocarbamates (e.g., Thiram [tetramethyl- Lungs are the primary excretory pathway of
thiuram disulfide]) may result in the appearance of unmetabolized carbon disulfide, whereas filtration in
carbon disulfide and its metabolites in the body and the kidneys is the primary route of excretion of the
excreta (van Doorn et al., 1982). metabolites. Of the total uptake of carbon disulfide,
Simon and colleagues observed an average 5–30% is eliminated unchanged in the breath
background level of 0.09 mg TTCA/g creatinine in (Djuric, 1967; Petrovic and Duric, 1966; WHO, 1979)
non-occupationally exposed individuals (Simon et and less than 1% is excreted unchanged in urine
al., 1994). This value is about 20% of the proposed (Djuric, 1967; Harashima and Masuda, 1962), while
BEI value of 0.5 mg TTCA/g creatinine. Therefore, 70–90% is excreted as metabolites (Djuric, 1967;
interpretation of the measurement of urinary TTCA in Riihimäki et al., 1992). About 3% of the amount
workers occupationally exposed to carbon disulfide absorbed via skin was found in breath of volunteers
may be confounded by other exposure sources. exposing their hands to aqueous solutions of carbon

2 — Carbon Disulfide BEI® ACGIH® © 2009


disulfide (Dutkiewicz and Baranowska, 1967). 1998a, b; Pergal et al., 1972a, b; Soucek, 1957;
Pulmonary elimination of carbon disulfide was Valentine et al., 1998). Figure 1 shows the likely
observed to be fast with a half-life of about 10 metabolic pathways of carbon disulfide in humans
minutes (Harashima and Masuda, 1962). A biphasic (adapted from Amarnath et al., 2001).
elimination with half-lives of 1 minute and 110
minutes has also been observed (Rosier et al., Summary of Toxicology
1987). However, carbon disulfide was found in the
breath of workers 16 hours after the end of high Associations between occupational exposure to
exposure, but the breath carbon disulfide carbon disulfide and neurological and cardiovascular
concentrations did not correlate with blood carbon effects have been observed (reviewed in Newhook
disulfide levels (Campbell et al., 1985). Small and Meek, 2002). The most common finding has
amounts of carbon disulfide are excreted in saliva been a reduction in conduction velocity in the motor
and sweat and through the skin of exposed and sensory nerves at average carbon disulfide
individuals (Merlevede and Casier, 1961). Excretion concentrations between 1–66 ppm (3–200 mg/m3)
in feces is negligible (< 1%) (Harashima and and, generally, this has been most pronounced in
Masuda, 1962). the distal portions of the peripheral nervous system
Carbon disulfide is present in blood in both a (Gilioli et al., 1978; Johnson et al., 1983; Reinhardt
free and bound form (Bartonicek, 1959; Soucek and et al., 1997a, b; Ruijten et al., 1993; Sandrini et al.,
Pavelkova, 1953; WHO, 1979). Free carbon disulfide 1983; Seppäläinen and Tolonen, 1974; Vanhoorne
(> 90%) in blood resides in erythrocytes (Bartonicek, et al., 1995; Vasilescu and Florescu, 1980). In
1959; Lam and DiStefano, 1983, 1986; Lam et al., addition, impaired performance on
1986). Free carbon disulfide in rat blood was neuropsychological testing, most often in
eliminated within one day, while bound carbon psychomotor tests of motor speed or dexterity, has
disulfide was eliminated over two to three days (Lam been reported (De Fruyt et al., 1998; Hänninen
and DiStefano, 1982, 1983, 1986; Lam et al., 1986). 1971, Hänninen et al.,1978; Putz-Anderson et al.,
Acid-labile carbon disulfide was also found in the 1983). Furthermore, an association between carbon
blood of workers in a viscose rayon plant (Campbell disulfide exposure and hyperintense spots on MRI of
et al., 1985). The observed second, slow elimination the brain has been observed in rayon manufacturing
phase of carbon disulfide and moderate accumu- workers (Nishiwaki et al., 2004). Huang and
lation over the workweek may be associated with colleagues observed brain lesions and debilitating
binding to amino acids or biological macromolecules neurological symptoms resembling Parkinson’s
(Campbell et al., 1985; Lam and DiStefano, 1986). disease after long-term occupational exposure to
carbon disulfide (Huang et al., 2004). Excess
mortality from coronary heart disease, as well as
Metabolic Pathways and Biochemical
clinical changes associated with the increased risk
Interactions for coronary heart disease, including increased
Carbon disulfide is extensively metabolized in blood pressure and serum levels of total cholesterol;
the body by two primary pathways: (1) nonenzymatic low-density lipoprotein cholesterol; and decreased
reaction with free amino groups or (2) conjugation high-density lipoprotein cholesterol have been
mediated by glutathione-S-transferase (Beauchamp reported (Egeland et al., 1992; Hernberg et al.,
et al., 1983). Metabolites are primarily excreted 1976; Price et al., 1997; Stanosz et al., 1994a, b;
through kidneys into urine. Three metabolites have Takebayashi et al., 2004; Vanhoorne et al., 1992). In
been identified in the urine of exposed workers: two other studies, no evidence of these clinical
thiocarbamide, 2-mercapto-2-thiazolinone-5, and changes was found (Cirla and Graziano, 1981;
TTCA (Pergal et al., 1972a, b; van Doorn et al., Drexler et al., 1995b). An increased risk for
1981a, b, 1982). TTCA has been shown to represent ophthalmological illness has been observed (De
about 6% of the carbon disulfide absorbed during Rouck et al., 1986). The biological plausibility of the
occupational exposure to ambient concentration of association between carbon disulfide exposure and
approximately 10 ppm (31 mg/m3) (Campbell et al., neurological and cardiovascular effects is supported
1985; Rosier et al., 1987). Brugnone and colleagues by a number of animal studies (reviewed in the TLV®
observed that glutathione conjugates of carbon Documentation) (ACGIH®, 2006).
disulfide after an enzymatic degradation and ring- Carbon disulfide was not observed to induce
closure reaction were excreted in urine as TTCA endocrine dysfunction at the ambient average level
(Brugnone et al., 1992). TTCA concentration in urine of 5.02 ± 1.84 ppm and mean TTCA concentration of
was observed to be quantitatively related to the 1.61 ± 1.91 mg/g creatinine (Takebayashi et al.,
uptake of carbon disulfide in rats (Cox et al., 1996). 2003). However, increased incidence of ischaemic
In addition to TTCA, 2-thioxothiazolidin-4- findings (OR 2.1; 95% CI 1.1–4.0), a significant
ylcarbonylglycine (TTCG) has been identified in the increase in blood pressure, and increase in retinal
urine of carbon disulfide-exposed workers microaneurysms in the highest exposed workers
(Amarnath et al., 2001). Carbon disulfide can bind to were observed (average air concentration 8.7 ppm
albumin and amino acids in blood (Erve et al., and average TTCA concentration of 3.6 mg/g

ACGIH® © 2009 Carbon disulfide BEI® – 3


creatinine in urine) (Takebayashi et al., 2004). system. Chou and colleagues observed skin lesions
No clear evidence of effects on human and dermatitis among rayon workers who had
reproduction and development has been observed frequent contact with carbon disulfide (Chou et al.,
(Cirla and Graziano, 1981; Cirla et al., 1978; 2004). However, a concomitant exposure to
Vanhoorne et al., 1994; Wägar et al., 1981). There hydrogen sulfide and sulfuric acid in the viscose
are limited data to assess the irritancy and rayon industry may have confounded these
sensitization potential of carbon disulfide on observations. The literature on carbon disulfide
humans. Carbon disulfide has been observed to be toxicity in humans has been reviewed in the TLV®
irritating to the eyes, skin, and the mucous Documentation (ACGIH®, 2006).
membranes including those of the respiratory
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- Biological Levels Without Occupational
Exposure
CARBOXYLIC ACID (TTCA)
IN URINE INDEX TTCA has been found in the urine of individuals
without occupational exposure to carbon disulfide
(Jian, 2002; Simon et al., 1994). Excretion of TTCA
Analytical Methods has been observed after consumption of brassica
High-performance liquid chromatography (cruciferous) vegetables (e.g., cabbage, broccoli,
(HPLC) with ultraviolet detection at 271 – 273 nm is turnip, lettuce) (Kikuchi et al., 2002; Simon et al.,
a specific and quantitative method for the 1994). Simon and colleagues observed urinary
determination of TTCA in urine (Amarnath et al., TTCA levels of 0.25–1.55 mg/g creatinine four hours
2001; Chang et al., 2002; Daemen et al., 1999; Jian, after consumption of 100 g crude cabbages while
2002; Lee et al., 1995; Ogata and Taguchi, 1989; levels without ingestion of cabbage were < 0.05–
Rosier et al., 1982). Acidification and solid phase 0.20 mg/g creatinine (Simon et al., 1994). Kivistö
extraction improves purification, and the use of an also confirmed that many cruciferous vegetables
internal standard tetrahydro-2-thioxo-2H-1,3- contain endogenous TTCA, which is excreted
thiazine-4-carboxylic acid (T3CA) improves unchanged in the urine (Kivistö, 2000). TTCA levels
quantification with HPLC (Amarnath et al., 2001). were significantly correlated with and increased
The limit of detection for TTCA is 40 pmol/mL (6.5 three hours after alcohol consumption (Jian, 2002).
μg/L) and the detection is linear over at least three The drug disulfiram, which is used in the treatment
orders of magnitude (Amarnath et al., 2001). of chronic alcoholism, is metabolized to carbon
A gas chromatography-mass spectrometry disulfide and TTCA (van Doorn et al., 1982).
analysis can also be used for quantitative Humans treated with 250 mg of disulfiram excreted
determination of TTCA in urine (Weiss et al., 1999). up to 0.49 mg TTCA/g creatinine 10 hours after
TTCA is separated from the urinary matrix using dosing. Exposures to other dithiocarbamates, such
liquid-liquid extraction after which the analyte is as Thiram and rubber accelerators metabolized to
converted into its diethyl derivative. 4-(4-Chloro-2- carbon disulfide, may also result in the excretion of
methylphenoxy)butanoic acid (MCPBA) is used as TTCA (Amarnath et al., 2001). In experimental
an internal standard. The detection limit is 0.7 μg/L animals, TTCA has been identified as a metabolic
in urine. product of Captan (Krieger and Thongsinthusak,
Determination of creatinine in the urine is 1993; van Welie et al., 1991). Simon and colleagues
required. Drexler and colleagues observed a observed an average background level of 0.09 mg
significant creatinine dependence of the TTCA TTCA/g creatinine in non-occupationally exposed
excretion and a correlation between creatinine individuals (Simon et al., 1994). In summary,
corrected TTCA concentration in end of shift urine measurement of urinary TTCA in workers
samples and the personal air levels (r = 0.84) occupationally exposed to carbon disulfide may be
(Drexler et al., 1994). Chang and colleagues confounded by diet and drinking of alcoholic
observed that creatinine adjustment provided more beverages in large quantities.
consistent and reliable results than volume
adjustment (r = 0.8 versus r = 0.64) (Chang et al., Kinetics
2002). Data from six volunteers exposed to carbon
disulfide concentrations of 10 ppm or 20 ppm for 50
Sampling and Storage minutes indicated that TTCA appears in urine shortly
Urine samples should be collected at the end of after the start of exposure. The concentration
the work shift into polyethylene or polycarbonate peaked at the end of exposure and then declined
containers. Although stability studies have shown with a half-life of about two hours (Rosier et al.,
that TTCA in refrigerated urine is stable for 40 hours, 1987). A similar excretion rate was observed in
freezing of the urine is recommended (Campbell et workers with occupational exposure to carbon
al., 1985; Rosier et al., 1982, 1984). TTCA was disulfide (Campbell et al., 1985; Rosier et al., 1982;
observed to degrade 10–15% when stored at 4°C for van Doorn et al., 1981a). Riihimäki and colleagues
three weeks (Lee et al., 1995). Stabilization of urine observed half-lives of 6 and 68 hours for urinary
samples is recommended by acidification prior to TTCA at a mean airborne carbon disulfide concen-
storage at –20°C; otherwise, immediate extraction tration of 3 ppm (range 0.1–8.5 ppm) among 20
and analysis should be performed (Lee et al., 1995). viscose rayon factory workers (Riihimäki et al.,
Sample contamination is not likely. 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

ACGIH® © 2009 Carbon disulfide BEI® – 5


hours at an average airborne carbon disulfide Toxicokinetic Studies
concentration of 10.1 ± 2.8 ppm (Chang et al.,
2002). 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
Factors Affecting Interpretation of
ppm at rest for 50 minutes with a 10-minute break
Measurements between each period (Rosier et al., 1987). Urine
Analytical Procedure and Sampling samples were collected pre-exposure and 30, 60,
120, 180, and 240 minutes after exposure. TTCA
The HPLC with ultraviolet detection is a specific appeared in urine shortly after the start of exposure
and sensitive method to detect occupational and the concentration peaked at the end of
exposure to carbon disulfide. Urinary excretion of exposure, and then declined with a half-life of about
TTCA has been observed to be biphasic with half- two hours. A small fraction (0.7–2.2%) of the
lives of approximately 6 hours and 68 hours (van absorbed carbon disulfide was transformed to TTCA.
Doorn et al., 1981a; Campbell et al., 1985; Riihimäki Carbon disulfide exposure correlated the best with
et al., 1992; Chang et al., 2002) and to increase the excretion rate of TTCA (r = 0.70) followed by
towards the end of the workweek (van Doorn et al., urinary concentration (r = 0.66) and creatinine
1981a; van Pouckel et al., 1990; Campbell et al., correction (r = 0.64).
1985; Shih et al., 2003). Therefore, the sampling Chang and colleagues investigated the kinetics
time is critical to correct interpretation of results. of urinary TTCA in 10 workers exposed to carbon
Exposure disulfide and observed a half-life of 7.96 ± 2.15
hours at average airborne carbon disulfide
Exposures to disulfiram and other dithio- concentration of 10.1 ± 2.8 ppm (Chang et al.,
carbamates, such as Thiram, rubber accelerators, 2002). They also observed a better correlation for
and Captan, which are metabolized to carbon creatinine-adjusted (r = 0.80) than for volume-
disulfide, may result in the excretion of TTCA and an adjusted (r = 0.64) TTCA values. Based on the first-
overestimation of an occupational carbon disulfide order kinetics, they estimated that 10 ppm TWA
exposure. carbon disulfide concentration corresponds to TTCA
Measurement of TTCA in urine may reflect not concentration of 3.0 mg/g creatinine.
only the exposure to carbon disulfide during the day
of sampling but also exposure on previous days due Field Studies
to moderate accumulation over the workweek. Meuling and colleagues investigated the
Exposure to substances that can be metabolized to relationship between exposure to carbon disulfide
carbon disulfide (e.g., pesticide Captan, the anti- and urinary TTCA concentration in 29 workers
alcoholic drug disulfiram [antabuse, tetrae- involved in the production of viscose rayon fibers
thylthiuram disulfide], some rubber accelerators, and (Meuling et al., 1990). Urine samples were collected
dithiocarbamates) may result in the appearance of immediately after waking up, prior to the start of
carbon disulfide and its metabolites in the body and exposure, and during the last four hours of
excreta. Consumption of cruciferous vegetables and exposure. The TWA carbon disulfide concentration
alcohol positively interfere with the measurements of was 4 ppm (< 0.3–21) and the corresponding
TTCA in urine (Jian, 2002; Kikuchi et al., 2002; average TTCA concentration was 0.1 mg/g
Kivistö, 2000; Simon et al., 1994). creatinine. The relationship between carbon disulfide
Population concentration in air and TTCA concentration in the
urine was described by the function log (TTCA
Workers undergoing treatment for alcohol abuse mmol/mol creatinine) = 0.84 log (CS2 mg/m3) – 1.10.
with disulfiram should not participate in biological Based on this equation, current TLV of 1 ppm for
monitoring of occupational exposure to carbon carbon disulfide results in urinary excretion of
disulfide. approximately 0.3 mg TTCA/g creatinine.
Riihimäki and colleagues measured personal
Justification carbon disulfide and TTCA concentrations in the end
of shift urine over a four-day workweek among 20
Both controlled laboratory and field studies are viscose rayon factory workers (Riihimäki et al.,
available to relate the BEI to the TLV–TWA for 1992). The TWA carbon disulfide concentrations
inhalation exposure. These studies are briefly varied from 0.1–8.5 ppm with a mean of 3 ppm. The
summarized below. For consistency, all TTCA estimated TTCA concentration at the current TLV of
concentrations reported as mmol/mol creatinine 1 ppm is approximately 0.2 mg TTCA/g creatinine.
(Rosier et al., 1987; Meuling et al., 1990; Riihimäki Drexler and colleagues investigated the carbon
et al., 1992; van Doorn et al., 1981a; Rosier et al., disulfide exposure in 362 rayon factory workers
1982; Campbell et al., 1985) have been converted to using personal air sampling (median concentration 4
mg/g creatinine. ppm; range < 0.20–65.7 ppm) and measurements of
TTCA in urine (median 1.63 mg/g creatinine; range

6 — Carbon Disulfide BEI® ACGIH® © 2009


< 0.16–11.57 mg/g creatinine) (Drexler et al., 1994, one and 3 ppm on day five. In post-shift urine
1995a). The investigators observed a significant specimens, TTCA levels averaged 6.9 mg/g of
creatinine dependence of the TTCA excretion and a creatinine on day one and 3.9 mg/g of creatinine on
correlation between creatinine corrected TTCA day five. All urine specimens collected from control
concentration in end of shift urine samples and the subjects were below the limit of detection, 0.5
personal air levels. This relationship is described by μmol/L. van Pouckel and colleagues measured
the function TTCA mg/g creatinine = 0.59 + 0.315 × average TTCA concentrations of 7.6 mg/g creatinine
CS2 ppm (r = 084). According to this equation, the (n = 25) and 0.1 mg/g creatinine (n = 14) in viscose
TTCA level corresponding to the current TLV of 1 factory workers exposed to TWA carbon disulfide
ppm for carbon disulfide is 0.9 mg/g creatinine. concentrations of 38 ppm (range 37–47 ppm) and
Shih and colleagues measured personal 1.8 ppm (range 1.3–2.3 ppm), respectively (van
breathing-zone carbon disulfide and pre- and post- Pouckel et al., 1990). Tan and colleagues measured
shift urinary TTCA concentrations over a period of geometric mean TTCA concentration of 1.18 mg/g
one week for five workers working eight-hour shifts creatinine in staple viscose hall workers (N = 74)
and seven workers working 12-hour shifts (Shih et exposed to geometric mean carbon disulfide
al., 2003). The TWA air concentration for workers concentration of 4.4 ppm, while the filament spinning
working 8-hour shifts was 2 ± 0.2 ppm and for hall workers’ (N = 61) geometric mean carbon
workers working 12-hour shifts was 3.6 ± 0.5 ppm disulfide concentration was 6.4 ppm and geometric
while the corresponding average TTCA levels were mean TTCA concentration was 1.07 mg/g creatinine
3.24 ± 1.21 mg/g creatinine and 5.88 ± 2.04 mg/g (Tan et al., 2000). Chang and colleagues
creatinine, respectively. They concluded that the investigated the kinetics of urinary TTCA in 10
TTCA accumulation was dependent on exposure workers and estimated that 10 ppm TWA carbon
magnitude only for workers working 12-hour shifts disulfide concentration corresponds to TTCA
but no accumulation was observed for workers concentration of 3.0 mg/g creatinine (Chang et al.,
working eight-hour shifts. When the daily average 2002). Takebayashi and colleagues measured
carbon disulfide and TTCA concentrations for the personal breathing-zone carbon disulfide concen-
five workers are plotted, a linear relationship trations and collected end of shift urine samples
between urinary TTCA and airborne carbon disulfide simultaneously twice a year over a six-year study
concentration can be derived as TTCA mg/g period for 432 male rayon workers (Takebayashi et
creatinine = –0.17 + 0.54 × CS2 ppm (r = 0.95). al., 2004). Geometric mean carbon disulfide and
According to this equation, the TTCA level TTCA levels were 5.02 ppm and 1.61 mg/g
corresponding to the current TLV of 1 ppm for creatinine for all workers, 6.11 ppm and 1.94 mg/g
carbon disulfide is 0.4 mg/g creatinine. creatinine for spinning and refining workers, and
The eight studies in which the measured carbon 3.08 ppm and 0.98 mg/g creatinine for other
disulfide exposures were above 1 ppm indicate great workers, respectively.
variability when urinary excretion levels were In summary, the review of the published
extrapolated from these data to the current TLV of 1 literature indicates a clear correlation between
ppm. van Doorn and colleagues observed a mean airborne carbon disulfide exposure in viscose rayon
TTCA concentration of 12.5 ± 0.98 mg/g of plants and urinary TTCA concentration. In eight of
creatinine in urine at TWA concentration of 32 ppm the studies, the measured carbon disulfide
of carbon disulfide in 22 viscose rayon process exposures were substantially above the TLV of 1
workers (van Doorn et al., 1981a). Extrapolation of ppm (3.13 mg/m3) and, thus, it was not feasible to
these data to exposure at the current TLV of 1 ppm ascertain the relationship between the TTCA
for carbon disulfide results in urinary excretion of concentration and airborne carbon disulfide
approximately 1 mg TTCA/g creatinine. In the exposure at or below 1 ppm from these studies.
studies by Rosier and colleagues, the carbon However, from four studies, the correlation between
disulfide concentration in a viscose rayon process personal airborne carbon disulfide exposure at the
varied between 2.4 and 51 ppm (Rosier et al., 1982, current TLV of 1 ppm and urinary TTCA concen-
1984). Although there was a significant dose- tration could be ascertained (Meuling et al., 1990;
response relationship between average carbon Riihimäki et al., 1992; Drexler et al., 1994; Shih et
disulfide concentration in air and the increase of al., 2003). In these studies, the mean TTCA
TTCA concentration in urine during the workday, concentration at mean TLV of 1 ppm varied from 0.2
estimation of the TTCA concentration at airborne to 0.9 mg/g creatinine. Based on these data, an
concentration of 1 ppm of carbon disulfide was not average urinary excretion of 0.5 mg TTCA/g
feasible from this data because the measured creatinine is estimated at 1 ppm of carbon disulfide
exposure levels were substantially above 1 ppm. exposure.
Campbell and colleagues monitored 23 workers, 13
exposed to carbon disulfide and 10 controls, in a
Laboratory Studies
viscose rayon plant by personal sampling on day Rosier and colleagues studied the excretion of
one and day five of a workweek (Campbell et al., TTCA in six human volunteers in a laboratory
1985). Inhalation exposure averaged 11 ppm on day
ACGIH® © 2009 Carbon disulfide BEI® – 7
chamber by exposing them to 3 ppm of carbon end of exposure or end of shift as the Biological
disulfide at 50 W workload, 10 ppm at rest or at 50 Tolerance Value (BAT) (DFG, 2006). The BAT value
W workload, or 20 ppm at rest for four consecutive is based on the relationship between TTCA in urine
periods of 50 minutes with a 10-minute break and health effects.
between each period (Rosier et al., 1987). Carbon The Finnish Ministry of Social Affairs and Health
disulfide was excreted as TTCA representing 0.7– recommends 2 mmol TTCA/mol creatinine (2.9 mg
2.2% of the absorbed dose, with a half-life of two TTCA/g creatinine) for a sample collected at the
hours. Carbon disulfide exposure correlated best end-of-shift, end of workweek, or end of exposure
with the excretion rate of TTCA (r = 0.70) followed period as the Biological Limit Value (Finnish Ministry
by urinary concentration (r = 0.66) and creatinine of Social Affairs and Health, 2005).
corrected urinary concentration (r = 0.64). The
average TTCA concentration at 3 ppm carbon Other Indicators of Exposure
disulfide exposure level was 1.08 ± 0.71 mg/g
creatinine (0.77 ± 0.51 mmol/mol creatinine). 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,
Current Database Available
1983; NIOSH, 1977; Rosensteel et al., 1974; Rosier
A sufficient database is available to recommend et al., 1984). However, the test is not sensitive
a BEI for TTCA as an indicator of carbon disulfide enough to detect exposures equivalent to the current
exposure. The measurement of TTCA in urine TLV (Campbell et al., 1985; WHO, 1979), and the
collected at the end of the shift, end of workweek is BEI Committee does not recommend this
suitable for monitoring exposure to carbon disulfide. determinant.
The excretion is a good indicator of exposure on the The measurement of carbon disulfide in urine
sampling day. The TTCA measurement is a non- and blood collected immediately after exposure has
specific indicator of exposure to carbon disulfide. been suggested (Herber, 1976; Teisinger and
TTCA may be excreted in the urine following Soucek, 1949). Lam and DiStefano exposed rats to
exposure to some medications, industrial chemicals, carbon disulfide and observed that blood-bound
and consumption of large quantities of cruciferous carbon disulfide increased linearly for four hours and
vegetables (e.g., cabbage, broccoli, turnip, lettuce) thereafter showed a curvilinear rise for at least 32
or possibly alcoholic beverages. The iodine-azide hours (Lam and DiStefano, 1982). Elimination was
test, used widely to assess carbon disulfide observed to be biexponential with a half-life of two
exposure in the past, is not recommended because hours and 43 hours. Acid-labile carbon disulfide in
of the lack of sensitivity at the current TLV. blood (Campbell et al., 1985) and toluene-3,4-dithiol
(free and protein bound) analysis of plasma and
Recommendation hemolysate (Johnson et al., 1983; Valentine et al.,
1999) may also be useful in assessing carbon
ACGIH® recommends monitoring TTCA in urine disulfide exposure. The BEI Committee does not
collected at the end of the work shift as an indicator recommend these determinants because of the lack
of current exposure to carbon disulfide. The of reliable data in humans.
recommended BEI of 0.5 mg TTCA/g creatinine Breath analysis for exposure monitoring has
corresponds to an eight-hour exposure at the current only been reported in one study (Campbell et al.,
carbon disulfide TLV of 1 ppm. Dermal exposure to 1985). Due to the limited data, ACGIH® does not
liquid carbon disulfide may alter the relationship recommend this determinant.
between concentrations of carbon disulfide in air and Djuric and others have recommended the
TTCA in urine. The sampling time is critical. Sample administration of disulfiram to workers and
contamination is unlikely. The recommended BEI is measurement of diethylthiocarbamates in urine as
equivalent in the International System of Units (SI) to an exposure test for carbon disulfide (Djuric, 1967;
0.35 mmol/mol of creatinine. WHO, 1979, 1981). This test is not recommended by
ACGIH®.
Other Reference Values
The German Commission for the Investigation of BEI® Chronology
Health Hazards of Chemical Compounds in the See Table 1.
Work Area recommends 4 mg TTCA/g creatinine,
with a skin notation, for a sample collected at the

8 — Carbon Disulfide BEI® ACGIH® © 2009


Table 1. BEI® Chronology
Date Action Determinant Sampling Time BEI® Notation

1986 Proposed 2-Thioxothiazolidine-4-carboxylic End of shift 5 mg/g creatinine


acid (TTCA) in urine
1988 Adopted 2-Thioxothiazolidine-4-carboxylic End of shift 5 mg/g creatinine
acid (TTCA) in urine
2009 Proposed 2-Thioxothiazolidine-4-carboxylic End of shift 0.5 mg/g creatinine Ns, B
acid (TTCA) in urine

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12 — Carbon Disulfide BEI® ACGIH® © 2009