Carbon disulphide

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result:

The toxicokinetics of CS2 have extensively been investigated. A large series of studies have been published, which cover a wide range of aspects. These studies have been reviewed thoroughly several times. They include human volunteer studies, studies with experimental animals and in-vitro studies. See further under "Discussion" below.

Short description of key information on absorption rate:

The following studies are available: a human volunteer study on the absorption from aqueous solutions, a study with rabbits on the absorption from the vapour phase and an in-vitro study with human skin. Part of the information is presented already in Section 7.1.1 Basic toxicokinetics

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

CS2 is rapidly and extensively absorbed upon inhalation. An equilibrium between exhaled air and inhaled air concentrations and a blood steady-state concentration is established within approx. 2 hours or less. Absorption after inhalation varies depending on various factors (excercise, body fat), but 80% has been measured initially, when the equilibrium is not reached, while at equilibrium 40% or less of the inhaled substance enters the circulation.

A human study shows that CS2 is absorbed through the skin from aqueous solutions. Concentrations of 0.33 -1.67 g/L resulted in a flux of 0.232 -0.789 mg/cm^2/h. An old study with rabbits indicated the dermal absorption of CS2 from the vapour phase. One study with rats is available that demonstrates the exhalation of 63% of an oral dose within 4 hours via the exhaled air, thus demonstrating a substantial and rapid oral absorption.

The compound itself (i.e. CS2) is largely eliminated via the exhaled air. After termination of exposure, the elimination of unaltered CS2 via the exhaled air amounts roughly to 5 -50% of the absorbed amount. Unaltered CS2 is hardly excreted via the kidneys: less than 1%. The elimination of the parent compound via exhalation is biphasic, both phases being exponential. In one human study a half-life of 1.1 min was followed by a half-life of 109.7 min.

No distribution studies with humans are available. Two studies with rats studied the distribution of free unaltered CS2 and acid-labile CS2 (ALCS2). ALCS2 is CS2 bound reversibly in the form of dithiocarbamates and other conjugation products. The CS2 is set free by acid and ALCS2 can give rise to CS2 exposure in vivo. CS2 or ALCS2 were found in a series of tissues, including liver, kidney, hearth muscle, brain, blood, fat and adrenals. The free CS2 reached a steady state in these organs within 4-5 hours, with the exception of fat, and rapidly disappeared upon termination of exposure. ALCS2 takes much longer to reach a steady-state concentration and to leave the body after termination of exposure. Whereas the elimination half-lifes from blood for free CS2 were in one of the studies 9 and 55 min, those for ALCS were 2.2 and 42.7 hours.

Human data show that CS2 metabolites are largely excreted via the kidneys. These metabolites result from several metabolic pathways: reaction with glutathione, cysteine and amino acids, and oxidation through CYP-dependent mixed function oxidases. Metabolites detected in human urine include 2 -thio-5 -thiazolidone, thiourea, 2 -thiothiazolidin-4 -carboxylglycine (TTCG) and 2 -thiozolidine-4 -carboxylic acid (TTCA). TTCA in urine is used for biological monitoring purposes. The oxidation of CS2 by mixed function oxidases results in carbonyl sulfide and elemental sulphur. In animals the formation of inorganic sulfate and CO2 occurs. There are no data pointing to the formation of these inorganic compounds in humans.

Discussion on absorption rate:

The dermal absorption was also discussed in Section 7.1.1 Basic toxicokinetics

A human study shows that CS2 is absorbed through the skin from aqueous solutions. Concentrations of 0.33 -1.67 g/L resulted in a flux of 0.232 -0.789 mg/cm^2/h. An old study with rabbits indicated the dermal absorption of CS2 from the vapour phase. A recent in-vitro study with human skin yielded a permeation coefficient of 0.00332 cm/h. It can be concluded that CS2 is readily absorbed by the body through the skin.

In the TK study it was demonstrated that systemic exposure to carbon disulfide, as evaluated by whole blood AUClast, is dose-proportional and that the distribution of carbon disulfide and 2-thiothiazolidine-4-carboxylic acid in the urine and expired air does not differ by dose or by dose route. In addition, single and, based on the data collected for 2 -thiothiazolidine-4-carboxylic acid and carbon disulfide, repeated oral doses can be scaled to match the desired equivalent inhalation exposure.