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Disulfiram is well and rapidly absorbed from the gastro intestinal tract. Based on physico-chemical data and information from the analogue substance thiram dermal absorption is rather low (≤10%). Disulfiram is widely distributed throughout the body in the lipids of the various tissues and is rapidly degraded by the rats to more polar products. The majority of the dose is eliminated from the body within 3 days after dosing either via urine or the expired air, and does not accumulate in the organism.

Key value for chemical safety assessment

Additional information

Disulfiram (tetraethylthiuramdisulfide, TETD) has been used extensively in the treatment of alcohol abuse for several decades.

It causes a blockade of the enzyme aldehyde dehydrogenase with consequently increasing levels of acetaldehyde upon ethanol consumption. The unpleasant clinical signs are known as Disulfiram-ethanol reaction (DER).

Therefore, relatively detailed toxicokinetic data for disulfiram in both, rat and man has been published as peer-reviewed literature.

Absorption

Disulfiram was found to be absorbed in a proportion of 70-90% of the administered dose upon oral administration in rats (Saint Blanquat, 1976). In rats,35S-disulfiram was rapidly absorbed by either route, upon oral or intraperitoneal administration (Faiman, 1980).

 

Regarding dermal absorption no data is available for disulfiram. On the basis of the following considerations, the dermal absorption of disulfiram is considered to be rather low. Regarding the molecular weight of 296.4 g/mol, the octanol/water partition coefficient of 3.6 in combination with the low water solubility of 4.09 mg/L, a low dermal absorption rate is anticipated. Based on the molecular weight absorption may occur (ECHA, 2012). Log Pow values between 1 and 4 (optimal 2-3) favour dermal absorption, particularly if water solubility is high (ECHA, 2012), which is not the case for disulfiram. A QSAR calculation with DERMWIN (v2.01) supports this assumption. Based on the physico-chemical properties, low dermal absorption was predicted (10% absorption). This is in concordance with the decision for thiram, which is similar to disulfiram in structure and physico-chemical properties, whereas default value of 10% has been set by the European Commission as result of the evaluation of thiram by RMS Belgium according to Directive 91/414/EEC. This is further supported from an acute dermal toxicity study with disulfiram, where no systemic effects and no mortality were observed up to the limit dose of 2000 mg/kg bw, which is in contrast to the results after oral application (LD50oral= 500 mg/kg bw).

 

Disulfiram has a very low vapour pressure of <0.0001 Pa at 20 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours is not significant.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols or dusts. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Among this inhalable fraction, only about 1.6% are ≤ 10 µm in diameter and belong to the thoracic fraction that reaches the tracheo-broncheal region. Only particles below 4 µm are likely to reach the alveolar region where absorption via lung can occur. Only about 0.02% of the airborne disulfiram particles belong to this fraction. Inhaled particles > 4 µm are eventually coughed out or swallowed which can then be treated as oral exposure.

Thus, absorption after inhalation of disulfiram is considered to be as high as after direct oral ingestion.

 

Distribution

Kidney, pancreas, liver, and the gastrointestinal tract exhibited the greatest uptake of radioactivity, while the least was found in brain. Preferential tissue uptake was similar with both routes of administration, oral and intraperitoneal (Faiman, 1980). Radioactivity in the various tissues investigated peaked between 0.5 and 1 hour after i.p. and between 4 and 6 hr following p.o.35S-disulfiram administration. Disulfiram, diethyldithiocarbamate (DDTC), and CS2are widely distributed throughout the body in the lipids of various tissues, and highest levels of these compounds are found in skeletal muscle (Peachey, 1981).

 

Metabolism

In rats35S-disulfiram was rapidly metabolized to the35S-diethyldithiocarbamate-glucuronide and35S inorganic sulfate. The main metabolite DDTC appeared already in the gut (Saint Blanquat, 1976).

Upon absorption, disulfiram is immediately reduced to DDTC when it reacts with thiol groups. DDTC is metabolized to diethylamine, carbon disulfide (CS2), DDTC methyl ester, DDTC glucuronide, and DDTC sulphate; a small amount of DDTC is reoxidized to disulfiram (Peachey, 1981). DDTC is a potent copper chelator, and it can thereby affect the activity of copper-dependent enzymes such as monooxygenases, amine oxidase, cytochrome oxidase, microsomal carboxylesterase, and plasma cholinesterase (Gaval-Cruz, 2009). In human blood, concentrations of zero to 0.6 µg carbon disulfide and 0.2 to 1.0 µg diethyldithiocarbamate per mL blood were found upon oral uptake of 200 mg disulfiram (Sauter, 1976).

It was suggested that the metabolite DDTC-methyl ester actually may be the metabolite of disulfiram which produces the disulfiram-ethanol reaction. It is proposed the reaction be more correctly identified as the DDTC-Me-Ethanol Reaction or D-MER (Yourick and Faiman, 1987).

 

Excretion

48 hours after oral administration of35S-disulfiram, 7% of the dose was excreted in the faeces and 67% via urine and approximately 11% of the dose was eliminated by the breath as CS2(Faiman, 1980).

In humans over 90% of orally administered disulfiram is eliminated within 3 days via the urine principally as DDTC and DDTC gluruconide and to a small extent as DDTC sulphate, and via the breath exclusively as CS2(Peachey, 1981).

Considering the likeness of the toxicokinetic characteristics of disulfiram and thiram (CAS# 137 -26 -8) it is possible to use thiram as a surrogate substance in a read-across on several endpoints. (For detailed information on the justification of read-across, please refer to the analogue justification document attached in IUCLID section 13). Thiram is well and rapidly absorbed from the gastrointestinal tract. The majority of the dose is eliminated from the body within four days after dosing either via urine (~34%) or the expired air (~48%), and does not accumulate in the organism (Banijamali et al, 1990). The highest tissue levels of thiram are found in blood and liver, independent of the administered dose and the elapsed time. Thiram is rapidly degraded by the rats to more polar products. The urine, which held ca. 30% of the [14C]-thiram-derived radioactivity, contained virtually no unchanged [14C]-thiram. Five urinary metabolites were detected and isolated by HPLC and identified by mass spectrometry (Gay et al., 1991).The same metabolites were described for disulfiram by Strome, 1963.