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Description of key information

Absorption: readily absorbed by all routes (gastrointestinal, respiratory tracts, slowest through skin).

Distribution: all organs, fast and relative to the perfusion of organs with exception of fat (higher half-life)

Metabolism: mainly by cytochrome P-450 enzymes (CYP 2E1 and CYP3Ax), with the production of the trichloromethyl radical. Aerobically: trichloromethyl radical -> phosgene, carbondioxide; anaerobically: trichloromethyl radical -> chloroform, hexachloroethane or carbon monoxide; covalent binding of aerobic and anaerobic metabolites to lipids, proteins, and DNA possible.

Excretion: primarily in exhaled air and in the faeces, relatively minimal amounts in the urine

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In addition to the study of Sanzgiri (1997) which is regarded as key study, many studies on the toxicokinetics of CTC have been carried out in the past 30 years. Following gastric infusion of 179 mg/kg of CCl4 in rats, the half-life in fat was about 12 hours, whereas the half-life’s in liver, kidney, lung, brain, heart, muscle and spleen were around 4 hours. Other findings are summarized in the citations from the ATSDR dossier 2005. CTC has a low but significant water solubility and a good fat solubility, is a small size (153,82 g/mol), it has a high membrane permeability and thereby a high absorption rate for the oral and the inhalation route and a reasonably fast absorption trough skin is found for mammals. The log Pow (2.83) is compatible with an accumulation in fat. Nevertheless the bioaccumulation potential is expected to be extremely low regarding the half-life’s of CTC in many organs.

As shown in Sanzgiri (1997), absorption of CTC is fast through either the gastro-intestinal tract or the lung (peak levels 30 min after start of exposure) except for the fat where maximal levels were reached later (after 2h in this test system). The same is reported for dermal absorption (see 7.1.2). CTC is distributed to all major organs, with highest concentrations in the fat, liver, bone marrow, adrenals, blood, brain, spinal cord, and kidney. Inhalation studies in monkeys, rats, and hamsters and mice reveal that the highest CTC concentrations occur in fat, and in organs or tissues with high fat content such as bone marrow, liver, brain, and kidney. The tissue concentrations reached are proportional to the diffusion rate of the organs and their fat content (highest concentrations in the fat, liver, bone marrow, adrenals, blood, brain, spinal cord, and kidney). Comparing inhalation and continuously gastric infusion a first pass effect becomes obvious, reducing CTC blood levels by metabolism. Once absorbed, CTC is metabolized by cytochrome P-450 enzymes with the production of the trichloromethyl radical: aerobically, metabolism of the trichloromethyl radical can eventually form phosgene; anaerobically, the radical can undergo reactions to form chloroform, hexachloroethane, as well as bind directly to lipids, proteins, and DNA. As found in other studies summarized in the ATSDR dossier, CTC is metabolized mainly by CYP2E1 and to a lower extent by other Cytochrome P450 enzymes. An electron is transferred to CTC to form chloride and a carbon trichloride radical. This reactive intermediate can react with oxygen to form trichloromethylperoxy radical and subsequently phosgene, can dimerise to hexachloroethane or can react with a proton and electron to form chloroform. Reductive dechlorination would lead to carbon monoxide. The trichloromethyl radical, the trichloromethylperoxy radical, phosgene and subsequent metabolites of chloroform can covalently modify biomolecules. Especially haloalkylation and lipid peroxidation are attributed to the toxicity of CTC seen in the metabolic active tissues of liver and kidneys. According to Draper (2009) the conversion rate of CTC in the liver is low compared to exhalation in the rat. Excretion occurs primarily in exhaled air and in the faces, while relatively minimal amounts are excreted in the urine. Depending on species and study design values of 34 -75% excretion via exhalation and 20 -62% excretion via faeces and only minor excretion via the urine have been determined (ATSDR 2005).