Chloroethane

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Exposure to chloroethane is most likely via inhalation, since the substance is a gas.

 

Absorption and Distribution

Chloroethane is readily absorbed into the blood via the lungs after inhalation. 25% of the amount in the blood is found in the plasma, whereas 75% is localized in the blood cells. When dogs were anaesthetized with chloroethane, the concentration is slightly higher in the arterial blood in comparison to the venous blood (Camus and Nicloux, 1908). In rabbits, this finding was not verified. At equilibrium in the brain of rabbits nearly a two-fold amount is found compared to the blood. The highest concentration of chloroethane in the animal body was found in fatty tissue around the kidney and the lowest was found in the cerebrospinal fluid (Konietzko, 1984).

 

Metabolism and Elimination

Halogenated hydrocarbons can be metabolized primarily by Cytochrome P450 enzymes (CYP) and by conjugation with glutathione.

The role of oxidation by Cytochrome P-450 dependent monooxygenases was examined in Fischer 344 rats and B6C3F1 mice exposed 6 hours/day for 5 consecutive days to 15000 ppm chloroethane or to air (Fedtke et al., 1994). Five days of chloroethane exposure prior to the isolation of microsomes increased the microsomal in vitro metabolism of chloroethane in mice and female rats by about 100%, but had no effect in male rats. It is concluded that chloroethane acts as an inducer of its own oxidative metabolism, except the male rat. The p-nitrophenol rates, which served as an indicator for the activity of the Cytochrome P450 subfamily 2E1 were increased in mice and female rats, but not in male rats. Catalytic activities (EROD and PROD) related to P450 1A and 2B subfamilies were not induced by chloroethane treatment. Pre-treatment of animals with phenobarbital and 3-methylchloanthrene decreased the chloroethane metabolism rates in microsomes, whereas pre-treatment with acetone induced the metabolism rate up to 500% in rats and 30-40% in the mice, respectively. These experiments also confirmed that the isoenzyme mainly involved in the dechlorination reaction is P450 2E1. Acetaldehyde was identified as main metabolite. It was detected in only slightly enhanced amounts in the urine samples of exposed mice but not in serum samples from the animals indicating that the metabolically formed acetaldehyde in vivo is rapidly degraded further.

In parallel, Fedtke et al. (1994) investigated the degradation of chloroethane via the conjugation to glutathione after exposure of rats and mice to 15000 ppm for 5 days, 6 hours/day. Catalyzed by GSH-S-transferases, chloroethane reacts with glutathione and forms S-ethyl-glutathione with cleavage of hydrogen chloride. S-ethylglutathione is decomposed further to S-ethyl-L-cysteine. This cysteine conjugate is metabolized through N-acetylation to the corresponding mercapturic acid (S-ethyl-N-acetyl-L-cysteine). In the urine of both species S-ethyl-N-acetyl-L-cysteine was detected and was generally higher in mice than in rats. S-ethyl-cysteine was excreted in mouse urine only, since rats metabolize S-ethyl-cysteine to more hydrophobic metabolites prior to urinary excretion. Chloroethane exposure resulted in a GSH depletion of about 50% in the lung and uterus of both species, whereas liver and kidney GSH concentrations were not dramatically affected. Whereas repeated chloroethane exposure induced the enzyme systems of the oxidative metabolism (CYP-450) in mice and rats, no induction was observed with regard to GSH-S-transferase. At high exposure the oxidative pathway is saturated and increasing amounts are metabolized via the GSH pathway.

 

Quantitative species differences were determined with regard to both pathways, revealing higher rates for mice compared to rats, e.g. the mouse metabolizes chloroethane via the GSH-S-transferase pathway by about a half of an order of magnitude faster than the rat. Pottenger et al. (1991, 1992) also showed species differences in chloroethane metabolism. In the mouse high chloroethane concentrations are mainly metabolized via GSH-conjugation, whereas in rats at high chloroethane concentrations exhalation of the unchanged substance predominates. 

Closed atmosphere gas uptake exposures were used to estimate the kinetic constants of metabolism of chloroethane in male Fischer-344 rats, using a physiologically based pharmacokinetic model (PB-PK). Chloroethane metabolism was best described as a combination of saturable and first-order processes.

 In a volunteer study by Morgan et al. (1970) human subjects were exposed to about 5 mg 38Cl-chloroethane by taking one single breath through the mouth. About 30% of the administered radioactivity was eliminated in the breath within 1 hour. Urinary excretion of 38Cl amounted to < 0.01% of the dose/min.

 

Toxicokinetics, in vitro data

Partition coefficients of chloroethane in various liquids and tissues from male Fischer-344 rats were determined in vitro at 37 °C by Gargas et al. (1989). The following table summarizes the results, suggesting that chloroethane has a higher affinity for fat than for blood, liver or muscle:

 

blood/air: 4.08 +/- 0.39

0.9% saline/air: 1.09 +/- 0.06

olive oil/air: 38.9 +/- 3.1

fat/air: 38.6 +/- 0.7

liver/air: 3.61 +/- 0.32

muscle/air: 3.22 +/- 0.68

 

The partition coefficient for human blood/air was found to be 2.69 +/- 0.20. Morgan et al. (1970) measured partition coefficients for human blood and serum in vitro at 40 °C and found 1.9 for blood/air and 1.2 for serum/air.

 

References:

Konietzko, H. (1984) Chlorinated ethanes: Sources, distribution, environmental impact and health effects. Hazard Assessment of Chemicals 3:401-448 (as cited in ATSDR, 1998)

Morgan, A., Black, A. and Belcher, D.R. (1970) The excretion in breath of some aliphatic halogenated hydrocarbons following administration by inhalation. Ann. Occup. Hyg., 13: 219-233 (as cited in IARC, 1991)