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Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):

Additional information


Considering the available data set (Mitoma et al., 1985, Reitz et al., 1982, Tsuruta, 1975, Yllner, 1971 and Jakobson et al., 1982), 1,2-dichloroethane was well absorbed by all routes of exposure and rapidly distributed throughout the body with preferential affinity to adipose tissues, but was readily released from all compartments without signs of accumulation. The greatest part underwent extensive metabolism, followed by rapid excretion of metabolites into the urine, another fraction mainly eliminated unchanged by exhalation (overall approx. 90 % within 48 hours). In a recent study conducted by Sweeney et al. (2008) a model calculation for physiologically based pharmacokinetics (PBPK) was established, which for route-to-route extrapolation of existing and future toxicity studies conducted by the oral route was considered to facilitate the quantitative evaluation of potential hazards posed by 1,2-dichloroethane inhalation. The focus of the model parameterization process was to identify a set of parameter values that would "fit" most of the experimental data on absorption, distribution, metabolism, and elimination of 1,2-dichloroethane in rats. In general, the resulting model fits were well within the 2-fold range specified in the ECA (U.S. EPA, 2003). The experimental results used for the model calculation and development process are summarized below.

Systemic absorption and elimination characteristics

After 6-hour inhalation (150 ppm, Osborne-Mendel rats), the maximum blood concentration (after 2-3 hours) was 8-10 μg/mL and disappeared by 80 % within 30 min and by more than 97 % within 80 min (Spreafico et al., 1980). Single oral application of 150 mg/kg bw (gavage, SD rats) caused peak blood levels after 15 min of 30 -44 μg/mL, i.e. 4–5x higher than after inhalation, and it took about 3 hours to reach the maximum level seen with inhalation (Reitz et al., 1982). Based upon the rapid elimination rate, 1,2-dichloroethane was expected to be quantitatively removed under either test condition. However, oral gavage application tended to create a prolonged state with blood concentrations significantly higher than during an inhalation cycle of 6 -7 hours with comparable body burden.

Blood levels and toxicity

Several blood levels in rabbits and dogs following 6-7 hours inhalation exposure towards concentrations of 1000 -3000 ppm were published by Heppel et al. (1946): Blood levels ranged from 8 -30 μg/mL at 1000 ppm in dogs and 20 -40 μg/mL at 1500 ppm in rabbits and dogs to 40 μg/mL and higher at 3000 ppm in rabbits. No data were reported at lower exposures for these species. The 1,2-dichloroethane blood level of 8–10 μg/mL after 6 hours inhalation of 150 ppm in rats (Reitz et al., 1982) was considered to possibly represent a non-toxic to toxic threshold dose in rats under the study conditions (see also: Spreafico et al., 1980; Maltoni et al., 1980). The corresponding blood level of 1,2-dichloroethane was 30 μg/mL after single 6 hours exposure to 250 ppm (Spreafico et al., 1980). Spreafico et al. (1980) found blood concentrations of 1.4 μg/mL after single 6 hours exposure to 50 ppm ethylene dichloride in SD rats, while after long-term exposure to 50 ppm, a lower concentration range of 0.22–0.28 μg/mL was detected in the blood of 2-year old SD rats when measured 15 and 135 min after the final 7 hours exposure (Cheever et al., 1990). There appeared to be a shift in kinetics due to prolonged exposure and/or age of the animals. In the 2-year study, after exposure to 50 ppm 1,2-dichloroethane with 0.05 % disulfiram, the blood levels were about 1.4 μg/mL, i.e. about 5 times higher than with 1,2-dichloroethane alone (Cheever et al., 1990). For oral administration by gavage, doses of 25, 50, and 150 mg/kg bw produced peak blood levels of 13, 30 and 67 μg/mL, respectively (Spreafico et al., 1980). Reitz et al. (1992) found 30 – 44 μg/mL in blood of Osborne-Mendel rats given a dose of 150 mg/kg bw by gavage. There were no blood data on corresponding doses administered in drinking water. The different 1,2-dichloroethane levels in blood and liver which were expected to be considerably higher after gavage administration than after drinking water consumption represented invasion kinetics comparable to that associated with inhalation exposure. These data suggested that a blood level of 5-10 μg/mL could be considered as a critical threshold level in rats under the study conditions beyond which saturation of metabolic pathways was considered to give rise to toxicity (Reitz et al., 1982; IARC, 1999). The relevance of metabolic saturation and overstress of liver metabolic capacity for the formation of oncogenic intermediates was still hypothetical (Spreafico et al., 1980).

Saturation kinetics

The elimination of 1,2-dichloroethane from the body was a saturable process and has been shown by overproportionate increases in tissue levels of 1,2-dichloroethane, reduction of elimination rates, and depression of the metabolising capacity, thereby concomitantly increasing the fraction of unmetabolised substance in exhaled air (Reitz et al, 1982). After single 6 -hours inhalation exposure, the 5 -fold increase in exposure concentration (from 50 to 250 ppm) led to a multifold enhancement of 1,2 -dichloroethane in the tissues (Spreafico et al., 1980): about 23x in blood, 20x in liver, 35x in lung, and 27x in adipose tissue. Thereby, the tissue-specific elimination half-lives of approx. 10 -13 min increased by a factor of 1.7 -2 at maximum in liver and blood, respectively, but in adipose tissue insignificantly from about 23 -28 min. After single oral doses of 25, 50 and 150 mg/kg bw (gavage), no such exponential increases were seen for 1,2-dichloroethane in the blood and relevant tissues, but ratios of the respective areas under the curve (AUCs) after 150 or 25 mg/kg bw determined in blood and liver were 16 and 8 rather than 6 as expected from the ratio of both doses (150 and 25 mg/kg)

Distribution characteristics after oral gavage and inhalation

Appreciable amounts of 1,2-dichloroethane accumulated in the various tissues in SD rats after oral administration of 25 mg/kg bw, but only very little after inhalation exposure to 50 ppm for 6 hours (Spreafico et al., 1980): tissue peak levels at 50 ppm were about 1/10, in liver about 1/30 of that at 25 mg/kg bw following oral exposure, even more striking for the corresponding AUCs. With increasing doses, tissue disposition went up more or less linearly, but resulted in substantial liver levels. However, after inhalation exposure, the liver values at 250 ppm were only similar to those found at the oral dose of 25 mg/kg bw and were about 1/4 of the peak concentration and about 1/8 of the AUC observed at 150 mg/kg bw. In relation to the low liver burden, 1,2-dichloroethane concentration in adipose tissue appeared to be very high. Overall, the kinetic parameters derived by Spreafico et al. (1980) suggested that the inhalation of 50 ppm (6 hours) correlated to an oral dose (gavage) significantly below 25 mg/kg bw, and 250 ppm to a dose between 25 and 50 mg/kg bw. This implied that during inhalation exposure to apparently high 1,2-dichloroethane concentrations (e.g. 250 ppm), the liver burden appeared to be low without noticeable metabolic limitation, whereas oral gavage applications tended to overstress liver metabolic capacities (Maltoni et al., 1980, Spreafico et al., 1980 and NCI, 1978).

Dermal absorption

In an in vitro dermal absorption study by Ward (1992) with rat and human skin a relatively fast absorption of 1,2-dichloroethane through the skin was observed. Consideration of the results and observations by the author suggested that neat 1,2-dichloroethane formed a reservoir in human epidermis, allowing fairly rapid absorption to continue for a very short time after the applied 1,2-dichloroethane had evaporated. With rat epidermis, however, little or no such reservoir was built up and absorption rapidly decreased after the applied 1,2-dichloroethane evaporated. From the study of Ward (1992), the dermal absorption of 1,2-DCE can be estimated to be about 1.5% in rats after unoccluded applications.

Metabolism and toxicity

About 50–86 % of absorbed 1,2-dichloroethane underwent metabolism and subsequent urinary excretion. Only a minor portion of the substance, i.e. 4–18 % was metabolically converted to carbon dioxide while 8 - 42 % was exhaled as parent compound (Mitoma et al., 1985, Reitz et al., 1982, Tsuruta 1975 and Yllner, 1971). Urinary metabolites consisted mainly of thiodiacetic acid, the corresponding sulfoxide and S-carboxymethylcysteine. Small amounts of chloroacetic acid and very low concentrations of S,S-ethylene-bis-cysteine and chloroethanol were also found in urine (Guengerich et al., 1980). The two metabolic routes involved in the biotransformation of 1,2-dichloroethane were oxidation by mixed-function-oxidases, i.e. enzymes of the cytochrome P 450 family, and glutathione-S-transferase mediated glutathione (GSH) conjugation, respectively. In SD rats, depletion of hepatic GSH was found to be substantial after a single oral, maximally tolerated dose (MTD) of 625 mg/kg bw: less than 10 % of the GSH level in untreated control livers was recovered after 18 hours posttreatment, which represented by far the highest GSH loss as compared with other structure-related compounds concurrently tested in this study (Moody and Smuckler, 1986). Both metabolic pathways lead to the formation of reactive intermediates with chloroacetaldehyde and chloroethanol being produced by cytochrome P 450 dependent metabolism and an episulfonium ion being formed by glutathione conjugation. The reactive species formed were both capable of binding to DNA and were suspect of being responsible for in vivo genotoxic and carcinogenic activity of 1,2-dichloroethane (Guengerich et al., 1980 and Storer et al., 1984). This was supported by the observation that after absorption of comparable doses of 1,2 -dichloroethane, five times higher peak plasma levels were observed after oral as compared to inhalation exposure which was accompanied by about a five times higher binding of radiolabeled 1,2-dichloroethane-borne compounds in the liver DNA after oral than after inhalation exposure (Reitz et al., 1982). The 5-fold increase in DNA-binding was explained by a saturation of the oxidative and detoxifying GSH-dependent metabolism occurring after oral but not after inhalation exposure because of the different invasion and distribution kinetics.

References for ethylene dichloride toxicokinetic evaluation

- Cheever KL, Cholakis JM, El-Hawari AM, Kovatch RM and Weisburger EK (1990). Ethylene dichloride: The influence of disulfiram or ethanol on oncogenicity, metabolism, and DNA covalent binding in rats. Fundam. Appl. Toxicol. 14: 243 -261

- Guengerich FP, Crawford WM Jr, Domoradzki JY, Macdonald TL and Watanabe PG (1980). In vitro activation of 1,2-dichloroethane by microsomal and cytosolic enzymes. Toxicol. Appl. Pharmacol. 55: 303 -317

- Heppel LA, Neal PA, Perrin TL, Endicott KM and Porterfield VT (1946). The toxicology of 1,2-dichloroethane (ethylene dichloride). J. Ind. Hyg. Toxicol. 28: 113 -120

- IARC (1999). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol 71 (Part II), Lyon, 501-529

- Jakobson I, Wahlberg JE, Holmberg B and Johansson G (1982). Uptake via the blood and elimination of 10 organic solvents following epicutaneous exposure of anesthetized guinea pigs. Toxicol. Appl. Pharmacol. 63: 181–187

- Maltoni C, Valgimigli L and Scarnato C (1980). Long term carcinogenic bioassays on ethylene dichloride administered by inhalation to rats and mice. Banbury Report 5. Ethylenedichloride: A Potential Health Risk? Cold Spring Harbor, NY, 3-29

- Mitoma C, Steeger T, Jackson SE, Wheeler KP, Rogers JH and Milman HA (1985). Metabolic disposition study of chlorinated hydrocarbons in rats and mice. Drug Chem. Toxicol. 8: 183–194

- Moody DE and Smuckler EA (1986). Disturbances in hepatic heme metabolism in rats administered alkyl halides. Toxicol. Lett. 32, 209 -214

- NCI (1978): National Cancer Institute. Bioassay of 1,2 -dichloroethane for possible carcinogenicity. NCI Tech. Rep. 55. NTIS/PB 285 -968

- Reitz RH, Fox TR, Ramsey JC, Quast JF, Langvardt PW and Watanabe PG (1982). Pharmacokinetics and macromolecular interactions of ethylene dichloride in rats after inhalation or gavage. Toxicol. Appl. Pharmacol. 62: 190–204

- Spreafico F, Zuccato E, Marcucci M, Sironi M, Paglialung S, Madonna M and Mussini E (1980). Pharmacokinetics of ethylene dichloride in rats treated by different routes and its long-term inhalatory toxicity. In: Ames B, Infante P and Reitz R (eds.): Ethylene dichloride: A potential health risk? Banbury Report 5. Cold Spring Harbor, NY, pp 107–133

- Storer RD, Jackson NM and Conolly RB (1984). In vivo genotoxicity and acute hepatotoxicity of 1,2-dichloroethane in mice: Comparison of oral, intraperitoneal, and inhalation routes of exposure. Cancer Res. 44: 4267 -4271

- Sweeney LM, Saghir SA and Gargas ML (2008). Physiologically based pharmacokinetic model development and simulations for ethylene dichloride (1,2-dichloroethane) in rats. Regulatory Toxicology and Pharmacology 51: 311 -323

- Tsuruta H (1975). Percutaneous absorption of organic solvents. 1) Comparative study of the in vivo percutaneous absorption of chlorinated solvents in mice. Ind. Health 13: 227 -236

- Ward, RJ (1992). Ethylene dichloride: In vitro absorption through human and rat epidermis. Unpublished study report

- Yllner S (1971). Metabolism of 1,2-dichloroethane-14C in the mouse. Acta Pharmacol. Toxicol. 30: 257 -265