Diethyl ether

Endpoint summary

Description of key information

Limited bioaccumulation potential is expected.

Absorption

Diethyl ether is absorbed by inhalation, passing the alveolar wall and into the blood. Absorption can occur by ingestion through the mucous membranes of the gastrointestinal tract. Dermal absorption is possible, though expected to be limited.

Distribution

Diethyl ether is distributed between the blood, central nervous system, fat and connective tissue. Concentrations in muscle remain lower than in the brain or fatty tissue.

Metabolism

In humans, approximately 8% of diethyl ether is metabolised by glucuronidation and eliminated via the kidneys. A further 2% is metabolised to carbon dioxide and water. (Price, H.L., General Anesthetics, in The Pharmacological Basis of Therapeutics, 5th Ed, 1975, McMillan, p89 - 96). Acetaldehyde and ethanol were identified as metabolites in radiolabelled animal studies.

Elimination

Over 90% of diethyl ether is expired via the lungs. 1 - 2% is excreted in urine. Concentrations of diethyl ether in fatty tissue remain high until blood levels have dropped significantly.

Diethyl ether is expected to be relatively rapidly eliminated from the body. No significant bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

The low molecular weight (74.12 g/mol) and log Pow (1.05) of diethyl ether favour its absorption via various routes of exposure (oral, dermal, and inhalation). The most relevant route of exposure is inhalation as the substance possesses a high vapour pressure (716 hPa at 25 ºC). Moreover, systemic absorption following dermal exposure would be minimal considering that diethyl ether would rapidly vaporize from the skin; this is supported by a dermal LD50 value of greater than the maximum application rate of 20 mL/kg body weight in rabbits. Consistent with the prediction that diethyl ether is systemically absorbed following inhalation exposure, a toxicokinetic study in humans demonstrated that the compound is immediately absorbed into the systemic circulation upon inhalation exposure and induces clinical anaesthesia, indicating that the substance crosses the blood-brain barrier. This in turn is consistent with the former use of diethyl ether as a general anaesthetic. A wide tissue distribution of diethyl ether is expected, particularly to organs with a rich blood supply; however, distribution to fat tissue is a slow process. The excretion of diethyl ether appears to consist of three phases; the first representing rapid elimination from the blood, the second representing elimination from tissues with a rich blood supply, and the third representing elimination from tissues with a poor blood supply, such as fat. In humans, the bulk of an absorbed inhalation dose of diethyl ether (34 to 84%) is rapidly excreted unchanged via the lungs in exhaled air. 

 

Toxicokinetic and toxicity data from animal studies are consistent with the above information. The mortality and central nervous system effects, including anaesthesia, observed in experimental animals following acute oral or inhalation exposure to diethyl ether are indicative of systemic absorption via these routes of exposure. In dogs, arterial blood levels of diethyl ether following inhalation exposure very closely reflect those in the brain, and accordingly, reflect the clinical status of anaesthesia. Following exposure to such anaesthetic concentrations, diethyl ether distributes mainly to omental fat, kidneys, and adrenal glands. The compound also distributes to the thyroid, brain, pancreas, heart, liver, spleen, skeletal muscle, and lungs. In rats, diethyl ether and/or its metabolites are distributed relatively uniformly throughout the body, with higher levels distributed to the brain, kidneys, liver, and brown fat and lower levels to general body fat. The compound has also been detected in the muscle and lungs of rats. Thus, diethyl ether is widely distributed throughout body tissues. Consistent with the human data, distribution to and elimination from fat tissue is relatively slow in animals; diethyl ether is eliminated from plasma within 12 hours and from fat within 24 hours in dogs. Results of repeated-dose inhalation and oral toxicity studies confirm the liver to be a target organ of diethyl ether toxicity. Furthermore, fetal effects observed in mice and rats following a single exposure of dams to diethyl ether during early or late embryogenesis suggest that the compound crosses the placental barrier at doses causing maternal anaesthesia. 

 

From in vivo and in vitro metabolic data, the mechanism of diethyl ether metabolism involves cleavage of diethyl ether to form acetaldehyde and ethanol, which are rapidly oxidized to acetate. Acetate, in turn, enters the 2-carbon pool of intermediary metabolism, resulting in the formation of CO2, cholesterol, and fatty acids, which are subsequently metabolized to mono-, di-, and triglycerides. Therefore, diethyl ether is metabolized to both non-volatile and volatile metabolites, particularly in the liver. The oxidative metabolism of diethyl ether to acetaldehyde and ethanol is catalyzed by cytochrome P450 2E1, which may be involved in the mechanism of diethyl ether toxicity in the liver via the production of oxidative stress. Diethyl ether also undergoes conjugation with glucuronic acid in the liver. However, the majority of an absorbed inhalation dose of diethyl ether (87% in dogs) is excreted unchanged via the lungs in expired air, the excretion of which is independent of exposure length. A small amount of unchanged diethyl ether is also excreted in urine (2 and 3.3% of an absorbed dose in rats and dogs, respectively) and in bile. The excretion of diethyl ether as CO2 via the lungs also occurs to a small extent (4% of an administered dose in rats). Based on the available metabolic data and taking into consideration its low molecular weight and log Pow and solubility in water, diethyl ether is not expected to bioaccumulate.