For information about other occupational safety and health problems, call 1-800-35-NIQSH ii DHHS (NIOSH) Publication No. 93-103 PREFACE A memorandum has been signed between the Centers for Disease Control, National Institute for Occupational Safety and Health (NIOSH), USA, and the Nordic Expert Group for Documentation o f Occupational Exposure Limits (NEG). The purpose o f the memorandum is to exchange information and expertise in the area o f occupational safety and health. One product of this agreement is the development of documents to provide a scientific basis for establishing recommended occupational exposure limits. The exposure limits will be developed separately by each country according to the different national policies. This document on the health effects of occupational exposure to ethyl ether is the second product of that agreement. The document was written by Bjorn Arvidson, Dr.# INTRODUCTION
Ethyl ether is a colorless, highly volatile, mobile liquid with a characteristic pungent odor. Ethyl ether is a serious fire hazard, as its vapor readily forms explosive mixtures with air and oxygen. It is miscible with the lower aliphatic alcohols, benzene, chloroform, petroleum ether, other fat solvents, and many oils. The primary physiologic effect of ethyl ether is general anesthesia. 1 ppm = 3.08 mg/m3 1 mg/m3 " 0.325 ppm Ethyl ether usually starts to oxidize soon after distillation, and ether peroxides, acetaldehyde and acetic acid are formed. Ether peroxide is less volatile than ethyl ether and tends to concentrate during evaporation or distillation. Ether peroxides, when concentrated, are a serious detonation hazard. Ethyl ether can be tested for the presence o f peroxides by shaking 10 ml of ether for one min with 1 ml of a freshly prepared 10% aqueous solution of potassium iodide in a 25-ml, glass-stoppered cylinder of colorless glass, protected from light. Appearance of a yellow color indicates peroxides (53). Other rapid tests for detecting peroxides in liquids are also available (53). Peroxides can be removed by distillation or by passage through an alumina column. If activated alumina is used, the ether is also dried in the process (53). Ferrous sulfate (30% solution in water) can be used in the proportion of 1 lb (0.4536 kg) to each 30 U.S. gallons (113.51) of ethyl ether to extract and to destroy peroxides (7).

# PHYSICAL AND CHEMICAL PROPERTIES*
Factors which delay decomposition of ethyl ether are absence of light, storage in a cool place, storage in copper tanks, or contact with a copper screen. Copper and certain other metals, particularly iron and mercury, prevent the oxidation o f ethyl ether since they are oxidized preferentially and consume the oxygen which is combined with ethyl ether (3). Ethyl ether should be stored in the original metal cans rather than in glass bottles. Very dry ethyl ether undergoes oxidation much more readily than ethyl ether containing a few tenths of a percent of water (7).
Ethyl ether is produced on a large scale by dehydration of ethanol or by hydration o f ethylene, both processes being carried out in the presence of sulfuric acid (3,28,80,151). Ethyl ether has a wide range of uses in the chemical industry. It is a good solvent for fats, oils, dyes, gums, resins, raw rubber, smokeless powder, perfumes, and nitrocellulose. Ethyl ether is also used in the manufacture of photographic films and pharmaceuticals, and as a reaction and extraction medium in the chemical industry. In addition, ethyl ether is used as an inhalation anesthetic in surgery, a refrigerant, in diesel fuels, in dry cleaning, and as a starting fuel for engines (

# USES AND OCCURRENCE

# Uses
Ethyl ether is commercially available in different grades. Depending on the consumer and use, specifications vary. In many instances the ether has to meet a specific test which is written in the specification (e.g., it may be important that the ether is free from alcohol and aldehyde, or completely anhydrous). The technical concentrated ether contains very small amounts of alcohol, water, aldehydes, peroxides, and other impurities such as sulfuric acid, sulfur dioxide, mercaptans, and ethyl esters (3,28,35,80). Some doubt exists as to whether or not these impurities as found in ethyl ether are toxic to man. In dogs, concentrations o f aldehyde up to 0.5% and mercaptans up to 1% produced no significant effects. Ether peroxides in a concentration of 0.3% had no effect whereas 0.5% caused a fall in blood pressure and respiratory difficulties. Ethyl sulfide in 1 % concentration caused gastroenteritis (23). Ethyl ether containing impurities produced anesthesia in mice more slowly than pure ethyl ether (84).
The more refined grades of ethyl ether, such as anesthetic ether, are obtained from technical ether by redistillation and dehydration followed by alkali or charcoal treatment (80). To prevent pollution by anesthetic gases in operating rooms, the Hospital Engineering Cooperative Groups of Denmark made recommendations in 1974 (146). The recommended highest permissible average concentration in the breathing zones of anesthesia personnel for ethyl ether was 3 ppm (9 mg/m3).

# Air Concentrations in the Working
Air concentrations of ethyl ether were measured in the laboratory of a brewing company in Illinois, USA (154). Ethyl ether was used in an extraction procedure to determine the fat content in com. Environmental monitoring was conducted using two methods; (1) a direct reading instrument, and (2) personal and area sampling to determine the integrated average exposures over the work shift. All results for the personal and area samples were less than 1 ppm. Measurements with the direct reading instrument showed peak concentrations up to 1,000 ppm (3,080 mg/m3) around the cork gaskets and pressure release valves on the extraction apparatus. However, the vapors were released inside a plexiglass enclosure where they were properly exhausted.
Personal breathing zone and area samples were taken in an analytical laboratory using solvents in the preparation o f soil and water samples (155). The values for ethyl ether were below the limit of quantitation (0.03 mg/sample).

# Analytical Methods for Ethyl Ether in Air and Body Tissues

# Direct Field Methods
Analysis of ethyl-ether-contaminated air in the work area may be done by means of a commercially available combustible gas indicator. Direct reading detector tubes are also available (8, 92).

# Laboratory Methods

# An air sampling technique for diethyl ether has been proposed by NIOSH (109)
. A known volume of air is drawn through a charcoal tube at a flow rate of 0.01 to 0.2 1/min. The charcoal in the tube is transferred to a small sample container and ethyl ether is desorbed with ethyl acetate. An aliquot of the desorbed sample is then injected into a gas chromatograph and the area of the resulting peak is determined and compared with standards. Advantages with this method is a small, portable sampling device and minimal interferences which can be eliminated by altering chromatographic conditions. A disadvantage is that the upper limit of the range of the method depends on the adsorptive capacity of the charcoal tube. In addition, the precision of the method is limited by the reproducibility of the pressure drop across the tubes.
Blood and tissue levels of ethyl ether can be analyzed by infrared analysis. This method was originally devised by Stewart et al. (144) and was used, with a slight modification, by Chenoweth et al. (33) for measuring blood and tissue levels of ethyl ether and other anesthetics in dogs. This method is also applicable to air analysis (8,31).
Ethyl ether in blood and urine can be analyzed by gas chromatography. The specimen is injected directly into a gas chromatograph equipped with a flame-ionization detector and a molecular sieve column. Specimens should be stored at 4C and analyzed as soon as possible. Breath samples may be analyzed by direct injection of 1-2 ml, using as standards suitably prepared dilutions o f ethyl ether in air. Calculation is based on a standard curve of peak height versus concentration of the standards (17).
Ethyl ether in air may be analyzed by passing the air through a fritted glass bubbler for reaction of the ethyl ether with acidic potassium dichromate and subsequent iodometric determination (133). A modification o f this method has also been used for determination of ethyl ether in blood (6, 117).

# Biological Monitoring
Tests for exposure may include expired breath for unmetabolized ethyl ether and blood for ethyl ether content (8). Blood concentrations of ethyl ether have been found to correlate with the degree of ethyl ether exposure and the extent o f intoxication. According to Baselt (17), the concentration o f ethyl ether in blood should not exceed a level o f about 20 mg/1 in asymptomatic workers. Gas chromatography can be used for determinations o f ethyl ether in blood, urine, and breath samples (17). Infrared analysis can be used for detection o f ethyl ether in breath and body fluids (8).

# DISTRIBUTION AND METABOLISM

# Uptake

# Uptake by Inhalation
After inhalation, ethyl ether is rapidly transferred from alveoli to blood. The normal alveolar membrane poses no barrier to the transfer of ethyl ether in either direction. The blood/gas distribution coefficient of ethyl ether is high-12.1. For oil/gas, the distribution coefficient is 65 (44). The more soluble an anesthetic is in blood, the more o f it must be dissolved in blood to raise its partial pressure there appreciably. Induction o f ethyl ether anesthesia is therefore slow. To achieve deep anesthesia with ethyl ether in medical practice takes 15-25 min (35) (the concentration of ethyl ether used for the induction o f anesthesia is usually 10 to 15 vol% or 308,000 to 462,000 mg/m3).

# Uptake from the Gastrointestinal Tract
No studies on the uptake of ethyl ether after peroral administration were found. According to Hayhursth (68), absorption of ether from the stomach and rectum is very prompt and may be used for anesthesia. No data were found on the extent of uptake of ethyl ether through undamaged skin in humans.
A case report described a 14-year-old boy who applied ethyl ether to his scalp under plastic occlusion to treat a seborrheic dermatitis. The boy was found dead and elevated but nonfatal concentrations of ethyl ether were found in the various postmortem tissues subjected to toxicological analysis. The authors conclusion was that the boy died from intoxication of resorbed ethyl ether. The authors interpreted the sublethal ethyl ether concentrations found in various tissues as probably incorrect due to ethyl ether's high volatility (29).

# Distribution
The The distribution of 14C-ethyl ether in the mouse was investigated with use of low-temperature autoradiography (34). Ethyl ether was administered by inhalation for 10 min. When the animals were killed immediately after the inhalation period, the anesthetic was rather uniformly distributed throughout the body, although higher concentrations were found in the brain, kidney, liver, and brown fat. After 2 hr, most of the radioactivity had left the body, but the liver, kidneys, intestines, and nasal mucous membranes were still labelled. A quantitative analysis showed that in 15 min, the radioactivity in brown fat had reached its peak relative concentration, whereas the relative concentrations of radioactivity in liver and kidneys continued to increase until the termination of the 2-hr experimental period. At 2 hr, 3.6% of the administered dose was present in metabolized form in the liver and intestine. By that time, all liver radioactivity was nonvolatile.
The distribution of ethyl ether and four other volatile organic solvents in blood was investigated in rats. The animals were exposed to 500 ppm (1540 mg/m3) of ethyl ether for 2 hr. Forty-nine percent of ethyl ether in the blood was found in the red blood cells. When a solution of ethyl ether was added to human plasma and red blood cell (RBC) samples, a large fraction of ethyl ether was recovered from ammonium-sulphate-precipitated plasma proteins and hemoglobin. A small fraction of ethyl ether was recovered from plasma water and RBC water. The authors conclude that proteins, chiefly hemoglobin, are the major carriers o f ethyl ether and other volatile organic solvents in blood (87).

# Biotransformation
It has been estimated that about 8-10% of absorbed ethyl ether is metabolized in the body (55) whereas the remainder is excreted unchanged through the lungs. Ethyl ether is metabolized to ethanol and acetaldehyde by an inducible hepatic microsomal enzyme system, a cytochrome P450-containing monooxygenase system (32,145). Ethanol and acetaldehyde are rapidly oxidized to acetate, and the acetate subsequently enters the 2-carbon pool o f intermediary metabolism.
Van Dyke et al. (160) showed in rats that approximately 4% o f an intraperitoneallyadministered dose (0.1 ml) o f 14C-ethyl ether was recovered as exhaled 14C 0 2 during a 24-hr period, and 2% of the radioactivity was transformed into nonvolatile urinary products. Green and Cohen (55) reported that a portion of 14C-diethyl ether administered to mice by inhalation was rapidly transformed into fatty acids (palmitic, stearic, and oleic acids) and cholesterol, which were recovered from an ether extract of liver. Three other nonvolatile radioactive metabolites were tentatively identified as monoglycerides, diglycerides, and triglycerides.
Two hr after administation of ethyl ether by inhalation to mice, 3.6% o f the administered dose was present in metabolized form in the liver and intestine. Thin-layer radiochromatography of extracts from the liver demonstrated four nonvolatile metabolites. The major metabolite was presumed to be a glucuronide of ether (34).
The hepatic microsomal oxidation of ethyl ether is catalyzed primarily by the cytochromes P450 (32). More recent investigations have implicated specific isoenzymes. Known in hibitors of isoenzyme HE1 strongly inhibited ether de-ethylation, and a monoclonal antibody to P450IIE1 had the same effect (24). A mixed-function oxidation known to be catalyzed by cytochrome P45013E1, the N-demethylation of dimethylnitrosamine, was inhibited by ethyl ether anesthesia (150). These findings all indicate that ethyl ether is oxidatively metabolized primarily by P450UE1 (24).

# Elimination
The The concentration o f ethyl ether in brain, blood, and muscle was investigated in rats during ether elimination. When the rats had breathed 300,000 mg/m3 (approximately 9 vol%) of ethyl ether for 10 min, there was an abrupt fall of the concentration o f ethyl ether in the brain and blood immediately after discontinuation of the inhalation. When the inhalation exposures were discontinued after 1 hr, the fall in the ether concentration in the brain and blood was slower (42). The elimination o f ethyl ether from fatty tissue occurred slowly, and was practically finished after about 8 hr (43).
According to the experience of anesthesiologists, termination o f anesthesia with soluble anesthetics like ethyl ether is slower in obese individuals than in those with a lean body mass. This might partly be due to partioning of the anesthetic agent into certain tissues (e.g., body fat) (25).

# Mechanism of Ether Resistance in Drosophila Melanogaster
A few studies have been performed to elucidate the mechanism of ethyl ether resistance in certain strains of Drosophila melanogaster. A strain named Eth-29, was found to be resistant to ethyl ether and other volatile anesthetic agents like chloroform and halothane. Ethyl ether resistance for lethality was determined using mortality as an endpoint when flies were exposed to very high concentrations of ethyl ether (111). Ethyl ether resistance to anesthesia uses loss of avoidance reflex as an endpoint, and is an incompletely dominant or polygenic character (49). The resistance for ethyl ether anesthesia and for ethyl ether lethality was found to be controlled by different genetic systems.
In 18 strains of Drosophila melanogaster with different genetic characteristics, a wide variation in sensitivities to ethyl ether anesthesia, gamma-ray knock-down and gamma-ray lethality was demonstrated. There was no correlation between DNA-repair capacity and ethyl ether sensitivity or gamma-ray knock-down sensitivity, whereas strains deficient in excision repair were found to be sensitive to gamma-ray lethality. These findings indicate that lethality is caused by DNA damage, whereas the targets for ethyl ether anesthesia should be different, possibly being the membrane (50).

# GENERAL TOXICOLOGY

# Mechanism of Action
The mechanism of action by which general anesthetics, including ethyl ether, produce reversible loss of consciousness is still unclear. Anesthesia can be produced by a wide variety of chemical agents, ranging from inert rare gases to steroid molecules (128). This apparent lack of specificity, together with the observation that general anesthesia can be reversed by high pressure, poses a unique pharmacological problem (48). Most theories concern interac tion of anesthetics with either membrane lipids or hydrophobic regions of specific membranebound proteins (for reviews see 48, 63, 128). One hypothesis is that the anesthetic changes the function o f an ion channel protein by modifying the conformation of the protein. Some investigators suggest that the GABA receptor may be the ion channel protein that is affected by inhalation anesthetic agents (25,101). According to Halsey (63), the most appropriate concept for the mechanism of general anesthesia is a heterogenous site o f anesthetic action, including both lipid and protein membrane components linked with the neuronal function.  Light ethyl ether anesthesia for 1-2 min did not affect the rate of protein synthesis measured in the mammary gland, liver, intestinal mucosa, and muscle of lactating rats using a flooding dose of 3H-phenylalanine that was injected intravenously. The fractional rates of protein synthesis were estimated from incorporation of 3H-phenylalanine into tissue proteins (131).

# Effects of Ethyl Ether on the

# Effects of Ethyl Ether on Protein Synthesis in Animals

# Acute Toxicity

# Human Experience

# Inhalation
Ethyl Oxygen therapy may be used in cases of narcosis (7).

# Ingestion
Moeschlin (99) has estimated the lethal dose o f ethyl ether after peroral intake to be about In ethyl ether addiction, tolerance develops and large daily quantities of ethyl ether may be ingested (16,52). A daily intake of up to 180 g has been reported (52).

# Animal Studies

# Inhalation
Differences in the induction mixture and the duration of anesthesia may lead to different results for lethal concentrations of inhaled ethyl ether in animals (124). During a continuous exposure for 97 min, the lethal concentration of inhaled ether for mice was 133,400 mg/m3 or 4.4 vol% (86). When rapid induction and short duration of anesthesia was used, the concentration necessary to produce respiratory arrest in mice was 18 vol% (554,000 mg/m3) (103). The lethal concentrations for the rat, rabbit, and dog were 6.4, 10.6 and 7.16 to 19.25 vol%, respectively (139). The age o f the animal has importance for susceptibility to inhaled ethyl ether. In rats, the median time to death (LT50) for neonates was 5 to 6.5 times greater than for adult rats and the mean concentration of ethyl ether in blood at the respective LT50 values was 2.5 to 3 times greater in neonatal rats than in adult rats (132).

# Ingestion
The oral LD50 in 2-week-old, young adult (body weight 80-160 g) and adult (body weight 300-470 g) Sprague-Dawley rats, were reported to be 2.3,2.4 and 1.7 ml/kg b.w., respectively (83). Smyth et al. ( 138) reported a single peroral LD50 for rats of 3.56 ml/kg. Ethyl ether is metabolized to acetaldehyde by hepatic microsomal enzymes. Long-term ethyl ether treatment of rats leads to induction of hepatic microsomal enzymes and to proliferation of smooth endoplasmic reticulum (127).

# Chronic Toxicity

# Long

# Kidneys

# Albuminuria from tubular irritation has been reported to occur in about one-fourth o f patients anesthetized with ethyl ether (68).
Chronic exposure to ethyl ether during the manufacture of smokeless powder has been claimed to cause occasional cases o f nephritis (28, 65, 68), but this effect has since been questioned. Hamilton (64) described a man who had worked continuously for 7 years and intermittently for 5 years in a smokeless powder factory, and who developed a severe chronic interstitial nephritis verified at autopsy.

# Ethyl ether has been used for dissolution of an obstructed Foley catheter balloon. The use of ethyl ether for this purpose has occasionally resulted in a chemical cystitis with permanent
damage to the urinary bladder (51, 91, 105).

# Centra! Nervous System
Acute exposure of humans to high concentrations of ethyl ether vapor causes initial excitement followed by narcosis and respiratory depression. The different stages o f ethyl ether anesthesia have been described in detail and are given in Table 1. The approximate blood and alveolar levels o f ethyl ether in relation to the depth of anesthesia are given in Table 2.

# Long-term exposure to low concentrations o f ethyl ether vapor in industry, for example during the manufacture of smokeless powder, has been reported to cause various symptoms from the central nervous system such as sleepiness, dizziness, excitation, headache and psychic dis turbances (47). Surgeons and nurses exposed for long periods o f time to ethyl ether in the operation theatre complained of tiredness, headache, loss of appetite, irritability and difficul ties in concentrating (168).
Ethyl ether has been reported to have complex effects on learning and memory in experimental studies in mice. Ethyl ether, like strychnine, appears to be a modulator of learning and memory (96). Some investigators have described retrograde amnesia after exposure to ethyl ether, but due to differences in methodology, the amnestic effects o f ethyl ether have not been found consistently (167 Ethyl ether causes cerebrovascular dilatation at twice the minimum anesthetic concentration (the minimum anesthetic concentration is the concentration at which 50% o f the subjects move in response to a surgical stimulus) (172). The cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), and cerebrovascular resistance (CVR) were measured in two groups of monkeys inhaling 2 vol% (61,600 mg/m3) and 5 vol% (154,000 mg/m3) ethyl ether in air.

# CVR fell by 30% when ethyl ether concentration was increased from 2 to 5% whereas CBF and CMRO2 were unaltered. The conclusion of this study was that the effect o f ethyl ether on CVR probably reflects a complex interaction o f a number of factors such as alterations in alfa-adrenergic tone associated with changes in plasma epinephrine levels, alterations in vasoactive metabolites and alterations in beta-adrenergic receptor activity (75).

# The effects of ethyl ether on the morphology of the blood-brain barrier within the optic tectum was investigated in hatching chick embryos and young chickens. Ethyl ether was administered on a small compress of surgical gauze covering the chick beak until anesthesia was reached (1 -3 min). Horseradish peroxidase was used as a marker of vascular permeability. Ethyl ether anesthesia was reported to produce extravasation of HRP by opening the tight interendothelial junctions. Areas of tracer extravasation were more numerous in the tecta o f hatching embryos than in young chickens (108).
Richards and White (122) investigated the effect of volatile anesthetics (ethyl ether, halothane, methoxyflurane and trichloroethylene) on the synaptic transmissions in the dentate gyrus. The experiments were performed in vitro using a preparation o f the dentate gyrus o f the hippocam pus in guinea pigs. Ethyl ether was applied to slices o f the dentate gyrus in the gas phase by mixing ethyl ether with the O2JCO2 gas mixture that superfused the upper surface of the slice. All four anesthetics depressed synaptic transmission in the dentate gyrus. The mechanism behind this effect was interpreted to be either a reduction of transmitter release, or a decrease in the sensitivity of the postsynaptic membrane to released transmitter, or both effects together.

# EEG monitoring in animals during anesthesia with ethyl ether has shown that ethyl ether reduces neuronal excitability (93,147). The depressive effect of increasing concentrations of
ethyl ether on the central nervous system is also evident from Table 1.

# Peripheral Nervous System
Larrabee and Pasternak (90) studied the concentrations of various anesthetics required to block synaptic excitation of sympathetic ganglion cells and compared that to concentrations neces sary to block conduction along sympathetic nerve fibers. The experiments were performed on in vitro preparations from cats, rats, and rabbits. Ethyl ether depressed synaptic transmis sion through a sympathetic ganglion in a concentration similar to that assumed to exist in the blood during surgical anesthesia. The conduction along autonomic fibers o f different types (A, B, and C) was blocked by ethyl ether, but synaptic transmission was depressed more readily than conduction along any type o f axon.
Ethyl ether and halothane were found to affect the kinetics of sodium and potassium current in vitro in the crayfish giant axon. Both anesthetics caused a reversible, dose-dependent speeding up of sodium current inactivation at all membrane potentials. The activation of potassium currents was faster with ethyl ether present, but there was no change in the voltage dependence o f steady-state potassium currents. A theory was proposed that the effects on sodium and potassium channel gating processes was due to ei ther an effect on the state of the lipids surrounding the channels, or a direct effect on the protein part o f the channels (18).
A bath concentration of 100-300 mM (7,412-22,236 mg/1) ethyl ether blocked the conduction of single action potentials in the bifurcating axon of the lobster deep extensor muscles (58). In frog sciatic nerve, 300 mM (22,236 mg/1) ethyl ether was needed to depress single axon sodium currents (81). Significant depression of mammalian B and C fibers was produced by 77 mM (5,707 mg/1) ethyl ether (90).

# Muscle
Ethyl ether causes muscle relaxation by its depressing effect on the central nervous system (CNS) and by affecting neuromuscular transmission and the muscle itself. The mechanism of neuromuscular blocking action of ethyl ether seems to be similar to, but not identical with that of d-tubocurarine (35,77). When these two drugs are used in the same patient, an additive effect results from their synergism (35). The neuromuscular block produced by ethyl ether was not effectively antagonized by edrophonium or succinylcholine (77) whereas neostigmine has been reported to reverse the effect of ethyl ether on the motor end-plate (57). The reduction of muscle contractility caused by ethyl ether might be due to a pharmacological effect at the level of the sarcoplasmic reticulum (82, 129).

# Gastrointestinal Tract

# Salivary and gastric secretions are increased during light ethyl ether anesthesia, but are decreased during deep anesthesia. Bowel movement is decreased due to stimulation of dilator fibers and to depression of plain muscle (162). Nausea and vomiting are common after anesthesia with ethyl ether. Ethyl ether stimulates the vomiting center in the medulla, and ethyl ether is absorbed in saliva and passes to the stomach where it irritates the mucosa (35).
The incidence of postoperative nausea varies with the length of operation and depth of anesthesia (162).

# Circulatory System
Ethyl ether vapor depresses myocardial activity if added to the circulation in a heart-lung preparation (119). Ethyl ether anesthesia causes increased sympathetic nervous activity in the dog and man (98) and the plasma levels of noradrenaline increase with increasing depth of ethyl ether anesthesia (21). Skovsted

# and Price (134) postulated that the increase in sym pathetic preganglionic activity caused by ethyl ether anesthesia in cats was due to a central action on the medullary vasomotor center or on spinal vasomotor neurons. The direct myocardial depressant action of ethyl ether seen in the isolated heart preparation is antagonized by the positive inotrope effect of adrenaline and noradrenaline released during ethyl ether anesthesia (26). Ethyl ether seems to block parasympathetic activity in normal man (118).
Ethyl ether anesthesia produces remarkably small alterations in blood pressure and pulse rate and rarely leads to cardiac arrythmias (35).
In a study in rats, the effects of ethyl ether anesthesia on whole-body hemodynamics and organ blood flow was measured using microspheres. Anesthesia was induced using a bell jar containing a gauze pad moistened with ethyl ether, and the animals were maintained between stage II and stage HI of anesthesia. Ethyl ether anesthesia initially decreased arterial pressure and the total peripheral resistance, whereas the cardiac index was increased. Later, the cardiac index returned to normal and there was an increase in total peripheral resistance index. The blood flow to the spleen, stomach, intestine, kidneys, and colon decreased during anesthesia whereas the blood flow to the brain and heart increased (141).

# Hematological System

# Anesthetic agents may have both direct and hormone-mediated effects on the leukocytes. After ethyl ether anesthesia in man, a postoperative leukocytosis has been reported which is related to the sympathomimetic effects of ethyl ether (164).
Blood samples from workers chronically exposed to ethyl ether fumes in the manufacture of smokeless powder showed in some individuals polycythemia and increased number of leukocytes (65). Plasma aldosterone levels and plasma renin activity increase during ethyl ether anesthesia (15,115). The plasma antidiuretic hormone levels also increase significantly after the induction of anesthesia with ethyl ether (97).
Ethyl ether anesthesia caused a significant decrease in serum calcium levels in 30 patients undergoing various routine surgical operations. Serum calcium returned to near normal levels after 24 hr. The mechanism behind this effect is not known (62).

# Laboratory Animals
Ethyl ether anesthesia administered by placing rats in an ether-saturated jar and then main tained with a nose cone for 3 min caused a significant increase in plasma adrenocorticotrophic hormone (ACTH) levels. Ethyl ether failed to raise the plasma ACTH levels o f rats in which an antero-lateral hypothalamic cut and adrenalectomy had been performed 7 to 8 days previously, and plasma ACTH was also unchanged in rats exposed to ethyl ether 2 hr after an antero-lateral cut. The results are interpreted as evidence that intact neural pathways entering the medial basal hypothalamus from the antero-lateral direction are necessary for the ACTHreleasing action o f ethyl ether stress (78).

# Plasma corticotropin releasing hormone (CRH), arginine vasopressin (AVP), oxytocin (OXY)
and ACTH levels rose to approximately twice the level o f control rats 2 min after the onset of a 1-min exposure to ethyl ether. Plasma CRH rose further 5 min after the onset o f ethyl ether stress, while plasma A VP and OXY returned to the baseline level at 5 min (67).
Ethyl ether anesthesia did not affect the mean concentrations or dissociation constants for rat uterine estrogen or progesterone receptors (173). No difference in plasma thyroxine levels were found between control rats and rats exposed to ethyl ether inhalation for 2 min (89). Ethyl ether anesthesia in rats increased the concentration of plasma beta-endorphin-like immunoreactivity, probably of pituitary origin. This increase was not associated with sig nificant changes in pituitary or brainstem beta-endorphin content (121).

# IMMUNE SYSTEM
After treatment of human sera with ethyl ether, there were no significant changes in im munoglobulin levels, whereas the complement activity was lost (142). Several commonly used volatile anesthetics were screened for mutagenicity in the Salmonella/ rat liver microsomal assay system. Ethyl ether was reported to be not mutagenic (165). When the genotoxic activity and potency of 135 compounds were investigated in the Ames reversion test and in a bacterial DNA-repair test, there was no evidence o f genotoxic activity for ethyl ether (38).  was termed objectionable. For ethyl ether, complaints of nasal irritation started at 200 ppm (616 mg/m3), and 300 ppm (924 mg/m3) was objectionable as a working atmosphere.

# CARCINOGENICITY
According to Cook (36), industrial exposure at 500 to 1,000 ppm (1,540 to 3,080 mg/m3) did not cause any demonstrable injury to health, but a limit of 500 ppm seemed justifiable to avoid irritation and complaint. Amor (5) also considered a concentration of ethyl ether in the atmosphere greater than 500 ppm (1,540 mg/m3) as indicative o f unsatisfactory conditions. He listed 2,000 ppm (6,160 mg/m3) as the concentration which may lead to symptoms of illness (not specified) if exposure continues for more than a short time.
Ethyl ether concentrations of 2,000 to 3,000 ppm (6,160 to 9,240 mg/m3) may occur in the air during the manufacture of smokeless powder and has been reported to result in an occasional slight intoxication (69). The inhalation o f ethyl ether at a concentration of 2,000 ppm (6,160 mg/m3), if continued to equilibrium, has been calculated to result in the absorption of some 6.25 g of ethyl ether and a blood concentration of 90 mg/1. According to Henderson and Haggard (69), inhalation of ethyl ether at these concentrations would probably induce dizziness in some individuals with an increased risk for industrial accidents.
Concentrations above 3,000 ppm (9,240 mg/m3) as high as 7,000 ppm (21,560 mg/m3) have been breathed by some workers for variable periods of time. It has been claimed that these concentrations do not cause any physiological or clinical signs of injury, or any increase in the incidence of industrial accidents (7).
According to Amor (5), inhalation o f ethyl ether at a concentration o f 8,000 ppm (24,640 mg/m3) for 1 hr will give rise to severe toxic effects (toxic effects not specified).
A concentration of 35,000 ppm (107,800 mg/m3) of ethyl ether usually produces unconscious ness in 30 to 40 min (69).
Postmortem blood ethyl ether concentrations of 2,880-3,750 mg/1 were reported in two surgical patients who died within 2.5 hr after cessation of ethyl ether administration (30).

# Ingestion
Ethyl ether is irritating to the mucous membranes, and humans therefore usually refrain from drinking it. The "ether habit" by ingestion is well known, however. The symptoms are said to be similar to those o f chronic alcoholism but they occur earlier (28).
The lethal dose of ethyl ether after peroral intake has been estimated to about 30 ml (21.

# Observations in Animals

# Inhalation
Effects of a 35-day continuous exposure to ethyl ether in concentrations o f 0.1 or 1.0 vol% (3,080 to 30,800 mg/m3) were investigated in young mice, rats, and guinea pigs which were in a phase of rapid body growth. Ethyl ether had a negligible effect on rat or mouse weight gain but produced a statistically significant weight loss in guinea pigs at the higher concentra tion. Livers from mice and guinea pigs treated with 1.0 vol% (30,800 mg/m3) ethyl ether showed only slight increases in lesions compared to controls, whereas no increase in lesions were seen in rats. No consistent injury to any other organ than the liver was observed. The higher dose of ethyl ether was reported to be lethal to mice and guinea pigs, but not to rats. A draw-back with this study is that the authors were unable to explain the mechanism behind ethyl ether lethality. The mortality was not related to changes in blood or any tissue examined, including the bone marrow. The animals showed enlargement of the liver, but how this was related to ethyl ether lethality was unclear (143).  and a blood concentration of 1,700 to 1,900 mg/1 (average for 20 dogs 1,870 mg/1). The experiments lasted from 20 min to 2 hr. The knee jerk was abolished at a blood ethyl ether concentration of 1,430 mg/1 and the lid reflex at 1,500 mg/1.

# The results obtained for the concentration of the ethyl-ether-air mixture required for the maintenance of anesthesia, and for the lethal concentration of inhaled ethyl ether varies between different species and also between different investigators for the same species. This variation can partly be explained by differences in induction mixtures and duration of the anesthesia (124). The results o f various investigations o f inhalation toxicity for ethyl ether in animals is presented in
The susceptibility to inhaled ethyl ether in rats is influenced by the age of the animal. The median time to death (L T 50) for neonates was 5 to 6.5 times greater than for adult rats. At the respective L T 50 values, the mean concentration of diethyl ether in blood was 2.5 to 3 times greater in neonatal rats than in adult rats (132).

# Ingestion
The oral LD50 in a 2-week-old, young adult (body weight 8 0 -1 6 0 g) and adult (body weight 300-470 g) rat, were reported to be 2.