Diethyl ether. MAK value (1964) 400 ml/m 3 (ppm) 1200 mg/m 3. Absorption through the skin Sensitization Carcinogenicity

Transcription

1 Diethyl ether MAK value (1964) 400 ml/m 3 (ppm) 1200 mg/m 3 Peak limitation (1983) Absorption through the skin Sensitization Carcinogenicity Prenatal toxicity (1989) Germ cell mutagenicity BAT value Synonyms Chemical name (CAS) Category II,1 CAS number Pregnancy risk group D anaesthetic ether diethyl oxide ether ethoxyethane ethyl ether ethyl oxide sulfuric ether 1,1'-oxybisethane Structural formula H 3 C CH 2 -O-CH 2 -CH 3 Molecular formula C 4 H 10 O Molecular weight Melting point Boiling point C 34.5 C Density at 20 C g/cm 3 Vapour pressure at 20 C 587 hpa 1 ml/m 3 (ppm) 3mg/m 3 1mg/m ml/m 3 (ppm) In the present document only those publications are discussed in detail which describe effects of diethyl ether in the low concentration range and therefore can play a role in the evaluation of potential effects on health of workplace exposure to the substance. Recorded effects on man and results of animal studies with high, anaesthetic concentra-

2 150 Diethyl ether Volume 13 tions of diethyl ether have been described in review articles by the Beratergremium für umweltrelevante Stoffe (BUA 1990) and the National Institute of Occupational Safety and Health (Arvidson 1992) and are therefore only summarized briefly here. 1 Toxic Effects and Mode of Action Diethyl ether is of low acute toxicity. In high concentrations, diethyl ether has anaesthetic effects. As an anaesthetic for man, diethyl ether has been used since the middle of the 19th century briefly in concentrations up to ml/m 3 to induce anaesthesia and in concentrations of ml/m 3 to maintain anaesthesia. At such high concentrations, diethyl ether causes mucosal irritation. In the low concentration range from 1000 to 2000 ml/m 3 which is relevant at the workplace, diethyl ether has no clear systemic effects in animal studies. Absorbed diethyl ether is largely (90 %) exhaled unchanged; the rest is broken down to yield metabolites such as ethanol and acetate which are also products of normal metabolism. In experimental animals which have inhaled anaesthetic concentrations of diethyl ether, unspecific foetotoxic effects are observed. In the Salmonella-mutagenicity test, the DNA repair test in Escherichia coli and in a test for sister chromatid exchange, diethyl ether was not genotoxic. 2 Mechanism of Action The feeling of mucosal irritation is induced by ethers by physical adsorption to receptors in the mucous membranes. For propyl ether it is known that rapid initiation of the irritative effects is followed immediately by a very rapid desensitization reaction. The mechanism has been suggested to involve desensitization of the receptor protein by the ether group via allosteric effects (Nielsen 1991). 3 Toxicokinetics and Metabolism 3.1 Absorption The usual route of exposure to diethyl ether at the workplace is by inhalation.

3 Volume 13 Diethyl ether 151 Diethyl ether is not readily absorbed through the skin. When the substance is applied occlusively to rabbit skin, the dermal LD 50 is greater than the maximum dose of 20 ml/kg (> 14.2 g/kg body weight) which can be applied (Smyth et al. 1962). 3.2 Distribution Although inhaled diethyl ether appears rapidly in the bloodstream, its good solubility in blood means that distribution into the tissues, organs and the CNS takes place only slowly. Thus the time for induction of anaesthesia in man even with pulmonary flooding (diethyl ether concentrations of ml/m 3 ) is as much as 15 minutes (reviewed in: Büch and Büch 1992). The distribution coefficients found for human tissues are: 12.0 for blood/gas phase, 50.0 for adipose tissue/gas phase and 10.0 to 13.0 for the distribution coefficients between muscle tissue, kidney, liver, brain and the gas phase (Steward et al. 1973). For the coefficients of distribution between tissues and blood, values of 1.0 for the brain and 3.7 for adipose tissue are given (Büch and Büch 1992). Accordingly, in early studies with rats and dogs, during ether anaesthesia (diethyl ether concentration in inhaled air ml/m 3 ) the diethyl ether concentrations found in blood and brain were about 1 mg/g and in adipose tissue 3 mg/g (BUA 1990). After exposure of rats for 2 hours to a diethyl ether concentration of 500 ml/m 3, the concentrations of the substance in blood plasma and in the erythrocytes were similar, in the individual animals in the range from 3.5 to 4.8 µg/ml, unlike the situation with more hydrophobic solvents (Lam et al. 1990). In studies carried out with rodents it was demonstrated that when pregnant animals inhaled diethyl ether, the substance rapidly crossed the placenta and was found in foetal tissue (Dybing and Stormorken 1952, see Section 5.5 below). 3.3 Metabolism The studies of the metabolism of diethyl ether have been described in detail by BUA (1990) and Arvidson (1992). They indicate that only 8 % to 10 % of absorbed diethyl ether is metabolised, the initial products being ethanol and acetaldehyde. These are rapidly oxidized to acetate, which enters the C 2 -pool of intermediary metabolism. Deethylation and oxidation are catalyzed mainly by cytochrome P450 2E1, which can be induced by ethanol, acetone or diethyl ether. Anaesthetic concentrations of diethyl ether have been shown to cause lipid peroxidation. As mechanism has been suggested the formation of reactive oxygen species and of radical intermediates during the deethylation of diethyl ether by cytochrome P450 2E1 (Liu et al. 1991, 1993a, 1993b).

4 152 Diethyl ether Volume Excretion In rats exposed to anaesthetic concentrations of diethyl ether ( ml/m 3 ), the concentrations in blood and adipose tissue sank within 2 hours after the end of exposure to about 15 % or 30 % of the respective initial levels (Dybing and Skovlund 1957). Of the absorbed diethyl ether, 90 % is exhaled unchanged, the rest is metabolized to products which are normal constituents of the organism and is then exhaled in part as carbon dioxide (BUA 1990). 4 Effects in Man There is no information available about genotoxic or carcinogenic effects of diethyl ether in man. 4.1 Single exposures When diethyl ether is used as an anaesthetic for man, concentrations of to ml/m 3 are used to induce anaesthesia and ml/m 3 to maintain anaesthesia (reviewed in: Büch and Büch 1992). Mucosal irritation and other effects which are observed at these high concentrations have been described in review articles (BUA 1990, Arvidson 1992). The lethal oral dose for man is given as 20 to 50 g (Arvidson 1992). However, information about effects of single exposures in the low concentration range which is relevant at the workplace is not available. 4.2 Repeated exposures The available reports of toxic effects after long-term occupational exposure date from the first half of the 20th century and provide inadequate documentation of exposure conditions. The described effects include loss of appetite, exhaustion, concentration disorders, headaches, sleepiness, excitability, psychic disorders and changes in the blood count (reviewed by Arvidson 1992). In these publications, workplace concentrations up to 500 ml/m 3 are considered to be tolerable. 4.3 Effects on skin and mucous membranes The concentration which was considered to cause irritation of the nasal mucosa during exposure of 10 test persons for 3 to 5 minutes was 200 ml/m 3 (calculated concentration).

5 Volume 13 Diethyl ether 153 The persons considered a concentration of 300 ml/m 3 to be intolerable for the workplace. A concentration of 100 ml/m 3 was classed as acceptable for the workplace although the test persons were never exposed for longer than 5 minutes (Nelson et al. 1943). Because the concentrations were not measured and the documentation of this study is inadequate, these results cannot be used in the present evaluation. 4.4 Allergenic effects Although a large number of persons are exposed to diethyl ether, there is no evidence for a sensitizing effect of the substance either from the workplace or from its use as an anaesthetic (BUA 1990, Arvidson 1992). 4.5 Reproductive toxicity Retrospective questionnaire studies have yielded evidence for a slight increase in the incidence of abortions and possibly also in the incidence of children with malformations born from women exposed occupationally in hospitals during pregnancy to gaseous anaesthetics (Cohen 1974, Axelsson and Rylander 1982). Such suspicions have also been expressed in a series of reviews of the relevant literature (Edling 1980, Infante and Tsongas 1981, Purdham 1981, Vainio 1982, Rogers 1986, Friedman 1988). However, attention is also drawn in these reviews to the methodical weaknesses of the available epidemiological studies (Edling 1980, Purdham 1981, Axelsson and Rylander 1982, Friedman 1988). In particular it should be pointed out that in the reports of these studies neither the kind or concentration of inhalation anaesthetics nor the duration of the exposures or the time during pregnancy are documented (Edling 1980, Friedman 1988). In addition, nowadays diethyl ether is very rarely used for inhalation anaesthesia (Friedman 1988). The cited human epidemiological studies are thus not conclusive, at least with respect to diethyl ether, and can hardly be used for the evaluation of the prenatal toxicity of the substance 5 Animal Experiments and in vitro Studies 5.1 Acute toxicity The LC 50 values given for the mouse after exposure for about 90 minutes are in the range between and ml/m 3 and for the rat exposed for 150 minutes ml/m 3. The lethal concentration for the monkey is between and ml/m 3 (BUA 1990).

6 154 Diethyl ether Volume 13 The LD 50 values for the rat after oral administration are given as 1215 to 2540 mg/kg body weight and for the mouse after intraperitoneal injection 2420 mg/kg body weight (BUA 1990, Arvidson 1992). 5.2 Subacute, subchronic and chronic toxicity Inhalation Groups of 16 Sprague-Dawley rats, 15 Hartley guinea pigs and 48 ICR mice were exposed to diethyl ether in concentrations of 1000 and ml/m 3 for a period of 35 days (22 hours/day). After 20 days the exposure of mice and guinea pigs at the high concentration was discontinued because of high mortality (about 25 % of the animals) and the surviving animals were killed. The rats tolerated the exposure at both concentrations without effects on survival, body weights or organ weights and without liver changes. In the guinea pigs, exposure to 1000 ml/m 3 produced a slight delay in body weight gain. During the exposure to ml/m 3, significant weight loss was seen within 7 days and 27 % of the animals died between days 7 and 14. Autopsy of the animals from this dose group revealed markedly enlarged livers without degenerative lesions. In the mice of the 1000 ml/m 3 group, significantly increased body weight gain was recorded between days 7 and 35. In the high concentration group between days 7 and 14, mortality of the mice was increased by about the same amount as for the guinea pigs but the delay in body weight gain was less marked. Significantly increased absolute and relative liver weights were seen in both sexes in the ml/m 3 group and only in the males in the 1000 ml/m 3 group. This liver enlargement was accompanied by degenerative morphological changes in the liver in 20 % of the animals only in the group exposed to the high concentration (Stevens et al. 1975). In another 35-day study with an exposure pattern like that at the workplace (7 hours/day, 5 days/week), exposure of 20 Wistar rats, 12 guinea pigs and 4 rabbits to a diethyl ether concentration of 2000 ml/m 3 did not result in significant changes in body weights, haematological parameters or transaminase activities nor in abnormal findings in the histopathological examination. The relative liver weights were significantly reduced in the rats but clearly increased in the rabbits. In addition there was a significant increase in testis weights in the guinea pigs. As no other relative organ weights were affected, the authors suggested that these changes might not be a result of the exposure to diethyl ether (Chenoweth et al. 1970) Ingestion In a 90-day study, groups of 30 male and 30 female Sprague-Dawley rats were given diethyl ether doses of 500, 2000 and 3500 mg/kg body weight and day in corn oil by

7 Volume 13 Diethyl ether 155 gavage. In the group given 500 mg/kg body weight, no effects were observed. In the 2000 mg/kg group, 2 animals of each sex died, in the 3500 mg/kg group 6 males and 9 females died; the animals in these groups had symptoms indicative of mild anaesthetic effects. In the 2000 mg/kg group, a marked delay in body weight gain was seen in the male animals from week 8 and a significant increase in relative liver weights was found in the females. Body weight gain in the males of the high dose group was clearly reduced during the whole exposure period and in the females from week 7. Reduced food consumption was, however, recorded only at times in the male animals. The absolute weights of brain, heart, liver, kidneys, spleen and testes were significantly reduced in the male rats and the relative weights of brain, kidneys and testes significantly increased. However, histological examination of 28 organs did not reveal pathological alterations. In addition, in the male animals the haemoglobin level, the haematocrit, alanine transferase activity (ALT) and cholesterol level were increased significantly, in the females only the ALT (American Biogenics Co 1988). The doses administered to the medium and high dose groups are higher than the LD 50 values which have been published elsewhere (see Section 5.1.2). It is, however, conceivable that the administration of the substance as a mixture of diethyl ether in oil led to delayed absorption and thus to reduced toxicity. 5.3 Effects on skin and mucous membranes Non-occlusive application of diethyl ether to the shaved skin of the rabbit did not cause irritation (Smyth et al. 1962). It is claimed that brief contact of the skin with diethyl ether does not result in damage but that repeated contact can make the skin dry and cracked because the substance is a good solvent for fats (no other data, Kirwin and Sandmeyer 1981). Mild reversible irritation of the rabbit eye after exposure to liquid diethyl ether or its vapour has been described without further details of exposure conditions (Grant 1974). After instillation of diethyl ether into the rabbit eye, mild signs of irritation were recorded (grade 2 on a scale from 1 to 10) (Smyth et al. 1962). During inhalation exposure of 20 Wistar rats, 12 guinea pigs and 4 rabbits to a diethyl ether concentration of 2000 ml/m 3 for 7 weeks (7 hours/day, 5 days/week), no signs of irritation of the mucosa of the eyes or nose were observed (Chenoweth et al. 1970). 5.4 Allergenic effects Apart from one report of a possibly sensitizing effect of diethyl ether in guinea pigs which could only be provoked by high concentrations of the substance (60 %) and which cannot be evaluated because of inadequate documentation (BUA 1990), studies of allergenicity of diethyl ether are not available.

8 156 Diethyl ether Volume Reproductive toxicity Exposure of mice 4 hours daily for 5 days to diethyl ether concentrations of 3200 and ml/m 3 did not result in morphological changes in sperm examined 28 days after the first exposure (Land et al. 1981). Toxic effects on reproduction are not to be expected from the metabolites of diethyl ether because these substances are also components of the normal metabolic pool. However, absorbed diethyl ether crosses the placenta very rapidly (Rosen 1967, Reynolds and Prasad 1982). Thus after anaesthesia of pregnant rats for 10 to 40 minutes with a diethyl ether concentration of 10 % v/v, the diethyl ether levels in the foetuses were 0.5 to 1.0 mg/ml, only slightly lower than those in the arterial blood of the dams ( mg/ml) (Dybing and Stormarken 1952). The literature search for papers on potential prenatal toxic effects of diethyl ether yielded only studies which had investigated the effects of high concentrations (5 % to 10 % v/v) used to produce anaesthesia. Detailed tests for embryo toxicity with several, in particular, low concentrations have not been reported (Friedman 1988). In two experiments with very small numbers of rats and mice (5 to 6 per group) only the heads of the foetuses were examined and especially for cleft palate. After daily anaesthesia of pregnant rats with diethyl ether from day 8 to day 14 post conceptionem, the incidence of cleft palate in the foetuses was increased (Chase et al. 1971). In mice, however, ether anaesthesia for 42 hours (day 13 to 15 post conceptionem) did not result in cleft palates (Jacobs 1971). In another study with mice, a significant reduction in head length was observed in the embryos on day 13 of gestation when the dams had been anaesthetized with diethyl ether for 20 minutes on each of days 9 to 12 post conceptionem (Lindskog 1958). Embryotoxicity tests with diethyl ether have been carried out with mice and rats (Schwetz and Becker 1970). The dams were anaesthetized by inhalation of diethyl ether at a concentration of 6.5 % or 7.3 % v/v for one hour during the early or late phases of organogenesis (exact details not given). The foetuses were removed one day before their birth date and were examined for external, visceral and skeletal anomalies. In the mice, increased mortality of the embryos, increased incidence of anomalies (generalized oedema) and clearly delayed ossification of various parts of the skeleton were observed. In the rat foetuses, only reduced body weights and reduced crown-rump lengths were found (Schwetz and Becker 1970). In the cited studies, the animals were generally exposed to high concentrations of diethyl ether (about 5 % to 10 % v/v) in the range which causes generalized anaesthesia in both experimental animals and man (Reynolds and Prasad 1982). Although in animals exposed to such high doses, unspecific toxic effects on the embryos in the form of embryonic deaths (mouse) and delayed development (mouse and rat) were seen, no specific organ teratogenicity of diethyl ether was found. This probably also applies to the increased incidence of cleft palate found in the range-finding study because, in rats, ether anaesthesia produces a marked increase in the levels of ACTH and corticosterone in maternal blood (Cohen et al. 1983). The findings of these teratogenicity studies in which animals were exposed to anaesthetic diethyl ether concentrations which produced unspecific embryotoxic effects are

9 Volume 13 Diethyl ether 157 not relevant for estimating possible effects of the concentrations found at the workplace. Studies of the reproductive toxicity of diethyl ether in the low concentration range are not available. 5.6 Genotoxicity The few available genotoxicity tests a Salmonella mutagenicity test, a test for DNA repair in Escherichia coli, a test for sister chromatid exchange (SCE) in CHO cells (a cell line derived from Chinese hamster ovary cells) have not yielded evidence of genotoxic effects of diethyl ether in vitro, even in the presence of metabolic activation systems (see Table 1). Table 1. Genotoxicity of diethyl ether in vitro Test system Test conditions Results without/with S9** gene mutation S. typhimurium TA98, TA ml/m 3 24 h exposure over the gas phase in a closed dessicator Authors / Waskell 1978 gene mutation not specified / De Flora et al. S. typhimurium TA98, TA100, 1984 TA1535, TA1537, TA1538 DNA repair E. coli pol A * DNA repair E. coli WP2, WP67, CM871 SCE CHO cells 50 µl/plate /not determined Fluck et al not specified / De Flora et al ml/m 3 not determined/ exposure over the gas phase in closed culture bottles * E. coli pol A DNA polymerase-deficient strain ** S9 mix from Wistar rats pretreated with Aroclor 1254 White et al After exposure of a DNA polymerase-deficient strain of E. coli to diethyl ether which had been in contact with air, DNA repair could be demonstrated in the absence of metabolic activation, an indication that peroxides were present (Fluck et al. 1976). Likewise, peroxide impurities isolated from ether and concentrated were shown to have mutagenic effects in the S. typhimurium strains TA100 and TA102, but not in strain TA1535. These peroxides were stable in aqueous solution only in the ph range between 3 and 6 (Chen et al. 1993). In vivo studies of genotoxicity or carcinogenicity of diethyl ether are not available.

10 158 Diethyl ether Volume Other effects Effects on the nervous system In an inadequately documented behavioural toxicology study, mice were exposed by inhalation to diethyl ether concentrations which were increased after an exposure period of 15 or 40 minutes. The concentrations calculated for the beginning of each exposure period were given as 1000, 3000, and ml/m 3. Clear changes in reaction times during the 15-minute exposures were first seen when the concentration was increased to ml/m 3 and for the 40-minute exposure periods from 3000 ml/m 3. After exposure to one of the above mentioned diethyl ether concentrations for 5 or 30 minutes, effects on the neuroendocrine system were detected such as changed levels of corticosterone and adrenocorticotropic hormone (ACTH) in blood from 3000 ml/m 3 and ml/m 3, respectively (Glowa 1993). This study can be used in the present evaluation only with reservations because the exposure concentrations were not measured and the results are inadequately documented. Neurotoxic effects of diethyl ether after short-term inhalation exposure have been recorded by determination of inhibition of seizures induced by electrical stimulation. Concentrations which caused 30 % inhibition (EC 30 ) were given as 2300 ml/m 3 for the rat after a 4-hour exposure and as 4100 ml/m 3 for the mouse after a 2-hour exposure (Frantik et al. 1994). 6 Manifesto (MAK value/classification) Inhalation of diethyl ether in a concentration of 1000 ml/m 3, 22 hours daily for 35 days, resulted merely in significant increases in liver weights without morphological liver changes in male mice and in no significant effects in female mice or in guinea pigs. Rats tolerated concentrations as high as ml/m 3 without any signs of toxic effects. In another 35-day study with an exposure pattern like that at the workplace (7 hours/day, 5 days/week) the only effects seen in rats, guinea pigs and rabbits exposed to diethyl ether concentrations of 2000 ml/m 3 were also occasional changes in organ weights and these were not considered to be necessarily substance-related effects. Thus, these results suggest that exposure to diethyl ether in concentrations of 1000 to 2000 ml/m 3 and for periods like those which can occur at the workplace has no systemic effects or at most very slight ones. Studies of effects in man are limited to one inadequately documented investigation of mucosal irritation of diethyl ether which was carried out with inadequate methods (Nelson et al. 1943); this publication cannot be used for the derivation of a MAK value. Research into the concentrations of diethyl ether which can cause mucosal irritation is still required.

11 Volume 13 Diethyl ether 159 On the basis of the results of animal studies and because of the inadequate database for effects in man, the MAK value of 400 ml/m 3 (1200 mg/m 3 ) has been retained. Diethyl ether remains in Peak limitation category II,1 for the limitation of exposure peaks. Since there are still no studies of the reproductive toxicology of diethyl ether in the low concentration range, the substance remains in Pregnancy risk group D. The currently available data do not suggest that designation with an H (for substances which can penetrate the skin in dangerous amounts) could be necessary. 7 References American Biogenics Co (1988) Ninety day gavage study in albino rats using ethyl ether. Final Report of the American Biogenics Co, Research Triangle Institute Study , submitted to: U.S. Environmental Protection Agency, Office of Solid Waste, Washington DC Arvidson B (1992) Ethyl ether. NEG and NIOSH basis for an occupational health standard. Arbete Och Hälsa 30 Axelsson G, Rylander R (1982) Exposure to anaesthetic gases and spontaneous abortion: response bias in a postal questionnaire study. Int J Epidem 11: BUA (Beratergremium für umweltrelevante Altstoffe der Gesellschaft Deutscher Chemiker) (1990) Diethylether. BUA-Stoffbericht 49 (also available in English translation) Büch HP, Büch U (1992) Narkotika. in: Forth W (Ed.) Allgemeine und spezielle Pharmakologie und Toxikologie. BI-Wissenschaftsverlag, Mannheim: Chase PF, Urban TJ, Buresh JJ (1971) Ether-induced cleft palates in rats. J dent Res 50: 700 (Abstract) Chen W, Lin J-M, Reinhart L, Weisburger JH (1993) Mutagenic peroxides in diethyl ether. Mutat Res 287: Chenoweth MB, Leong BKJ, Sparschu GL, Torkelson TR (1970) Toxicities of methoxyflurane, halothane and diethyl ether in laboratory animals on repeated inhalation at subanesthetic concentrations. in: Fink B, Raymond B (Eds) Proccedings of the Conference on Cellular Toxicity of Anesthetics, May 11 12, 1970, Seattle, Washington: Cohen A, Chatelain A, Dupony JP (1983) Late pregnancy maternal and fetal time-course of plasma ACTH and corticosterone after continuous ether inhalation by pregnant rats. Biol Neonat (Basel) 43: Cohen EN, Brown BW, Bruce DL, Cascorbi HF, Corbett TH, Jones TW, Whitcher CE (1974) Occupational disease among operating room personnel: a national study. Report of an ad hoc committee on the effect of trace anesthetics on the health of operating room personnel, American Society of Anesthesiologists. Anesthesiology 41: De Flora S, Zanacchi P, Camoirano A, Bennicelli C, Badolati GS (1984) Genotoxic activity and potency of 135 compounds in the Ames reversion test and in a bacterial DNA-repair test. Mutat Res 133: Dybing O, Stormarken H (1952) The passage of ether from mother to foetus. Acta Pharmacol Toxicol 8: Dybing O, Skovlund K (1957) Ether in fatty tissue during ether absorption and elimination. Acta Pharmacol Toxicol 13: Edling C (1980) Anesthetic gases as an occupational hazard a review. Scand J Work Environm Hlth 6: Fluck ER, Poirier LA, Ruelius HW (1976) Evaluation of a DNA polymerase-deficient mutant of E. coli for the rapid detection of carcinogens. Chem Biol Interact 15:

12 160 Diethyl ether Volume 13 Frantik E, Hornychova M, Horváth M (1994) Relative acute neurotoxicity of solvents: Isoeffective air concentrations of 48 compounds evaluated in rats and mice. Environ Res 66: Friedman JM (1988) Teratogen update: anesthetic agents. Teratology 37: Glowa JR (1993) Behavioral and neuroendocrine effects of diethyl ether exposure in the mouse. Neurotox Teratol 15: Grant WM (1974) Toxicology of the Eye. Charles C. Thomas, Springfield, Illinois: Infante PF, Tsongas TA (1981) Anesthetic Gases and Pregnancy: A Review of Evidence for an Occupational Hazard, in Hemminki, K. et al. (Eds): Occupational Hazards and Reproduction, p 287, Hemisphere Publishing Corp., Washington DC, USA, Jacobs RM (1971) Failure of muscle relaxants to produce cleft palate in mice. Teratology 4: Kirwin Jr CJ, Sandmeyer EE (1981) Ether. in: Patty's Industrial Hygiene and Toxicology. John Wiley & Sons, New York, Vol. 2A: Lam C-W, Galen TJ, Boyd JF, Pierson DL (1990) Mechanism of transport and distribution of organic solvents in blood. Toxicol Appl Pharmacol 104: Land PC, Owen EL, Linde HW (1981) Morphologic changes in mouse spermatozoa after exposure to inhalational anesthetics during early spermatogenesis. Anesthesiology 54: Lindskog BI (1958) Influence of ether narcosis on embryo development in mice with special reference to repeated cesarean sections. Acta anat (Basel) 33: Liu PT, Symons AM, Parke DV (1991) Autoxidative injury with loss of cytochrome P-450 following acute exposure of rats to fasting and ether anesthesia. Xenobiotica 21: Liu PT, Ioannides C, Shavila J, Symons AM, Parke DV (1993a) Effects of ether anesthesia and fasting on various cytochromes P450 of rat liver and kidney. Biochem Pharmacol 45: Liu PT, Kentish PA, Symons AM, Parke DV (1993b) The effects of ether anesthesia on oxidative stress in rats dose response. Toxicology 80: Nelson KW, Ege JF jr, Ross M, Woodman LE, Silverman L (1943) Sensory response to certain industrial solvents. J Ind Hyg Toxicol 25: Nielsen GD (1991) Mechanisms of activation of the sensory irritant receptor by airborne chemicals. Crit Rev Toxicol 21: Purdham JT (1981) Health Hazards to Operating Room Personnel from Exposure to Anaesthetic Gases, Abstract, Canadian Centre for Occupational Health and Safety, Hamilton, Ontario, Canada, Reynolds JEF, Prasad AB (Eds.) (1982) Martindale. The Extra Pharmacopoeia, 28th ed., p 748, The Pharmaceutical Press, London Rogers B (1986) Exposure to waste anesthetic gases a review of toxic effects. Amer Ass Occup Hlth Nurs J 34: Rosen MG (1967) Fetal electroencephalographic studies of the placental transfer of thiopental and ether. Obstet Gynec 30: Schwetz BA, Becker BA (1970) Embryotoxicity and fetal malformations of rats and mice due to maternally administered ether. Toxicol appl Pharmacol 17: 275 (Abstract) Smyth HF, Carpenter CP, Weil CS, Pozzani UC, Striegel JA (1962) Range finding toxicity data: List VI. Am Ind Hyg Assoc J 23: Stevens WC, Eger EI, White A, Halsey MY, Munger W, Gibbons RD, Dolan W, Shargel R (1975) Comparative toxicities of halothane, isoflurane, and diethyl ether of subanesthetic concentrations in laboratory animals. Anesthesiology 42: Steward A, Allott PR, Cowles AL, Mapleson WW (1973) Solubility coefficients for inhaled anaesthetics for water, oil and biological media. Br J Anaesth 45: Vainio H (1982) Inhalation anesthetics, anticancer drugs and sterilants as chemical hazards in hospitals. Scand J Work Environm Hlth 8: Waskell L (1978) Study of the mutagenicity of anesthetics and their metabolites. Mutat Res 57: White AE, Takehisa S, Eger EI, Wolff S, Stevens WC (1979) Sister chromatid exchanges induced by inhaled anesthetics. Anesthesiology 50: completed