A case-control study was conducted among first time patients at a clinic for reproductive disorders. The study group consisted of 1019 cases, defined as patients diagnosed infertile or subfertile on the basis of a spermiogram and 475 controls who were diagnosed as normally fertile by the same procedure. Possible exposure to ethylene glycol ethers was assessed by the presence of the urinary metabolites methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) respectively for 2-methoxyethanol and 2-ethoxyethanol or their acetates. In total, EAA was detected in 39 cases and six controls, with a highly significant odds ratio of 3.11 (p = 0.004). On the other hand, MAA was only found in one case and two controls. The presence of EAA in urine proved to be strongly associated with exposure to preparations containing solvents, especially paint products, and with some groups of occupations, the most important of which were also directly or possibly connected with paint products. The absence of a significant correlation between the concentration of urinary EAA and the various measures of sperm quality could be explained by the expected latent period between exposure and observed effects. Other temporal aspects of the relation between exposure as judged from the presence of urinary EAA and diagnosis are also discussed.

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The uptake of EGME and the urinary excretion of its major metabolite (MAA) was studied in seven male volunteers during experimental exposure to EGME at rest. The exposure concentration was set at 16 mg/m3, the present Threshold Limit Value. A high retention (0.76) remained unchanged during the 4-h exposure period. In combination with a constant pulmonary ventilation and a fixed exposure concentration this resulted in an uptake rate that showed no significant variation in time. The total amount of EGME inhaled corresponded to a dose of only 0.25 mg/kg. During and up to 120 h after the start of the exposure, MAA was detected in the urine. The elimination half-life was on average 77.1 h. The total amount of MAA excreted was calculated by extrapolation and averaged 85.5% of the inhaled EGME. The pharmacokinetic data are compared with those obtained from other human exposure studies to ethylene glycol ethers (EGEE and EGBE).

Ten healthy male subjects were exposed to ethylene glycol monoethyl ether (EGEE) under various conditions of exposure concentration and physical workload and their urinary excretion of ethoxyacetic acid was followed up for 42 hours. Maximal excretion of ethoxyacetic acid was reached three to four hours after the end of the four hour exposure period. Afterwards, ethoxyacetic acid excretion declined slowly with a biological half life of 21-24 hours. Ethoxyacetic acid excretion increased as the uptake of EGEE increased as a consequence of higher exposure concentration or pulmonary ventilation rate during physical exercise. On average, 23 1 + 6-3% of EGEE was recovered as ethoxyacetic acid within 42 hours and the recovery did not change as the uptake of EGEE increased. Quantitative relations between ethoxyacetic acid excretion and EGEE uptake were obtained and the relevance of ethoxyacetic acid excretion as a measure for exposure to EGEE is discussed.In recent years much effort has been given to the investigation of the metabolism and disposition of ethylene glycol ethers in animals. When ['4C]-ethylene glycol ethers were given to rats or dogs, 60-80% was recovered in urine after 48 hours.' 6 Furthermore, 10-14% of the label was recovered as 14CO2 in the expired air of treated animals when the label was in the ethanol part of the molecule.' 4 When the label was in the alkoxy part, however, only 1-5% of radioactivity appeared as C02.Methoxyacetic acid was identified as the major urinary metabolite (75-90%) in rats exposed to ethylene glycol monoethyl ether (EGME).'136 Analogously, ethylene glycol monobutyl ether (EGBE) was metabolised and excreted mostly in the form of butoxyacetic acid.7 On the other hand, two major urinary metabolites were identified in rats and dogs after the administration of the ethyl (EGEE) and isopropyl (EGiPE) ether, respectively, ethoxyacetic acid and isopropoxyacetic acid (45-30%) and their glycine conjugate (30-45%).24 Both metabolites accounted for approximately 75% of the administered dose.

Ten male volunteers were exposed to ethylene glycol monoethyl ether (EGEE) under various conditions of exposure concentration and physical workload. Steady state levels of retention, atmospheric clearance, and rate of uptake were reached immediately after the start of the exposure period for all experimental conditions. Retention was high (64% in resting condition) and increased as physical exercise was performed during exposure. Atmospheric clearance increased as the pulmonary ventilation rate increased. The rate of uptake was higher as exposure concentration or pulmonary ventilation rate, or both, increased. Individual uptake appeared to be governed mainly by transport mechanisms (pulmonary ventilation or cardiac output or both) and not by anthropometric factors. Respiratory elimination of unchanged EGEE accounted for < 0 4% of the total body uptake. Postexposure breath concentrations declined rapidly during the first minutes after cessation of exposure, after which a much slower decrease was observed. This slow decrease could be described by a regression equation containing two exponential terms indicating that at least two pharmacological compartments are concerned.In recent years much evidence has become available on the toxicity of ethylene glycol ethers and this has been recently reviewed.12 By contrast, data on the toxicokinetics and disposition of glycol ethers are scant. When beagle dogs were exposed to ethylene glycol monoethyl ether acetate (EGEEAc), approximately 70% of the inhaled vapour was retained at equilibrium (ca 3 h). Postexposure breath concentrations declined rapidly indicating a rapid removal of the component from the blood.3 When rats were orally dosed with "4C-labelled ethylene glycol monomethyl ether (EGME), 50-70% of the radiolabel was excreted in the urine within 48 hours, mostly in the form of methoxyacetic acid,4" whereas 15% of the radioactivity was identified as the parent compound.5Analogously, when rats were exposed to the ethylether (EGEE), the major urinary metabolite was ethoxyacetic acid and its glycine conjugate.6Depending on the position of the radiolabel, different amounts of "4C were recovered in expired air as '4CO2: when the label was in the ethanol part of the molecule, 5% appeared as exhaled '4CO2 in the first 10 hours, whereas 12-14% were recovered as "4C02 when the label appeared in the ether group.Only minor fractions in the expired air (04-3%) were identified as the parent compound and there was no indication for the presence of volatile metabolites other than C02.4-6