In vivo metabolism and kinetics of ethylene glycol monobutyl ether and its metabolites, 2-butoxyacetaldehyde and 2-butoxyacetic acid, as measured in blood, liver and forestomach of mice.
1. Ethylene glycol monobutyl ether (EGBE) causes forestomach hyperplasia and neoplasia in mice when administered chronically by inhalation. 2. The study was initiated to test the physiologically based pharmacokinetic (PBPK) model prediction that 2-butoxyacetaldehyde (BAL), a transient, labile intermediate in the oxidation of EGBE to butoxyacetic acid (BAA), is unlikely to achieve concentrations sufficient to cause DNA damage in target tissues. 3. Male and female B6C3F1 mice were administered a high oral dose of EGBE (600mgkg(-1)), and tissues were collected at 5, 15, 45 and 90min following the dose. The tissues were processed for determination of EGBE, BAL and BAA by gas chromatography-mass spectrometry. 4. BAL was detected at low concentrations in all tissues sampled and at all time points following EGBE administration (about 0.3-33 microM). BAL concentrations were highest in the initial samples (5 min) in all tissues and declined from that point. 5. BAL concentrations in liver and forestomach tissues corresponded to the peak concentrations predicted by an already published PBPK model, and are higher than BAL concentrations that could be achieved by inhalation exposure to EGBE. 6. Mouse inhalation exposure to EGBE is therefore unlikely to generate BAL concentrations in tissues sufficient to initiate a carcinogenic response.
Deisinger
P J
PJ
Health and Environment Laboratories, Eastman Kodak Company, Rochester, NY 14652-6272, USA. peter.deisinger@kodak.com
Boatman
R J
RJ
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D006016:Glycolates / Q000097:blood / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013270:Stomach / Q000187:drug effects; D014018:Tissue Distribution
D005026:Ethylene Glycols; D006016:Glycolates; C017095:n-butoxyacetic acid; C053320:n-butoxyacetaldehyde; D000079:Acetaldehyde; C017096:n-butoxyethanol