Hematological effects of exposure to mixtures of selected ethylene glycol alkyl ethers in rats

Pharmacol Rep. 2012;64(1):166-78. doi: 10.1016/s1734-1140(12)70743-0.


Exposure to various ethylene glycol monoalkyl ethers (EGAEs) is known to result in hemolytic effect caused by their metabolites, appropriate alkoxyacetic acids, generated via both alcohol dehydrogenase and aldehyde dehydrogenase. It has been shown in many studies that administration of single doses of EGAEs to rats lead to dose- and time-dependent hemolytic anemia. The repeated exposure to isopropoxyethanol (IPE), and butoxyethanol (BE), contrary to methoxyethanol (ME) and ethoxyethanol (EE), resulted in significantly less pronounced hematological changes. While the majority of hematological effects were dramatic at the beginning of the exposure, later these changes clearly regressed despite continued weekly exposure to these ethers. The gradual recovery from the hemolytic anemia may be associated with tolerance development to the hemolytic effect of IPE and BE. ME demonstrated high hematotoxicity, which increased progressively and reached a maximum at the end of 4 week exposure, whereas EE revealed moderate hematological effects. It might be suspected that ME and EE may modified of IPE hemolytic activity in rats simultaneously treated with these compounds. In the rats co-exposed to IPE and ME subcutaneously at a relatively low doses of 0.75 mM + 0.75 mM for 4 weeks, a significantly less pronounced hematological changes at the beginning of the exposure in comparison with animals treated with IPE (0.75 mM) alone were observed. At the later period, i.e., at the end of 4 weeks exposure, the hematological alterations in the same animals were markedly pronounced and progressively elevated with exposure time, except for mean corpuscular volume (MCV) values, which were significantly lower in comparison with IPE group. ME at the higher dose of 1.25 mM/kg and EE at both doses of 0.75 and 1.25 mM/kg did not modify the hematotoxicity of IPE (at doses of 0.75 mM and 1.25 mM) at the beginning of the exposure, whereas increased its harmful effects at the end of the treatment. The amelioration in the majority of the hematological parameters at the beginning of the exposure may be caused by inhibitory effect of ME on IPE metabolism. On the contrary, an accumulation of the methoxyacetic acid and ethoxyacetic acid, toxic metabolites of ME and EE, respectively, and no tolerance development to the hemolytic effect of these two chemicals may be responsible for elevated hematological alterations at the end of the exposure.

MeSH terms

  • Acetates / adverse effects
  • Alcohol Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase / metabolism
  • Anemia, Hemolytic / blood
  • Anemia, Hemolytic / chemically induced*
  • Anemia, Hemolytic / metabolism
  • Animals
  • Complex Mixtures / toxicity
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Erythrocyte Indices / drug effects
  • Ethers / toxicity*
  • Ethylene Glycol / toxicity*
  • Ethylene Glycols / toxicity
  • Hematologic Agents / toxicity
  • Leukocytes / drug effects
  • Leukocytes / metabolism
  • Male
  • Rats
  • Rats, Wistar


  • Acetates
  • Complex Mixtures
  • Ethers
  • Ethylene Glycols
  • Hematologic Agents
  • ethoxyacetic acid
  • isopropylethanediol
  • Alcohol Dehydrogenase
  • Aldehyde Dehydrogenase
  • methoxyacetic acid
  • Ethylene Glycol