TR 064 : The Toxicology of Glycol Ethers and its Relevance to Man | August 1995
A previous ECETOC review (1985) discussed the toxicological effects of ethylene and propylene glycol alkyl ethers and explained the toxicological observations in the context of metabolism. The current report includes a larger number of glycol ethers, presents the updated relevant toxicological information in animals and man, and reviews the knowledge of mechanisms underlying the observed toxicology.
Glycol ether acetates have the same systemic toxicological effects as their parent glycol ethers and it is reasonable to consider that their toxicity is equivalent on a molar basis.
Consideration of new data and other glycol ethers has not fundamentally altered the previously known toxicological effects exhibited by some members of this chemical group. The short chain ethylene glycol methyl and ethyl ethers (and their acetates), as well as other glycol ethers capable of being converted to ethylene glycol methyl or ethyl ethers, cause testicular atrophy, teratogenicity/foetotoxicity and bone marrow depression. In contrast, longer chain ethylene glycol ethers (ethylene glycol butyl ether, – propyl ether, – isopropyl ether and – phenyl ether) do not cause these effects, but do cause erythrocyte fragility in rats; human erythrocytes are significantly less sensitive for haemolysis than the rodent erythrocytes. The immunological effects, particularly for ethylene glycol methyl ether have now been studied in more detail.
The toxicity of propylene glycol ethers with the alkoxy group at the primary position is quite different to that of the ethylene glycol ethers. None of the effects mentioned above have been reported and the only evidence of toxicity is towards liver and kidney. Teratogenic effects (but no testicular or bone marrow effects) have been reported when the primary position is occupied by a hydroxyl group (1-propylene glycol 2-methyl ether or acetate, neither of which are commercially available).
The principle clinical signs of acute intoxication in animals are consistent with the non-specific CNS depression commonly seen with organic solvents. Those glycol ethers that cause haemolytic effects have lower LD50 or LC50 values than the other glycol ethers. Glycol ethers generally do not appear to be appreciably irritating to the skin on acute exposure. Consistent with the solvent properties of these materials, prolonged or repeated exposure may lead to more severe skin irritation. There is no evidence from animal experiments or human observations that glycol ethers are skin sensitisers.
Glycol ethers have the potential to penetrate the skin and this therefore represents a potentially significant route of exposure. Some comparative in vitro data show that the degree of penetration varies with chemical structure. Recent studies with ethylene glycol butyl ether indicate that dermal absorption from the vapour phase can contribute significantly to total systemic exposure.
Target organ toxicity has been related to the extent of formation of the following metabolites: methoxy- and ethoxy-acetic acid (affecting testes, bone marrow, thymus and embryonic tissue) and butoxyacetic acid (erythrocyte haemolysis). A similar relation is presumed for methoxypropionic acid (embryonic tissue). In contrast, ethylene glycol phenyl ether (phenoxyethanol) is a more potent haemolytic agent than the metabolite phenoxyacetic acid.
Apart from target organ toxicity, the liver has frequently shown an increased weight (in the absence of pathological change) following high doses of glycol ethers. This has been interpreted as an adaptive change.
Kidney weight changes and histopathological changes have been identified following dipropylene glycol ethyl ether and 2-propylene glycol 1-methyl ether administration. These changes are diagnosed for 2-propylene glycol 1-methyl ether to result from the accumulation of alpha 2 microglobulin. They occurred only in male rats and are not considered relevant for man. This is also most likely the case for dipropylene glycol ethyl ether but definitive analytical confirmation is not available.
The database on mutagenicity tests has been significantly enlarged, with the majority of tests indicating no genotoxic activity. Whilst in vitro tests for clastogenic action showed an increase in chromosomal aberrations (e.g. for ethylene glycol ethyl ether), this effect could not be confirmed with mammalian in vivo test systems.
The general conclusion that glycol ethers, when tested according to internationally accepted test protocols, do not pose a significant genotoxic risk to man is still valid.
The characteristic toxic effects of specific glycol ethers have all been observed following short term exposure and do not increase in severity in studies of longer duration. This observation, together with the absence of significant genotoxic effects, indicates that long-term exposure is not likely to lead to more severe or different effects, relevant for the risk assessment for human beings. The few long-term studies available support the contention that glycol ethers are not likely to be potential human carcinogens.
Metabolism plays a key role in explaining the different toxicological effects observed in structurally related compounds. The main metabolic route is oxidation via alcohol dehydrogenase when a terminal hydroxyl group is available, leading to the formation of the alkoxy-acetic or alkoxy-propionic acids.
The toxic effects observed correlate with the extent of metabolite formation and its elimination rate.
A second important route of metabolism is oxidation by the microsomal P450 mixed function oxidase (O-dealkylation). This leads to the production of ethylene glycol or propylene glycol, which enter into the tricarboxylic acid cycle and are partially excreted as carbon dioxide.
Significant adverse systemic health effects in man have been reported for ethylene glycol methyl ether, ethyl ether and their acetates and diethylene glycol dimethyl ether based on evaluation of worker populations exposures and case reports. Ethylene glycol methyl and ethyl ethers exposure has been associated with anaemia, granulocytopenia and leucopenia and several reports have indicated an association between exposure and increased risk of abortion. Ethylene glycol methyl and ethyl ethers have also been associated with reduced sperm count in painters. The number of observations and the limited information on the level of exposure do not allow firm conclusions to be made.
A single case report has associated significant occupational dermal exposure to ethylene glycol phenyl ether with nervous system effects in 3 women. Data on aplastic anaemia in lithographers are considered to be related to exposure to ethylene glycol ethyl ether, rather than to the confounding presence of dipropylene glycol methyl ether.
Although the individual literature references on ethylene glycol methyl ether, – ethyl ether and acetate do not provide conclusive evidence, the multitude of data on effects in man is compatible with the experimental data in several animal species and suggests at least a similar sensitivity in man for the effects described in animals. The data on haemolytic effects with ethylene glycol butyl ether and – phenyl ether indicate that man is significantly less sensitive to this effect than some animal species.
This evidence indicates that metabolites are of great importance in the toxicology of the glycol ethers. Linked to this is the clear observation that small differences in glycol ether structure can significantly affect toxicity. Structural comparisons may be misleading if applied separately from a knowledge of the metabolism of the material being considered.