2001). High exposures to EM and EE cause testicular atrophy and a decrease in white blood cells in mice. Treatment of rabbits and rats for 13 weeks with EM caused degeneration of testicular germinal epithelium and infertility; partial recovery was seen after 13 weeks. Exposure of pregnant rats to EE for 7 h/day on gestational days 7–15 caused fetal death with no signs of maternal toxicity. Cardiovascular and skeletal malformations were seen. Cardiovascular malformations have also been seen in the offspring of pregnant rabbits exposed to EE.

Exposure to PM, however, is not associated with reproductive or teratogenic effects (Bruckner and Warren, 2001). The differences in toxicity between PM and the other glycol ethers appear to be due to differences in their metabolism. Evidence indicates that the toxic effects of EM, EE, and EB are mediated by alkoxyacid metabolites (for example, methoxyacetic acid is a metabolite of EM). In contrast, the nontoxic PM does not have an alkoxyacid metabolite; it is metabolized to propylene glycol.

ESTERS

Organic esters are produced by the condensation of an alcohol and carboxylic acid with removal of water (see Figure 4.6 for structures of esters). The chemical properties of the ester depend on the structure of its alcohol and acid moieties. The two esters of potential concern in this document, because of their use in the Gulf War, are butyl acetate, an aliphatic ester, and 1-methoxy-2-propanol acetate, a propylene glycol ether ester. Butyl acetate is used as a flavoring agent and a solvent for cosmetics, lacquers, and adhesives. 1-Methoxy-2-propanol ether acetate (propylene glycol monomethyl ether acetate, or PGMEA) is an ester of acetic acid and 1-methoxy-2-propanol. Because it contains both an ester and an ether linkage, PGMEA has unique solvent properties and is valued as a solvent for oils, gums, and resins.

FIGURE 4.6 Structure of various esters.

Both butyl acetate and PGMEA are considered to have low toxicity in humans. Although hepatotoxicity has been seen in workers exposed to a mixture of solvents that included butyl acetate, no direct evidence supports butyl acetate as the agent responsible for the hepatotoxicity (Franco et al., 1986).

Only mild reproductive effects have been reported for butyl acetate in experimental animals. Increased testicular weights were reported in rats exposed to n-butyl acetate by inhalation over 13 weeks, but no testicular lesions accompanied the change in weight. n-Butyl acetate had no adverse effect on female fertility and fetal development (David et al., 2001). Another study found that pregnant rats exposed to n-butyl acetate had fetuses with lower weights than controls, but this was attributed to decreased food consumption by dams. No significant differences were seen in developmental defects in the fetuses of the exposure group, relative to controls, so the



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