Elimination

In human volunteers less than 0.4% of absorbed EGEE was excreted via the lungs (Groeseneken et al., 1986a). Less than 0.03% of inhaled EGBE is excreted unchanged in the urine (Johanson et al., 1986). Urinary excretion of the alkoxyacetic acid metabolites of glycol ethers is very variable (Johanson et al., 1986; Johanson and Johnsson, 1991).

EAA is detected in urine within one hour of exposure to EGEE. The rate of excretion of EAA increased to a maximum 3-4 hours after cessation of exposure in human volunteers. The excretion rate of EAA had not returned to pre-exposure levels after 42 hours. On average 23% of absorbed EGEE was excreted as EAA in 42 hours (Groeseneken et al., 1986b). Similarly, 22% of absorbed EGEEA was excreted as EAA in 42 hours (Groeseneken et al., 1987). In another study only 12% of a dose of EGME and 14% of a dose of EGEE were excreted as MAA and EAA within 48 hours (Kezec et al., 1997). The total amount of MAA excreted was estimated (by extrapolation) to be 85.8% of an inhaled dose of EGME (Groeseneken et al., 1989). After inhalation of EGBE, 17-55% was excreted in the urine as BAA (Johanson et al., 1986).

The elimination half-life of the alkoxyacetic acid metabolites increases as the length of the alkyl chain decreases; so the elimination half-life increases in the order of butoxyacetic acid, ethoxyacetic acid and methoxyacetic acid. See Table 11.7.

Table 11.7 Elimination half-lives of glycol ethers and their metabolites in humans

Exposed to:

Route

Chemical measured

Mean urinary half-life (range)

Mean blood half-life (range)

Reference

EGBE

dermal

EGBE

(0.6-0.72)

Corley et al., 1997

EGBE

inhalation

EGBE

-

0.66 hours

Johanson and Johnsson, 1991

EGBE

inhalation

EGBE

-

39.5 minutes (21.2-63.4)

Johanson et al., 1986

EGBE

dermal

EGBE

-

36 minutes (19-53)

Johanson and Boman, 1991

EGBE

ingestion

EGBE

-

210 minutes *

Gijsenbergh et al., 1989

EGBE

dermal

BAA

-

3.27 hours (2.35-4.38)

Corley et al., 1997

EGBE

inhalation

BAA

-

4.3 hours

Johanson and Johnsson, 1991

EGME

inhalation

MAA

77 hours (66.1-89.7)

-

Groeseneken et al., 1989

EGME

inhalation or dermal

MAA

72 hours

-

Kezic et al., 1997

EGEE

inhalation or dermal

EAA

42 hours

-

Kezic et al., 1997

EGEE

inhalation

EAA

21-24 hours

-

Groeseneken et al., 1986b

EGEEA

inhalation

EAA

23.6 hours

-

Groeseneken et al., 1987

EGBE

inhalation

BAA

5.77 hours

-

Johanson et al., 1986

EGBE

ingestion

BAA

5.3 hours

-

Gijsenbergh et al., 1989

*The product ingested in this case also contained ethanol, which may have inhibited metabolism and so prolonged the half-life.

Toxicology of Solvents Mode of action

Glycol ethers have a wide spectrum of toxicity and for the most part the mechanisms are unclear. The alkoxyacetic acid metabolites are thought to be responsible for toxicity. There is strong evidence that these metabolites are responsible for testicular (Gray et al., 1985; Moss et al., 1985) and haematological (Ghanayem et al., 1987) toxicity. Cell culture testing has shown that while the glycol ethers themselves have no discernible toxic effect, toxicity occurs with their metabolites at much lower concentrations (Gray et al., 1985). The parent compounds vary in the severity of testicular toxicity but it is not clear whether this reflects differences in metabolism or in the inherent toxicity of the metabolites (Gray et al., 1985). MAA causes the most severe testicular changes; EAA is less toxic and n-propoxyacetic acid (PAA) and BAA produced no effects. However toxicity may occur at high doses with these compounds (Gray et al., 1985). It is suggested that the free carboxyl group on MAA may be important in toxicity, when conjugated with glycine the toxicity of MAA in vitro was abolished (Gray et al., 1985). It has been reported that MAA but not EGME inhibits the production of lactate by Sertoli cells in culture (Beattie et al., 1984). Lactate is an important energy substrate for developing spermatocytes and this may be a mechanism of toxicity. However, in cell cultures supplementation with lactate did not reduce toxicity, even though it has been shown that spermatocytes can utilise exogenous lactate (Gray et al., 1985).

Further evidence for the role of the alkoxyacetic acid metabolites in the toxicity of glycol ethers is the observation that treatment with substances which block the enzyme alcohol dehydrogenase (responsible for metabolism) reduces toxicity. Animal studies have demonstrated that pre-treatment with pyrazole provides protection against testicular damage (Moss et al., 1985) and haematological toxicity (Ghanayem et al., 1987).

Haemolysis in rat erythrocytes exposed in vitro to BAA is preceded by swelling and adenosine triphosphate (ATP) depletion, suggesting that the target is the erythrocyte membrane. Incubation of cells with EGBE found that blood was capable of metabolising it in vitro and that EGBE was essentially devoid of haemolytic activity (Ghanayem, 1989). The osmotic fragility of erythrocytes is increased by exposure to glycol ethers rendering them more sensitive to osmotic lysis (Carpenter et al., 1956).

The severe metabolic acidosis observed with acute ingestion of glycol ethers is due to the presence of the alkoxyacetic acid metabolite.

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