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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

The metabolism of ethoxypropoxy propanol

Ethoxypropoxypropanol (propylene diglycol ethyl ether – PDGEE) is produced by the reaction of ethanol and propylene oxide. It is a minor product from a process that primarily produces ethoxypropanol. These products are part of a series of glycol ethers known as the ‘P’ series glycol ethers. The ‘P’ series glycol ethers produced by the reaction of methanol and propylene oxide are more commercially important and have been more thoroughly studied, including metabolism studies.

 

The structures of these glycol ethers are shown in the attachment to this record (figure 1). Alkoxypropanol forms two structural isomers and alkoxypropoxypropanol forms four structural isomers. It should be noted that all of the isomers of the alkoxypropoxy propanols also each exist as four stereoisomers, making a total of sixteen in all.

 

Metabolism studies have been carried out on both methoxypropanol (both isomers)(Miller 1983, 1986) and methoxypropoxypropanol (main isomer) (Miller 1985).The metabolic pathways indicated by these studies along with quantification where possible are shown in appendices 2 to 4 in the attachment to this record. On the basis that the length of the alkoxy chain is not likely to qualitatively affect the metabolic pathways, it is possible to predict with some degree of confidence the metabolic routes of all isomers of ethoxypropoxypropanol.

Parent glycol ether metabolism - methoxypropanol

It is important to understand the differences in the metabolism of the parent propylene oxide glycol ethers, since not only are they metabolites of the diglycol ethers, but they also illustrate the differences in metabolism between primary and secondary propylene glycol ethers.

 

The studies on methoxypropanol (propylene glycol methyl ether - PGME) show that the predominant isomer with the secondary hydroxyl group (s-PGME) is primarily metabolised to propylene glycol (PG), probably by dealkylation via microsomal O-dealkylase. PG is in turn oxidised to lactate and pyruvate and eventually exhaled as CO2(Ruddick JA, 1972). Small quantities of unchanged PGME, PG and the glucuronide and sulphate conjugates of PGME are excreted in urine, with evidence that a greater proportion of the administered dose is excreted in the urine at higher doses. At a dose level of 90mg/kg, 63% was exhaled as CO2, and about 11% was excreted in the urine, whereas at 780 mg/kg the proportion exhaled fell to 57% but that excreted in the urine approximately doubled. The pathways of PGME metabolism and their relative importance are shown in figure 2 of the attachment to this record.

 

It is reasonable to predict that the predominant isomer of ethoxypropanol would be metabolised in a qualitatively similar manner as the respective isomer of PGME, although there may be minor quantitative differences.

Metabolism of methoxypropoxypropanol

The metabolism of methoxypropoxypropanol (dipropylene glycol methyl ether – DPGME) has also been studied. In this case, the metabolic routes for the main isomer (secondary/secondary) alone have been followed. Three main metabolic routes were identified. Microsomal O-dealkylation is a significant route of biotransformation since dipropylene glycol (DPG) is observed in the urine. This in turn is believed to enter into intermediate metabolism, as does PG. The second major route of biotransformation is hydrolysis of the ether linkage to form s-PGME and PG. The metabolites seen are consistent with the s-PGME formed metabolising as indicated by the study with s-PGME itself, that is primarily to PG. Rates of elimination of metabolites were consistent between studies. Due to overlapping peaks in the gas chromatogram, it was not possible to quantify these two routes. However, the data on s-PGME alone suggests that the major route of metabolism will be to PG and therefore that the unresolved peak is substantially DPG.The third and least important route of elimination is conjugation with sulphate and glucuronic acid followed by urinary excretion. (See figure 3 of the attachment to this record.)

 

Subsequent in vivo and liver section in vitro metabolism studies on a closely related substance (dipropylene glycol dimethyl ether, DPGDME) confirm that significant cleavage of the dipropylene glycol backbone does not occur in the first instance, and that the major metabolic path is via O-deakylation to DPG rather than hydrolysis to PGME. Since DPGDME is metabolized to DPG via DPGME, it is reasonable to conclude that this pathway is also more important for DPGME.

 

There are some quantitative differences between the findings of the studies with s-PGME and ss-DPGME, principally in the proportion of metabolites in urine versus CO2; more metabolites are found in the urine with DPGME. The DPGME study was done at a single equimolar dose comparable to the higher of the two doses used in the two PGME studies. This is known to favour urinary metabolites, made more so by the fact that an equimolar concentration of DPGME will produce up to twice the amounts of PG. Certainly the proportions of PG eliminated directly in urine versus metabolised to CO2is more in line with other reported metabolic data which indicates 45% eliminated unchanged by humans (Ellenhorn 1988). No major differences in the systemic toxicological properties of DPGME and PGME would be anticipated in view of the fact that they are apparently metabolised via the same routes to the same general types of metabolites.

 

It is reasonable to predict that ss-DPGEE would be metabolised by the same routes as ss-DPGME. In this case, the primary metabolites would be DPG, propylene glycol ethyl ether, and sulphate and glucuronide conjugates; with DPG being further oxidised to PG, lactate, pyruvate and CO2. Although there may be quantitative differences in the flux through each route, none of the metabolites are of toxicological concern.

 

Supportive evidence for this conclusion comes from consideration of the kinetic and toxicological profile of s-PGME. The distribution of radioactivity following s-PGME, which is metabolised via PG, is distinctly different to that of ethoxyethanol and p-PGME [1,2], which are oxidised to the respective acids. In the case of s-PGME, radioactivity was concentrated in the liver, compared to concentration in the blood for ethoxyethanol and p-PGME. This coincides with the observation of increased absolute and relative liver weight in animals exposed to high concentrations of PGME. Such an observation was also noted in the 90 day sub-chronic study with DPGEE, with the additional fact noted that the liver changes (suggesting metabolic adaptation) were reversed after dosing was stopped (Huntingdon Life Sciences 2000).