Propane-1,2-diyl diacetate

Endpoint summary

Additional information

Absorption

1,2-propyleneglycol diacetate (PGDA) is a colourless liquid mainly used as a solvent for paints and coatings.

The oral LD50 of PGDA in rats and guinea pigs has been reported to be 13,530 and 3420 mg/kg bw, respectively (Smyth et al, 1941). In a toxicokinetics/metabolism study performed with radiolabelled PGDA, the absorption half-life was determined to be 0.192h (11.5 min) when dosed neat at 500 mg/kg bw. Evaluation of the blood time course showed a T_maxof 1hr.

The steady-state dermal permeability coefficient of PGDA through human epidermis has been estimated to be 0.000696 cm/h by Dermwin version 2.01 (EPIWEB version 4.1). This is consistent with its expected extremely low dermal absorption based on high water solubility.

Inhalation of PGDA is not likely due to low vapour pressure (0.578 mm Hg at 25^oC) and moderate log octanol: air partitioning (log K_oa= 5.34; EPIWEB version 4.1). However, due to high water solubility and low molecular weight (<200), any inhaled PGDA would be expected to be completely absorbed.

Distribution

Due to its neutral hydrophilic nature and low plasma protein binding (~22%), a low volume of distribution (1.1 L/kg) is estimated for PGDA in humans by ACD/ADME Suite. No animal data on PGDA is available in the literature and the TK/metabolism study on PGDA did not evaluate distribution. Based on this volume of distribution, the relative partitioning of any trace levels of PGDA to tissues, prior to hydrolysis, would be expected to be comparable to levels seen in the blood.

Metabolism

In the toxicokinetics/metabolism study comparing radiolabelled PGDA and propylene glycol (PG) , blood samples collected at C_max(1 hr) from molar equivalent dosed rats showed only one radioactive peak in the PGDA and PG animals. The peak seen in blood for both substances had the same retention time which corresponded to PG. There was no peak in the PGDA sample at 1 hr post-dose that corresponded with the retention time of PGDA. Evaluation of the skin/carcass, 7 days after dosing, showed radioactivity recovery of approximately 10% of the dose for both PGDA and PG. This indicates that PGDA is hydrolyzed to PG which is then further metabolized to pyruvate and incorporated into thetricarboxylic acidcycle. Further reasoning that PGDA was rapidly hydrolyzed to PG is evident by comparing the lack of PGDA at the 1 hr C_maxand the absorption t_½. Based on no PGDA being present after 1 h (metabolic steady state) and knowing it takes 5 half-lives to reach steady state, the metabolic t_½can be calculated at 0.2 h. Since this is identical to the absorption t_½(0.192 h), this indicates that PGDA is metabolized shortly after it is absorbed.

Since PGDA was radiolabelled on a carbon in the PG moiety, it was not possible to evaluate for the presence of acetic acid. However, as the ester bond was easily hydrolyzed by carboxylesterasesto form PG it can be expected that acetic acid would be the other metabolite. It is known that there are numerous sites of esterase activity in the body, including blood, liver, skin, nasal mucosa, heart, muscle, adipose tissue and kidney (Stott 1985, McCracken 1993, Satoh 1998).

Information on other glycol ether acetates indicates that the hydrolysis of the ester in vivo would be rapid. In a published study with an analogue, propylene glycol methyl ether acetate (PMA), Domoradzki et al. (2003) showed hydrolysis of the parent acetate ester to PM when this test material was given to rats with at_1/2of 1.6-2.3 min. In the same fashion, Gargas et al. (2000) found no detectable acetate ester of ethylene glycol ethyl ether (EGEEA) immediately after inhalation exposure to rats (t_1/2< 1 min). Finally, Gallaher and Loomis (1975) studied the metabolic fate of ethyl acetate and found the in vivohalf-life was 5-10 min. All of these analogues substances show rapid hydrolysis of the acetate group similar to that seen with PGDA.

Once formed, 1,2-propanediol (PG) and acetic acid can also be further metabolized to other metabolites. 1,2-propanediol will be metabolized to lactaldehyde, methylglyoxal, and lactic acid by alcohol dehydrogenase and aldehyde dehydrogenase [2]. The formed lactic acid and acetic acid can also further provide energy by further oxidation through tricarboxylic acid cycle (Ruddick 1972; Mookerjea 1955)

Accumulation

PGDA is a hydrophilic compound with an expected low volume of distribution and low plasma protein binding. As a result, this compound is expected to reside entirely in the water fraction and freely exchange between the blood and tissues (Lemke 2007) therefore not accumulating in any tissue. PGDA has been shown to undergo rapid metabolism and hydrolysis in rats therefore is not considered likely to accumulate in the body. However, in the toxicokinetic/metabolism study with radiolabelled PGDA, residual radioactivity (10% of dose) was found in the carcass/skin 7 days after dosing. This was likely due to PGDA being metabolized to pyruvate and incorporated into the tricarboxylic acid cycle.

Excretion

Analysis of the recovered radioactivity from urine, feces and CO₂in the toxicokenitic/metabolism study showed very similar values between PGDA and PG. The majority of the radioactivity was found as CO₂(~50%), with most being recovered in the first 12 hours post-dosing, for both PGDA and PG, indicating again that PGDA is quickly hydrolyzed to PG (which is metabolized to CO₂). A much smaller amount of radioactivity was eliminated in the urine (~13%) with minimal amounts being found in feces (~2%) and as volatile organics (~1%). Total recovery of radioactivity was 74% and 82% for PGDA and PG, respectively, with the remainer likely lost as CO₂during the early blood collections (opening of metabolism chambers). 

References

Domoradzki J. Y., Brzak K. A. and Thornton C. M. (2003). Hydrolysis kinetics of propylene glycol monomethyl ether acetate in rats in vivo and in rat and human tissues in vitro. Toxicological Sciences: An Official Journal of the Society of Toxicology 75, 31-39.

Gallaher E. J. and Loomis T. A. (1975). Metabolism of ethyl acetate in the rat: hydrolysis of ethyl alcohol in vitro and in vivo. Toxicology and Applied Pharmacology 34, 309-313.

Gargas M. L., Tyler T. R., Sweeney L. M., Corley R. A., Weitz K. K., Mast T. J., Paustenbach D. J. and Hays S. M. (2000). A toxicokinetic study of inhaled ethylene glycol ethyl ether acetate and validation of a physiologically based pharmacokinetic model for rat and human. Toxicology and Applied Pharmacology 165, 63-73.

McCracken N. W., Blain P. G. and Williams F. M. (1993). Nature and role of xenobiotic metabolizing esterases in rat liver, lung, skin and blood. Biochemical Pharmacology 45, 31-6

Mookerjea, S., and Sadhu, D. P. (1955) Metabolism of acetic acid in kidney and liver slices of the hypothyroid rats,Endocrinology 56, 507-510.

Ruddick, J. A. (1972) Toxicology, metabolism, and biochemistry of 1,2-propanediol,Toxicol. Appl. Pharmacol. 21, 102-111.

Satoh T. and Hosokawa M. (1998). The mammalian carboxylesterases: from molecules to functions. Annu Rev Pharmacol Toxicol 38, 257-88. 

Smyth HF, Seaton J and Fischer L(1941). The single dose toxicity of some glycols and derivatives. J Indust Hygiene Toxicol 23, 259-268

Stott W. T. and McKenna M. J. (1985). Hydrolysis of several glycol ether acetates and acrylate esters by nasal mucosal carboxylesterase in vitro. Fundamental and Applied Toxicology: Official Journal of the Society of Toxicology 5, 399-404.

The Dow Chemical Company, Midland, MI 48674 (2017). Propylene Glycol Diacetate: Toxicokinetic Bridging Study in Crl:CD(SD) Rats. Testing laboratory: Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674. Study no.: 171039. Owner company: The Dow Chemical Company, Midland, MI 48674. Report date: Draft (2017-09-11).