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Description of key information

After ingestion diethylene glycol was rapidly and quantitatively absorbed by rats and distributed in all tissues. After a single, 12-hour application of diethylene glycol to the skin of rats in doses of 50 mg/kg bw, about 10 % of the dose was absorbed. The main metabolite found was 2-hydroxyethoxyacetic acid (HEAA).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):

Additional information

Several publications concerning toxicokinetics are available. After ingestion diethylene glycol was rapidly and quantitatively absorbed by rats and distributed in all tissues (Heilmair et al. 1993). After a single, 12-hour application of diethylene glycol to the skin of rats in doses of 50 mg/kg body weight, about 10% of the dose was absorbed (Mathews et al. 1991).

In the acutely toxic dose range, oxalic acid was found in the urine of male rats (Durand et al. 1976) and oxalate crystals in the kidneys (Hebert et al. 1978). After a single high dose of diethylene glycol, no metabolism to either monoethylene glycol or oxalate was observed in rats (Heilmair et al. 1993; Lenk et al. 1989; Matthews er al. 1991; Wiener and Richardson 1989). In long-term experiments an increase was observed in the level of oxalate excreted in the urine of male rats (Gaunt et al. 1976). This indicates that the ether bridge can, in principle, be split; however, the oxalic acid concentrations in the blood and kidneys after administration of diethylene glycol remain lower than after administration of the same amounts of ethylene glycol (Winek et al. 1978). After a single oral or intravenous dose of 14C-labelled diethylene glycol of 1.1 g/kg body weight, no ether cleavage products were found in the urine of male rats, only the administered substance, and after 6 and 12 hours about 20% and 32% of the dose was recovered as 2-hydroxyethoxyacetic acid. Contamination with monoethylene glycol has been suggested in other studies as the source of oxalic acid. After inhibition of alcohol dehydrogenase (ADH) with pyrazole the authors found almost exclusively diethylene glycol in urine and no 2-hydroxyethoxyacetic acid. The acute toxicity was also lowered by pyrazole, which indicates that the metabolites are the cause of the nephrotoxic effects (Wiener and Richardson 1989). After administration of single oral doses of 14C-diethylene glycol of 1, 5 and 10 mg/kg body weight (1.1, 5.6, 11.2 g/kg body weight) to male rats, the radioactivity in the blood was found to decrease with a half-life of about 3.5 hours; 73% - 96% of the total radioactivity was excreted with the urine. As a result of the diuretic effect, the two higher doses of diethylene glycol were excreted at a faster rate than was the low dose. The main metabolite found was 2-hydroxyethoxyacetic acid. (cited in MAK documentation, 1995)

In a study on rats (Besenhofer et al., 2010) after single low and high dose oral administration of DEG at 2 mg/kg bw and 10 mg/kg bw, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the urine, with only minor amounts of urinary diglycolic acid (DGA). Small amounts of ethylene glycol (EG), but not oxalate or glycolate, were observed in the urine.

Rats treated with highdose DEG had metabolic acidosis, increased blood urea nitrogen and creatinine, and marked kidney necrosis, noted by histopathology. A minor degree of liver damage was noted at the high dose.

In another study on rats (Besenhofer, 2011) after single low and high dose oral administration of DEG at 2 mg/kg bw and 10 mg/kg bw, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the blood (ca. 4 mmol/L), with only low concentrations of diglycolic acid (DGA) - ca.0.04 mmol/L. In contrast, renal and hepatic concentrations of DGA and of HEAA at 48 h were similar (ca.4 mmol/L), indicating a 100-fold concentrative uptake of DGA by kidney tissue. Treatment with fomepizole blocked the formation of HEAA and DGA and the kidney toxicity. Both HEAA and DGA concentrations in the kidney correlated strongly with the degree of kidney damage. Accumulation of HEAA in blood correlated with increased anion gap and decreased blood bicarbonate so appeared responsible for the DEG-induced acidosis.

In an in vitro study human proximal tubule (HPT) cells in culture, obtained from normal cortical tissue were incubated with increasing concentrations of DEG, 2-HEAA, or DGA separately and in combination for 48 h at pH 6 or 7.4, and various parameters of necrotic and apoptotic cell death were measured (Landry, 2011). The results of the examinations show that DEG and 2-HEAA did not produce any cell death.

DGA produced dose-dependent necrosis at concentrations above 25 mmol/L. DGA did not affect caspase-3 activity and increased annexin V staining only in propidium iodide-stained cells. Hence, DGA induced necrosis, not apoptosis, as corroborated by severe depletion of cellular adenosine triphosphate levels. DGA is structurally similar to citric acid cycle intermediates that are taken up by specific transporters in kidney cells. HPT cells, incubated with N-(p-amylcinnamoyl)anthranilic acid, a sodium dicarboxylate-1 transporter inhibitor showed significantly decreased cell death compared with DGA alone. These studies demonstrate that DGA is the toxic metabolite responsible for DEG-induced proximal tubular necrosis and suggest a possible transporter-mediated uptake of DGA leading to toxic accumulation and cellular dysfunction.

To assess the proximal tubule cell necrosis seen in DEG poisoning caused by the toxic metabolite DGA in vitro experiments with human proximal tubule (HPT) cells were conducted to examine whether the mechanism of toxicity involves disruption of cellular metabolic pathways resulting in mitochondrial dysfunction (Landry, 2013).

It was shown that DGA preferentially inhibited succinate dehydrogenase, including human kidney cell enzyme, but had no effect on other citric acid cycle enzyme activities. DGA produces a cellular ATP depletion that precedes cell death. Human proximal tubule (HPT) cells, pretreated with increasing DGA concentrations, showed significantly decreased oxygen consumption. DGA did not increase lactate levels, indicating no effect on glycolytic activity. DGA increased reactive oxygen species (ROS) production in HPT cells in a concentration and time dependent manner.

These results indicate that DGA produced proximal tubule cell dysfunction by specific inhibition of succinate dehydrogenase and oxygen consumption. Disruption of these processes results in decreased energy production and proximal tubule cell death.

To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims were analysed in a case control study (Schier, 2011). Significantly elevated HEAA (serum) and diglycolic acid (serum and urine) concentrations were identified among cases, which is consistent with animal data. Low urinary glycolic acid concentrations in cases may have been due to concurrent acute kidney injury (AKI). Although serum glycolic concentrations among cases may have initially increased, further metabolism to oxalic acid may have occurred thereby explaining the similar glycolic acid concentrations in cases and controls. The increased serum oxalic acid concentration results in cases versus controls are consistent with this hypothesis.

Conclusion: Diglycolic acid is associated with human DEG poisoning and may be a biomarker for poisoning.