Reaction mass of 2,2'-(ethylenedioxy)diethanol and 2,2'-oxydiethanol and ethane-1,2-diol

Endpoint summary

Additional information

There is no toxicokinetic data available on the multiconstituent substance, but data is available on the main two components from which it can be established that the substance is likely to be readily metabolised in mammals and does not show any tendency to bioaccumulate.

 

Data on individual components:

 

MONOETHYLENE GLYCOL (ETHAN-1,2,-DIOL):Several studies/publications are available regarding this endpoint (Carney et al., 1998 and 1999; Corley et al., 2005 and 2008; Cruzan et al., 2004). DOW (Carney et al., 2005) reported an in vivo toxicokinetic study with pregnant rabbits. Female animals were given orally (gavage) ethane-1,2 -diol doses of 100 and 1000 mg/kg on gestation day 9 or 15. The authors concluded, that the relative insensitivity of the rabbit to EG is due to a lower embryonic exposure to GA; likely related to maternal metabolism, compounded by limited distribution to the embryo during critical periods of development. The relevant metabilite for developmental toxicity which was observed in rats and mice but not in rabbits appears to be glycolic acid. This metabolite achieved higher concentrations in rats than in rabbits (Carney et al., 2005)  The relevant metabolite for the (sub)chronic nephropathy is oxalic acid which is slowly transported from liver to kidneys and forms Ca-oxalate crystals in the kidney (Corley et al., 2008). These authors also showed strain differences in rats where different sensitivities were related to the accumulation of Ca-oxalate.

 

DIETHYLENE GLYCOL (2,2’-OXYDIETHANOL) :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). It can be assumed that the nephrotoxic effects are caused by the formation of monoethylene glycol and its nephrotoxic metabolites (glyoxylic acid, glyoxale and oxalic acid), but also 2-hydroxyacetic aldehyde appears to be conceivable which is considered as the nephrotoxic metabolite of 1.4-Dioxane. It should be noted (in the light of the notorious high toxicity in humans) that humans may be more prone than rodents to build up such metabolites.

 

TRIETHYLENE GLYCOL (2,2’(ETHYLENEDIOXY)DIETHANOL): there is no data available. McKennis (1962, cited in CIR 2006) stated, that the test substance is believed to be metabolized in mammals by alcohol dehydrogenase to acidic products causing metabolic acidosis. TEG metabolism by alcohol dehydrogenase can be inhibited, e.g. by 4-methylpyrazole or ethanol.