Registration Dossier

Administrative data

Description of key information

In an oral study on rats (Gaunt, 1976) a NOAEL of 300 mg/kg bw/day was determined from a 98-days experiment. After prolonged exposure of 225 days effects on kidney were already seen in dose groups at 300 mg/kg bw/day.

Vacuolization of the tubular epithelium (hydropic degeneration) and tubular necrosis were the histopathological findings. For the crystaluria and increased urine volumes after concentration tests, the results in the male and the female rats were inconsistent, and no clear dose-response relationships was observed for these effects. Therefore, the evaluation is based on the histopathological findings. Hydropic degeneration of the kidneys started to occur at oral dose levels of 1550 mg/kg bw/day for 14 weeks and was not seen at 300 mg/kg bw/day. The conclusion is that the NOAEL for hydropic degeneration is 300 mg/kg bw/day (0.4% 2,2’-oxydiethanol in food) in the male rats.


The dermal NOAELwas determined to be 2200 mg/kg bw/day, based on a study performed with a structural analogue of DEG in which dogs were exposed for weeks.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
120 mg/m³
Study duration:
subacute
Species:
other: human

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
4 440 mg/kg bw/day
Study duration:
subacute
Species:
dog

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Repeated dose toxicity: oral

BASF (1988) reported a 4-week study according to OECD guideline 407. DEG was administered in the diet to two groups of five males and five females rats per dose. Dose groups were 500, 2500, 10000 or 40000 mg/kg diet. One group was killed just after 28 days administration, the other group was killed after a 30-day observation period. At a dose of 40000 mg/kg diet, a significant concentration and amount of oxalic acid was found in the urea of both sexes, and oxalic acid stones in males after 28 days. However, these effects were not observed after the 30-day observation period. The NOAEL was 10000 mg/kg diet corresponding to 936 mg/kg body weight/day.

Gaunt et al. (1975) reported a study with 98 -day and 225 -day oral feeding experiments. Male and female rats were given concentrations of 0.085, 0.17, 0.4 and 2.0 % (= 64, 128, 300, 1500 mg/kg bw/day) for 225 days or 0.4 and 2.0 and 4.0 % for 98 days. Dietary concentrations of 0.4 and 2.0 % resulted in oxalate crystalluria and mild defects in renal function as measured by concentration tests. The elevated levels of oxalic acid in urine in this study were considered to be a biomarker and do not indicate toxicity. Kidney effects were reported consisting of oxalate crystalluria, increased urine volumes and histopathological evidence of hydropic degeneration and tubular necrosis to define the NOAEL as 128 mg/kg bw/day. Health Council of the Netherlands (2007) regarded a NOAEL based on renal histopathological findings as more relevant than a NOAEL based on increased urine volumes. From the 98 day study, a LOAEL based on renal hydropic degeneration was established at 1.6 g/kg bw/day with the NOAEL at 300 mg/kg bw/d (Health Council of the Netherlands, 2007).

In the SUBSTANCE EVALUATION CONCLUSION as required by REACH Article 48 and EVALUATION REPORT (CORAP) for 2,2’-oxydiethanol, EC No 203-872-2, CAS No 111-46-6, Evaluating Member State: Hungary, Dated: 07 September 2016, the initial concern for specific target organ (kidney) toxicity was dismissed due to the following reasons (page 9, table 3 of the SEV report):

"2,2’-oxydiethanol causes metabolic acidosis, cortical necrosis (proximal tubule cell death) resulting in permanent renal failure. However, it was established in human proximal tubule cells in vitro that it is the metabolite of 2,2’-oxydiethanol rather than the parent compound itself, which is responsible for the adverse effects on the kidney. Moreover, the NOAEL from the oral rat study is above the guidance value (10 < C ≤ 100 mg/kg body weight/day) for classification for that category. Thus, the evaluating Member State supports the above conclusion and the initial concern [specific target organ (kidney) toxicity] is removed."

Repeated dose toxicity: inhalation

For DEG no data for repeated inhalation toxicity is available. Hence, read-across is made to MEG and the following data are also taken into account for DNEL derivation (please also refer to IUCLID chapter 7.10 "Exposure related observations in humans"):

To determine whether an atmosphere containing aerosolized ethylene glycol in a concentration that could be tolerated by human volunteers for most of each 24-h period would have any deleterious action on man, in a prison hospital twenty volunteers were exposed during 20 to 22 h per day to aerosolized ethylene glycol in mean daily concentrations between 3 and 67 mg/m3 (Wills, 1974).

Nineteen men finished the planned one-month exposure. When the concentration of ethylene glycol within the chamber was raised to 200 or more mg/m3, the atmosphere could not be tolerated for more than a minute or two, the period of tolerance decreasing progressively as the concentration was increased further. Blood and urine specimens obtained from the volunteers at intervals during their prolonged exposure gave little evidence of the absorption of important quantities of ethylene glycol. No subject experienced any serious signs of toxicity assignable to the exposure, but there were complaints of irritation of the throat and fauces. Slight headache and low backache also were reported occasionally. The irritative phenomena became common when the concentration of ethylene glycol in the ambient air was raised to about 140 mg/m3. The irritative effects appear to rule out the possibility that a harmful amount of ethylene glycol could be absorbed from the respiratory tract of a healthy Individual who was unaware that he had been exposed to this substance.

Repeated dose toxicity: dermal

No valid data for diethylene glycol are available for repeated dermal toxicity. Therefore a read-across is made to MEG.

BASF (1991a) reported a 4-week dermal application study with Glysant G 105 according to OECD guideline 410. Male dogs were given the unchanged test substance (>92.5% ethylene glycol and <1.42% na-p-tert-butyl-benzoat; PTBBA) daily to the clipped skin in concentrations of 0.5, 2 and 8 mL/kg. Further studies followed to establish whether the severe testicular damage that was found in all dogs at 8 mL/kg and in one dog at 2 mL/kg was caused by na-p-tert-butyl-benzoic acid or whether it must be regarded as a direct or indirect consequence of ethylene glycol administration. Some urinary oxalate crystals were found at 2 mL/kg but due to the absence of histological findings considered as not adverse. The NOEL was 2 mL/kg bw (2220 mg/kg bw). At this level, some urinary oxalate crystals were observed but considered as not adverse due to the absence of histological findings.

In a second study (BASF, 1991b), 2 and 4 mL/kg bw/day were administered; with this dose design a NOAEL of 4 mL/kg bw/day (4440 mg/kg bw/day) was identified. Again, an increase of urinary oxalate crystal formation could be detected but no adverse histopathological findings.

Tyl et al. (1995) reported about the assessment of the developmental toxicity of ethylene glycol (CAS: 107-21-1) applied cutaneously to mice. No clear effects were found in maternal animals dermally exposed to ethylene glycol at 3549 mg/kg.

Data in rodents on repeated dose toxicity/nephrotoxicity of DEG can partially be cross-read from MEG.

Justification for classification or non-classification

Based on the available information classification for repeated dose toxicity is not warranted in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.