2,2'-oxydiethanol

Endpoint summary

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

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Principles of method if other than guideline:

The present experiments were initiated to provide adequate short-term investigations, with particular reference to effects on urinary oxalate excretion, using a DEG sample with a low (less than 0-01 %) MEG content.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

The sample of DEG sed was supplied by Imperial Chemical Industrial Ltd. (Petrochemical Divisions) and gave the following analysis:
Colour (Hazen units), less than 5; specific gravity (15.5/15.5°C), 1 .120; initial boiling point, 244.4 °C; dry point, 250.3 °C; ash (w/w), less than 0.002%; acidity (as acetic), 0.0015; water (w/w), 0.035%; iron, less than 0.1 ppm; monoethylene glycol (w/w), less than 0.01%; triethylene glycol (w/w), 0.03%.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: obtained from a specified-pathogen-free colony
- Housing: five per cage
- Diet: Spillers' Laboratory Small Animal Diet, ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 40 - 50

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

98 days (first experiment)
225 days (second experiment)

Frequency of treatment:

daily

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

0.4% in diet; equivalent to 300 and 400 mg/kg bw/day for males and females, respectively (first experiment, 98 days)

Dose / conc.:

1 500 mg/kg bw/day (nominal)

Remarks:

2.0% in diet; equivalent to 1600 and 1800 mg/kg bw/day for males and females, respectively (first experiment, 98 days)

Dose / conc.:

3 000 mg/kg bw/day (nominal)

Remarks:

4.0% in diet; equivalent to 3000 and 3700 mg/kg bw/day for males and females, respectively (first experiment, 98 days)

Dose / conc.:

64 mg/kg bw/day (nominal)

Remarks:

0.085% in diet; equivalent to 50 and 60 mg/kg bw/day for males and females, respectively (second experiment, 225 days)

Dose / conc.:

128 mg/kg bw/day (nominal)

Remarks:

0.17% in diet; equivalent to 100 and 130 mg/kg bw/day for males and females, respectively (second experiment, 225 days)

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

0.4% in diet; equivalent to 230 and 290 mg/kg bw/day for males and females, respectively (second experiment, 225 days)

Dose / conc.:

1 500 mg/kg bw/day (nominal)

Remarks:

2.0% in diet; equivalent to 1200 and 1500 mg/kg bw/day for males and females, respectively (second experiment, 225 days)

No. of animals per sex per dose:

15 rats in the first experiment (99 days)
10 rats in the second experiment (225 days)

Control animals:

yes, plain diet

Details on study design:

Groups of 15 rats of each sex were given diets containing 0, 0.4, 2.0 or 4.0 % diethylene glycol (DEG) containing less than 0.01 % monoethylene glycol for 98 days.
In a second experiment groups of 10 rats of each sex were given diets containing 0, 0.085, 0.17, 0.4 or 2.0 % of the same sample of DEG for 225 days.

Observations and examinations performed and frequency:

FIRST EXPERIMENT
- Body weight: The animals were weighed initially, on days 1, 2, 6, 9 and 14 and then at weekly intervals throughout the study.
- Food and water consumption: the intakes of food and water were measured for each cage of rats over the 24-hr period preceding each day of weighing.
- Urinalysis: Urine was collected during wk 2, 6 and 14 of treatment and examined for microscopic constituents and content of glucose, albumin, ketones, bile salts and blood and concentration tests were carried out. These involved measuring the specific gravity and volume of urine produced in a
6-hr period of water deprivation and in the 2-hr period following a water ! load of 25 mL/kg. At wk 6 and 14 the same measurements were made on the urine produced between 16 and 20 hr after the water load.
- Haematology and chlinical chemistry: Blood samples collected at autopsy were examined for haemoglobin content, packed cell volume and counts of erythrocytes, total leucocytes, reticulocytes and differential leucocytes . In addition serum was separated and analysed for its content of urea, protein and albumin and for the
activities of glutamic-oxalacetic and glutamic-pyruvic transaminases and lactic dehydrogenase.

SECOND EXPERIMENT
- Body weight: The animals were weighed initially, on days 1, 4 and 8 and then at approximately weekly intervals throughout the study.
- Food and water consumption: Food and water intake over a 24-hr period were measured at the same intervals.
- Urinalysis: Urine samples were collected in week 8, 13 and 19 from the males and in week 9, 14 and 19 from the females over 24-hr periods, during which the rats were denied access to food and water. These samples were rendered strongly acid with hydrochloric acid and analysed for oxalic acid by the method of Hodgkinson & Williams (1972). Urine analyses, renal concentration and dilution tests and urinary cell counts on samples collected during the last week of the study.
- Haematology: collection of blood for haematological examination was carried out as described for the first experiment. In the haematological examination the reticulocyte and differential leucocyte preparations were not examined.

Sacrifice and pathology:

FIRST EXPERIMENT
At autopsy a search was made for macroscopic abnormalities, and the brain, pituitary, thyroid, heart, liver, spleen, adrenal glands, kidneys, gonads, stomach, small intestine and caecum were weighed. Samples of these and of oesophagus, various lymph nodes, thymus, salivary gland, trachea, aorta, lung, skeletal muscle, pancreas, colon, rectum, urinary bladder and uterus or prostate were preserved in 10% buffered formalin. Paraffin-wax sections of these tissues were stained with haematoxylin and eosin for microscopic examination.

SECOND EXPERIMENT
Post-mortem examinations and organ-weight analysis was carried out as described in the first experiment. Histological examination was confined to the kidneys.

Clinical signs:

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

FIRST EXPERIMENT
Six of the male rats given the diet containing 4% DEG died, or were killed because of ill health, during the study. The deaths occurred on days 19, 39, 55 (two rats), 82 and 85 of treatment. The animals were lethargic, bad lost weight over the preceding 3-10 days, adopted a hunched position in the cage and had a rough coat. Although the body temperature serum-urea levels in three of the rats were 45, 80 and 85 mg/100 mL compared with normal values of 15-25 mg/100 mL.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

FIRST EXPERIMENT
In the female rats there were no differences between treated and control groups in the rate of body-weight gain. However, the males fed the diet containing 4% DEG gained less weight than the controls, particularly during the second half of the study, the differences in mean body weight being statistically significant from day 43. At the lower dietary levels the body weights were lower than those of the controls in the males but there were no statistically significant differences.

SECOND EXPERIMENT
The increase in body weight was less in the rats of both sexes given 2.0% DEG than in the controls. The differences in body weight were statistically significant from day 36 to 113 in the male s and from day 8 to 204 in the females.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

FIRST EXPERIMENT
The food intake was not affected by the treatment. The mean intakes at the three dietary levels being 0.3, 1.6 and 3.0 g/kg/day in the males and 0.4, 1.8 and 3.7 g/kg/day in the females.

SECOND EXPERIMENT
There were no consistent differences between the treated and control groups in food intake. The calculated intakes of DEG for the four dose levels were approximately 50, 100, 230 and 1200 mg/kg/day in the males and 60, 130, 290 and 1500 mg/kg/day in the females.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

FIRST EXPERIMENT
The mean water intake over the whole experiment was increased in both sexes at the 4% dietary level and in the males given the diet containing 2% DEG. Despite the fact that the individual observations of water intake were based on only three values, as measurements were made on a cage basis, most of the values obtained from day 6 for the males given 4% DEG showed a statistically significant increase compared with the control values. In the females, significant differences were recorded only with one or two isolated values. In males given the lowest dietary level most of the values from day 9 onwards were slightly greater than the corresponding control values and, although the overall mean was not statistically greater than the control, it was increased by 6%.

SECOND EXPERIMENT
The water intake values were variable, the overall experimental means for the males given 0.49% and females given 0.17% DEG being less than those of the corresponding controls. On the other hand, the mean value for males given the highest dose level (2.0%) was higher than that of the controls. When analysed on the basis of the means up to or after day 93, it was found that there were no significant differences in the first part of the study, but the differences in the second part were the same as those seen over the whole study. The water intakes of the female rats did not show any dose-related differences from that of the controls.

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

FIRST EXPERIMENT
There were no differences in the haematological indices between the female rats given DEG and the appropriate controls. Male rats given 4% DEG for 14 wk showed a statistically significant increase in the packed cell volume, haemoglobin concentration and total erythrocytes. With the lower dietary concentration (2%), the haemoglobin concentration was J the only measurement that was affected to a statistically significant degree although there was a slight increase in the erythrocyte count and
packed cell volume. A similar change involving only the haemoglobin concentration was evident at wk 2 in the males given 4% DEG. Calculation of the absolute values showed that the erythrocytes were of a normal size and haemoglobin content. The only changes in white cells were slightly increased total counts in males after treatment for 2 wk, without any change in the distribution of the different types of white cell.

SECOND EXPERIMENT
At the end of treatment there were no differences between treated and control rats in the results of the haematological examinations, since total counts did not differ the reticulocyte and differential leucocyte preparations were not examined.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

FIRST EXPERIMENT
The only abnormal values in the serum analyses were seen in the male rats given 4% DEG for 14 wk and consisted of lowered values for glutamic-pyruvic transaminase, total protein and albumin.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

FIRST EXPERIMENT
During a 6-hr period of water deprivation, the urine volume produced by males given 4% DEG was greater than that of the controls at all three examinations but the difference was significant only at wk 6 and 14. A similar but less marked increase was evident in the females given 4% DEG. In the dilution test there was a tendency for the rats of both sexes to produce a smaller volume of more concentrated urine than the controls, although this difference reached statistically significant proportions only in the males at the first, examination (2 wk). A similar and very marked effect was found in the males given the diet containing 2% DEG for 6 wk, but this was found to be due to two animals. which produced very small volumes of highly concentrated urine and when the test was repeated 24 hr later the finding could not be reproduced.
Oxalate crystals were found in the urine from some of the rats of both sexes given 2 or 4% DEG at all examinations. At the lowest dietary level oxalate crystals were found only in the urine from female rats. There were no increases in the number of cells excreted in the urine . The only other finding in the urine was the presence of blood at wk 6 and 14 in males fed the high dietary level.

SECOND EXPERIMENT
The results of the measurements of urinary oxalic acid concentrations show that the values for the rats given 2% DEG were greater than those of the controls throughout the experiment. The differences were statistically significant in most of the comparisons. At a lower dietary concentration (0.4%) there were no differences from controls after 8-9 wk treatment or in the females at wk 14, but in males at wk 13 as well as in both sexes at wk 19 the urinary oxalate concentrations in this group were significantly higher than those of the controls. With a dietary level of 0.17% urinary oxalic acid concentrations significantly higher than those of the controls were confined to the males at wk 19 whilst with the lowest dietary level (0.085%) the oxalic acid concentrations were comparable with those of the controls throughout the experiment.
There were no significant differences between treated and control rats in the specific gravity and volume of urine produced during a 6-hr period of water deprivation or in the first 2-hr after a water load. On the other hand the volume of urine produced after the longer period without water by male rats given 0.4 or 2.0% DEG was significantly greater than that produced in the same interval by the controls. At the higher of these dietary levels there was a lower specific gravity, but this was not statistically significant. There were no statistically significant increases in urinary cell excretion or differences in urinary pH.
The analysis of the urine collected over a 6-hr period showed no differences between the groups in the incidence of rats with blood, glucose, ketones, sperm or the various concentrations of albumin in the urine. There were significant differences between controls and the group on the highest dose level in the incidence of rats with phosphate crystals. This incidence was lower in the treated males but higher in the corresponding females. Oxalate crystals were found in the urine of the treated groups and at the two highest dietary levels the incidence of this finding was significantly higher than in the controls. Oxalate crystals were found in the urine from two control rats and at the two lower dose levels there was no indication of a significantly increased incidence of this finding.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

FIRST EXPERIMENT
In the organ-weight studies at wk 2 and 6, when the body weights of all groups were similar, the only statistically significant differences from controls were heavier livers in males given 4% for 2 wk, heavier kidneys in females given 4% DEG for 6 wk and lighter small intestines and thyroids in males fiven 2% for 6 wk. When the organ weights were expressed relative to body weight, statistically significant differences from control values were apparent in the liver values, which were higher in both sexes given 4% DEG for 2 wk and in the kidney values, which were higher in females given 4% for either 2 or 6 wk. In addition, the relative kidney weights of females given 2% DEG for 2 wk were higher than those of the controls. After the longer period of exposure (14 wk) the only change in organ weight in the females was a lower kidney weight at) the lowest dietary level (0.4%), a difference that was no longer statistically significant when expressed relative to body weight. In the males given 4% DEG for 14 wk the weights of most of the organs were lower than those of the controls to a statistically significant degree, but this was associated with a markedly reduced body weight. When expressed in relation to body weight the figures for most of the organs in this group were increased compared with the controls.

SECOND EXPERIMENT
There were scattered statistically significant differences between treated and control rats in the various organ weights, but none of these were found in the rats given the highest dietary level. Similarly there were scattered statistically significant differences in relative organ weights. In this comparison, however, the relative kidney and adrenal weights of both sexes given 2.0% DEG and the relative spleen weight of males fed the same dietary level were significantly greater than those of the controls.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

FIRST EXPERIMENT
At autopsy the rats that died had enlarged kidneys with a distended pelvic area and very pale cortical tissue. In two of the animals there were obvious cortical cysts. In the animals that survived to 14 wk the only abnormalities found at autopsy 1 were in the male rats given 4% DEG and consisted of one animal with bladder calculi, containing calcium oxalate crystals, and two with kidneys having a pale cortex and distended pelvis.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

FIRST EXPERIMENT
On histological examination tubular necrosis, mainly of the proximal convoluted tubules, was evident in five rats and hydropic degeneration of the proximal tubule in the remaining animal of the six animals that died. The bladder and ureters were distended in all six animals, and obvious calculi, containing calcium oxalate crystals, were found in these bladders together with marked haematuria. Cannibalism prevented examination of the liver in two rats but in the remainder the liver was enlarged and pale. Histopathological examination revealed pale vacuolated hepatocytes in the centrilobular area with some centrilobular necrosis in one rat. In animals that survived to 14 wk the histopathological findings were confined to the kidney and liver. Lesions in the liver, hydropic degeneration and a single case of necrosis, were seen only in the females at the highest dose level. The most marked change 4 in the kidneys was tubular necrosis, encountered only in rats given 4% DEG, although at this level, one animals was affected as early as wk 2. Hydrophobic degeneration of the cells in the renal tubules was found as early as wk 2 in rats given 496 DEG and by wk 14 one male animal from the group given 2% DEG was affected. No changes were seen in the kidneys of the rats given 0.4% DEG.

SECOND EXPERIMENT
The examination of histological sections of the kidney did not reveal in any differences between the treated and control animals.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Details on results:

Dietary concentrations of 0.4 and 2.0% resulted in oxalate crystalluria and mild defects in renal function as measured by concentration tests. The only finding at a dietary level of 0.176 was a 13.2 % increase in urinary oxalate excretion in male, while with the lowest level (0.085 %) no effects were observed.
Extrapolation: Since no effects were observed at the dietary level of 0.085%, application of a safety factor of 100 in the extrapolation to man indicates an acceptable daily intake for a 70 kg man of 38 mg, and on a pro rata basis a lesser or greater value for individuals of different body weight.
The significance of the 13.2% increase in oxalate excretion found in rate on the 0.17% dietary level is debatable. If this level is considered to have no significant effect on the oxalate concentration of kidney and bladder urine, the acceptable daily intake (calculated as above) would be 76 mg/day for a 70 kg individual.

Dose descriptor:

NOAEL

Remarks:

(225 days)

Effect level:

128 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

urinalysis

Key result

Dose descriptor:

NOAEL

Remarks:

(98 days)

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

1 600 mg/kg bw/day (nominal)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

Since no effects were observed at the dietary level of 0.085%, application of a safety factor of 100 in the extrapolation to man indicates an acceptable daily intake for a 70-kg man of 38 mg, and on a pro rata basis a lesser or greater value for individuals of different body weight. The significance of the 13.2% increase in oxalate excretion found in rate on the 0.17% dietary level is debatable. If this level is considered to have no significant effect on the oxalate concentration of kidney and bladder urine, the acceptable daily intake (calculated as above would be 76 mg/day for a 70-kg individual.
Elevated levels of oxalic acid in urine in this study were considered to be a biomarker and do not indicate toxicity. Mild defects of renal function at 0.4% DEG (increased urine volume) were therefore considered to define the LOAEL as 230 mg/kg bw/day, and the NOAEL as 300 mg/kg bw/day.

Executive summary:

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.

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

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

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

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See attached read-across justification.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

2 220 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see "Remarks"

Remarks on result:

other: No correction for molecular weight performed.

Remarks:

This value is taken in a 1:1 relation also for DEG since DEG can generate 2 molecules of MEG in a worst case assumption (see toxicokintetics, IUCLID section 7.1.1).

Key result

Dose descriptor:

NOAEL

Effect level:

4 440 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: No correction for molecular weight performed.

Remarks:

This value is taken in a 1:1 relation also for DEG since DEG can generate 2 molecules of MEG in a worst case assumption (see toxicokintetics, IUCLID section 7.1.1).

Dose descriptor:

NOAEL

Effect level:

ca. 3 549 mg/kg bw/day

Based on:

test mat.

Sex:

female

Remarks on result:

other: No correction for molecular weight performed.

Remarks:

This value is taken in a 1:1 relation also for DEG since DEG can generate 2 molecules of MEG in a worst case assumption (see toxicokintetics, IUCLID section 7.1.1).

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

8 880 mg/kg bw/day

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

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

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See attached read-across justification.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

2 220 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see "Remarks"

Remarks on result:

other: No correction for molecular weight performed.

Remarks:

This value is taken in a 1:1 relation also for DEG since DEG can generate 2 molecules of MEG in a worst case assumption (see toxicokintetics, IUCLID section 7.1.1).

Key result

Dose descriptor:

NOAEL

Effect level:

4 440 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: No correction for molecular weight performed.

Remarks:

This value is taken in a 1:1 relation also for DEG since DEG can generate 2 molecules of MEG in a worst case assumption (see toxicokintetics, IUCLID section 7.1.1).

Dose descriptor:

NOAEL

Effect level:

ca. 3 549 mg/kg bw/day

Based on:

test mat.

Sex:

female

Remarks on result:

other: No correction for molecular weight performed.

Remarks:

This value is taken in a 1:1 relation also for DEG since DEG can generate 2 molecules of MEG in a worst case assumption (see toxicokintetics, IUCLID section 7.1.1).

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

8 880 mg/kg bw/day

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

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.