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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Short–term toxicity of diethyleneglycol monoethylether in the rat, mouse and pig .
Author:
Gaunt IF, Colley J, Grasso P, Landsdown ABG, Gangolli SD
Year:
1968
Bibliographic source:
Food Cosmet Toxicol 6, 689–705. 1968

Materials and methods

Principles of method if other than guideline:
A Repeated Dose Oral Toxicity study was performed for 90 days in pig at doses 167, 500 or 1500 mg/kg/bw/day to evaluate the toxic effects of diethylene glycol monoethyl ether.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(2-ethoxyethoxy)ethanol
EC Number:
203-919-7
EC Name:
2-(2-ethoxyethoxy)ethanol
Cas Number:
111-90-0
Molecular formula:
C6H14O3
IUPAC Name:
2-(2-ethoxyethoxy)ethanol
Test material form:
other: Liquid
Details on test material:
- Name of test material (as cited in study report):diethylene glycol monoethyl ether(DGME)
- Molecular formula (if other than submission substance):C6H14O3
- Molecular weight (if other than submission substance):134.174 g/mole
- Substance type:organic
- Physical state:liquid
- Impurities (identity and concentrations):ethanediol: maximal concentration of 0.4%.; arsenic: maximal concentration of 2 ppm; lead: maximal concentration of 10 ppm.

Test animals

Species:
pig
Strain:
other: Large White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 6 weeks
- Weight at study initiation: 9.8-10.8 kg (males) and 9.5-10.2 kg (females)
- Housing: Animals were penned individually.
- Diet (e.g. ad libitum): BOCM Hi-lean Rearers Pencils at 0.5-1.5 lb/day
- Water (e.g. ad libitum): Ad libitum
- Acclimatization period: 2 weeks

ENVIRONMENTAL CONDITIONS: Not available

Administration / exposure

Route of administration:
oral: feed
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The amount of DGME corresponding to each dose level was dissolved in water to give a dose volume of 10 ml/kg. This was added to part of the daily ration given before the main feed.
DIET PREPARATION: Not available
VEHICLE: Water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0,167, 500, 1500/1000 mg/kg/bw/day, The top dose level was decreased to 1000 mg/kg/day after 3 weeks as severe toxic effects were seen.
Basis:
nominal in diet
No. of animals per sex per dose:
Total: 23 pigs
Control:3 males, 3 females
167 mg/kg/day: 3 males, 3 females
500 mg/kg/day: 3 males, 2 females
1500 mg/kg/day: 3 males, 3 females

Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A previous study in rats had been performed at dietary levels of 0.25, 1.0 and 5 % DGME and adverse effects were observed at the highest dose. The test substance in that study did not meet the required specification, as the sample used contained 0.6% ethylene glycol which was greater than maximum limit of 0.4%. Hence, it was decided that studies using DGME will be carried out with the samples containing less than 0.4% ethylene glycol and including species other than the rat.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data available
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available
-OPHTHALMOSCOPIC EXAMINATION: No data available
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At termination of the study.
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: All surviving animals.
- Parameters examined: Haemoglobin concentration, haematocrit values, erythrocyte count, reticulocyte count, and total and differential leucocyte counts.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination of the study
- Animals fasted: No data available
- How many animals: All surviving animals.
- Parameters examined: Transaminase and urea levels
URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected during week 2 and 4 and at week 6 for crystal examination and week 13 for the below mentioned parameters.
- Animals fasted: No data available
- Parameters examined:
Color, pH, microscopic constituents and content of protein, reducing substances, bile salts, blood and glutamic-oxaloacetic transaminase. In addition, as mentioned above, urine samples collected at week 2, 4 and 6 were examined for crystal content.
NEUROBEHAVIOURAL EXAMINATION: No data available
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
At autopsy the brain, heart, liver, kidneys, adrenals, spleen, gonads and thyroid were weighed.

HISTOPATHOLOGY: Yes
Paraffin-wax sections of brain, pituitary, heart, liver, kidneys, adrenals, spleen, gonads, thymus, aorta, lungs, various lymph nodes, stomach, duodenum, ileum, caecum, colon, rectum, sternum, pancreas, skeletal muscle, uterus and urinary bladder were stained with haematoxylin and eosin for histological examination.

Other examinations:
No other examinations given other than described above
Statistics:
No data available

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mortalities at highest dose of 1500mg/kg bw/day. No deaths on reduction to 1000 mg/kg bw/day.
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortalities at highest dose of 1500mg/kg bw/day. No deaths on reduction to 1000 mg/kg bw/day.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
MORTALITY: Mortalities observed at the highest dose level when 1500 mg/kg/day dose was administered. One male and one female were killed in extremis on day 14 and a female died on day 21.
Clinical signs prior to death were lethargy at 4-5 days prior to death and laboured respiration and comatose during 24 hours before death.
BODY WEIGHT AND WEIGHT GAIN: No effects observed.
Food consumption: No effects observed.
HAEMATOLOGY:
Lower haemoglobin was observed in males of the 1000 mg/kg bw/day males and severe anaemia associated with reduced erythrocyte count, crenated erythrocytes was evident in animals which died on 1500 mg/kg bw/day dose.
CLINICAL CHEMISTRY: No treatment-related effects were observed.
URINALYSIS: No treatment-related effects were observed.
ORGAN WEIGHTS: Treatment with 1000 mg/kg/day: increased absolute and relative kidney weights.
GROSS PATHOLOGY: No treatment-related effects were observed.
HISTOPATHOLOGY: NON-NEOPLASTIC:
Liver
Centrilobular and midzonal hepatocyte hypertrophy with pyknotic nuclei which was considered to suggest advanced intracellular oedema was observed in both sexes at ≥ 1000 mg/kg/day and in 1/2 females at 500 mg/kg/day. Periportal fatty change was also observed at 1000 mg/kg/day in both sexes and in one female at 500 mg/kg/day.
Kidney
The kidneys showed extensive areas of tubular hydropic degeneration affecting most of the renal cortex in both sexes of the highest dose group and in one female at 500 mg/kg/day.

Effect levels

Dose descriptor:
NOAEL
Effect level:
167 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed in hematology, clinical chemistry, urinalysis, gross pathology, organ weights or histopathology.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Summary of the lowest treatment levels at which various effects were seen in pigs treated with DGME

Effect

Pig (mg/kg/day )

Growth reduction

-

Anaemia

1000

Increased kidney weight

1000

Hydropic degeneration of

Kidney

-

Liver changes

 500

Oxaluria

500

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 167 mg/kg/day when male and female Large White pigs were exposed to diethylene glycol monoethyl ether.

Executive summary:

In the subchronic study, the toxic effect of diethylene glycol monoethyl ether were evaluated in male and female Large White pigs. The pigs were exposed to the test chemical orally in feed at a concentration of 0, 167, 500, or 1500 mg/kg/day for 90 days. The top dose level was decreased to 1000 mg/kg/day after 3 weeks as severe toxic effects were seen. At 1500 mg/kg/day, severe toxic effects were seen in the form of uraemia, renal and hepatic damage. As a results, the dose was reduced to 1000 mg/kg/day in the remaining survivors (2 males and 1 female) after 21 days. At 1000 mg/kg/day anaemia was seen in males, as well as increased kidney weight and liver changes along with tubular hydropic degeneration were seen in the animals receiving 1000 mg/kg. At 500 mg/kg/day, hydropic degeneration of kidney and liver changes were seen, while no effects were reported in any of the parameters examined at 167 mg/kg/day. Therefore, NOAEL was considered to be 167 mg/kg/day when male and female Large White pigs were orally exposed to diethylene