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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990
Reference Type:
publication
Title:
Subchronic Peroral Toxicity of Triethylene Glycol in the Fischer 344 Rat.
Author:
VanMiller, J.P., Ballantyne, B.
Year:
2001
Bibliographic source:
Vet. Human Toxicol. 43 (5), 269 - 276, Oct. 2001

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,2'-(ethylenedioxy)diethanol
EC Number:
203-953-2
EC Name:
2,2'-(ethylenedioxy)diethanol
Cas Number:
112-27-6
Molecular formula:
C6H14O4
IUPAC Name:
2-[2-(2-hydroxyethoxy)ethoxy]ethan-1-ol
Test material form:
liquid
Specific details on test material used for the study:
- Source: Union Carbide Corporation (Texas City, TX)
- Purity: ≥ 99.74%

Test animals

Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
A pretest health screen was carried out 2 d after arrival, using 5 males and 5 females from the 14-d study, and 10 males and 10 females from the subchronic study. The screen consisted of clinical examination, examination for fecal parasites, viral screen, necropsy, and histology of multiple organs and tissues. They were housed 2/side of divided stainless steel cages mounted on a stainless steel rack. One to two weeks later, they were housed in similar cages but 1/side and this was maintained throughout the study. They were allowed free access to food and water from an automatic system. Environmental temperature was maintained at 19 - 25 °C and relative humidity at 40 - 70%. A 12-h photoperiod was used.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: The rats were approx. 6 weeks of age at first dose.
- Housing: Animals were housed 2/side of divided stainless steel cages mounted on a stainless steel rack. One to two weeks later, they were housed in similar cages but 1/side and this was maintained throughout the study. A layer of Deotized Animal Cage Board (Shepherd Specialty Papers, Inc., Kalamazoo, MI) was kept under each cage and changed at least three times pew week.
- Diet: Ground Purins Certified Rodent Chow #5002 (Ralston Purins Co., St. Louis, MO) was available ad libitum.
- Water: Water (Municipal Authority of Westmoreland County, Greensburg, PA) was provided by an automatic watering system with demand control valves mounted on each rack. Water was available ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 40-70%
- Photoperiod: 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Experimental diets were analysed using a gas chromatographic procedure developed at BRRC. Homogeneity of the test substance at each diet concentration was established prior to the start of the study. Stability of the test substance in diets at the 10000 and 50000 ppm concentrations was determined prior to administration of the diets to the animals for the first four preparations. Thereafter, one sample from each preparation (concentration selected sequentially) was retained frozen and analysed in weeks 8 and 13 with one control sample.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
748 mg/kg bw/day (actual dose received)
Remarks:
low dose males (10000 ppm)
Dose / conc.:
848 mg/kg bw/day (actual dose received)
Remarks:
low dose females (10000 ppm)
Dose / conc.:
1 522 mg/kg bw/day (actual dose received)
Remarks:
mid dose males (20000 ppm)
Dose / conc.:
1 699 mg/kg bw/day (actual dose received)
Remarks:
mid dose females (20000 ppm)
Dose / conc.:
3 849 mg/kg bw/day (actual dose received)
Remarks:
high dose males (50000 ppm)
Dose / conc.:
4 360 mg/kg bw/day (actual dose received)
Remarks:
high dose females (50000 ppm)
No. of animals per sex per dose:
- 262 rats (130 males, 132 females) were used
- 30/sex/group in the control and high dose and 20/sex/group in the low and mid dose groups
Control animals:
yes, plain diet
Details on study design:
Fresh diet was prepared and offered to the animals each week. All diet concentrations were prepared by dilution of the premix and mixing for 15 minutes.
Homogeneity of the test substance at each concentration was established prior to the start of the study. Stability of the test material in the diets at 10000 and 50000 ppm was determined prior to dosing after storage in open glass feed jars. Diet concentrations were verified for all dose levels prior to administration of the diets to the animals for the first 4 preparations.

Examinations

Observations and examinations performed and frequency:
- Detailed clinical observations were conducted weekly and daily observations were made for overt clinical signs.
- Rats were given ophthalmoscopic observations (indirect ophthalmoscopy) before dosing and at the end of the dietary dosing period.
- Body weights and food consumption were measured at weekly intervals. Body weight gains were calculated at each weighing period for the time since initial (day 0) body weight measurement.
- Blood was collected on day 30, immediately following the end of dietary dosing, and at the end of the recovery period for hematology and serum chemistry (10 animals/sex/group).
- The following blood parameters were measured or calculated: hemoglobin concentration, erythrocyte count, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, total and differential leukocyte count.
- The following elements were measured or calculated in serum: glucose, urea nitrogen, albumin globulin, total protein creatinine, bilirubin (total, conjugated and unconjugated), phosphorus, Ca++, Na+, K+, CI-, aspartate and alanine aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, creatine kinase, lactate and sorbitol dehydrogenases.
- The following urine values were determined: volume, pH, specific gravity, colour, microscopy, blood, protein, ketones, glucose, bilirubin and urobilinogen.
Sacrifice and pathology:
20 rats/sex/group were sacrificed at the end of the dosing period, and 10 rats/sex from the control and high-dose groups were sacrificed after the recovery periods and subjected to necropsy examination for any signs of gross pathology. The following organs were removed and weighed: liver, kidneys, heart, spleen, brain, adrenal glands, testes, and ovaries. A further number of tissues and organs were removed and processed for histological examination.
Other examinations:
- Examination for fecal parasites was conducted using a cellophane tape test and by zinc sulfate flotation from cecal contents obtained at neropsy on 5 animals per sex. Histopathology was performed on 3 sacrificed animals/sex. At least the following tissues were examined: liver, kidneys, trachea, lungs, heart, spleen, salivary glands, submandibular lymph notes, and nasal cavities.
- Each rat was uniquely numbered by ear notch and toe-clipping. Only rats with body weights within +/-20% of the population mean for each sex were used.
Statistics:
Data for continuous, parametric variables were intercompared for the dose and control groups using Levene's test for homogneity of variances, by analysis of variance, and by pooled variance t-tests. Frequency data were compared using Fisher's exact tests where appropriate. All statistical tests, except the frequency comparisons were performed using BMDP Statistical Software. The fiducial limit of 0.05 was used as the critical level of significance for all tests.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight depression compared to controls occurred in males from the high dose group throughout the study and in females during the latter weeks of the study. Body weights for males from the recovery group were similar to controls after the 6-week period but females did not show recovery of body weight. In fact, the largest difference from the control value occurred during the recovery period for the females. Based on the larger magnitude of change in the high dose group than was observed for the other dose groups, the body weight differences were considered related to treatment. A transient decrease from control in cumulative body weight gain was observed for the animals from both sexes in the middle weeks of the study. Due to the unusual pattern of weight differences, the relationship to treatment of these decreases was unclear.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Haematology measurements, including decreased erythrocytes and haematocrit in males from the high and mid dose groups and decreased haemoglobin and increased MCV in the high dose group only, were altered at the 13-week measurement period. These changes were considered to be of questionable biological significance based on a lack of similar effect in the females, the small magnitude of the changes, and the lack of corresponding effects in other cell indexes.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Decrease in urine pH at all dose levels in males and the mid and high dose levels in females and an increase in urine volume in males from the high dose group were considered to be related to TEG treatment.
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):
Observations of small increases in kidney weight (high dose group females) and kidney weight relative to body weight (all groups of males and mid and high dose group females) were considered to be probably treatment related. Based on the lack of any other significant toxic effects, particularly the lack of histologic evidence of renal injury, hyperplasia, or hypertrophy, the altered urine measurements were considered to be most likely related to excretion of the large amounts of test material (or metabolites) during the course of this study.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
20 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
urinalysis
Key result
Dose descriptor:
NOAEL
Effect level:
1 522 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
urinalysis
Dose descriptor:
NOAEL
Effect level:
1 699 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
urinalysis

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion