3,6,9-trioxaundecane-1,11-diol

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

prior to or in 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP , no specific information whether a guideline study but appears to follow intent of OECD 407.

Data source

Reference

Reference Type:

publication

Title:

Subacute oral toxicity of tetraethylene glycol and ethylene glycol administered to Wistar rats.

Author:

Schladt L, Ivens I, Karbe E, Ruhl-Fehlert C, Bomhard E.

Year:

1998

Bibliographic source:

Exp. Toxicol. Pathol. 50:257-265

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3,6,9-trioxaundecane-1,11-diol

EC Number:

203-989-9

EC Name:

3,6,9-trioxaundecane-1,11-diol

Cas Number:

112-60-7

Molecular formula:

C8H18O5

IUPAC Name:

2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethan-1-ol

Test material form:

not specified

Details on test material:

Tetraethylene glycol, 98.2% pure, was used.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were 6-7 weeks of age at study initiation.

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

Test material was diluted in double distilled water to provide 0, 220, 660, 2000 mg/kg/d

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not applicable.

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

ad libitum

Doses / concentrations

Remarks:

Doses / Concentrations:
Concentrations were adjusted to deliver 0, 220, 660, 2000 mg/kg/d
Basis:
actual ingested

No. of animals per sex per dose:

10 males and 10 females/dose level

Control animals:

yes, concurrent vehicle

Details on study design:

Test material was administered in the drinking water to provide 0, 220, 660, 2000 mg/kg/d to groups of Sprague-Dawley rats for 4 weeks. Animals were examined twice a day except on weekends and holidays. Body weights were measured daily and food and water consumption was determined weekly. At the end of the 4 week period, blood was obtained for hematology and clinical chemistry determinations and urine for urinalysis determinations. Organ weights were obtained at necropsy and gross and histopathologic examination of selected tissues conducted.

Positive control:

Not applicable

Examinations

Observations and examinations performed and frequency:

Clinical observations performed and frequency: 2x/day (clinical signs), except 1x/day on weekends and public holidays; body weights determined daily, food and water consumption weekly. Hematology (5 rats/group in week 4) included erythrocyte count, hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, leukocyte count, differential blood count and platelet count. Clinical chemistry (5 rats/group in week 4) include determination of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, cholesterol, creatinine, glucose, calcium, potassium, sodium, inorganic phosphate, urea, and total protein. Urine samples (week two, 20 hr collection from 5 animals per group, and week 5, 24 hour collection; all animals) were cooled during the collection period. Urinalysis included measurement of urine volume, specific gravity, osmolality, N-acetyl beta-D-glucosaminidase, lactate dehydrogenase, alanine aminopeptidase, urea, sodium, calcium, potassium, and inorganic phosphate. Occult blood, protein, glucose, ketones, bilirubin, urobilinogen were estimated semiquantitatively. Sediment of urine samples was microscopically examined for leukocytes, erythrocytes, epithelial cells, amorphous crystals, and bacteria. Additional urine samples collected on day 2 (5 animals/group, 20-h collection) and day 25 (all animals, 24-h collection) for determination of oxalic acid.

Sacrifice and pathology:

Organs examined at necropsy: weights of brain, heart, lungs, adrenals, spleen, ovaries, liver, kidneys, and testes were recorded. Brain, urinary bladder, ureter, testes, epididymes, heart, liver, spleen, kidneys and adrenals of control and high-dose animals were evaluated histopathologically. The following tissues and organs were collected and examined histologically: adrenals, aorta, bone, bone marrow, brain (cerebrum, brain stem, and cerebellum), cecum, cervix, coagulating glands, colon, duodenum, epididymides, esophagus, eyes, gross lesions, heart, ileum, jejunum, kidneys, lacrimal/Harderian glands, larynx, liver, lungs, mammary gland, mediastinal lymph node, mediastinal tissues, mesenteric lymph node, mesenteric tissues, nasal tissues, oral tissues, ovaries, oviducts, pancreas, parathyroid glands, peripheral nerve, pituitary, prostate, rectum, salivary glands, seminal vesicles, skeletal muscle, skin (normal and treated), spinal cord (cervical, thoracic, lumbar), spleen, stomach, testes, thymus, thyroid gland, tongue, trachea, urinary bladder, uterus and vagina.

Other examinations:

No additional information available

Statistics:

U-test for significance.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

No treatment-related effects of toxicological significance were noted in any of the animals treated

Effect levels

Dose descriptor:

NOEL

Effect level:

> 2 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment-related effects of toxicological significance were noted in any of the animals treated at 2000 mg/kg/day, the highest dose examined.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

No additional information available.

Applicant's summary and conclusion

Conclusions:

NOEL >2000 mg/kg/day

Executive summary:

The subacute toxicity of tetraethylene glycol was examined in Sprague Dawley rats. Test material was administered in the drinking water to provide 0, 220, 660, 2000 mg/kg/d to groups of Sprague-Dawley rats for 4 weeks. Animals were examined twice a day except on weekends and holidays. Body weights were measured daily and food and water consumption was determined weekly. At the end of the 4 week period, blood was obtained for hematology and clinical chemistry determinations and urine for urinalysis determinations. Organ weights were obtained at necropsy and gross and histopathologic examination of selected tissues conducted.

No treatment-related effects of toxicological significance were noted in any of the animals treated. The NOEL >2000 mg/kg/day, the highest dose examined.