Reaction mass of 2,2'-(ethylenedioxy)diethanol and 3,6,9,12,15-pentaoxaheptadecane-1,17-diol and 3,6,9,12-tetraoxatetradecane-1,14-d

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented study report, GLP, similar to OECD 408

Justification for type of information:

Read across is based on the category approach. Please refer to attached category document.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

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)

Remarks:

testing lab.

Limit test:

no

Test material

Test material information

Constituent 1

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'-[ethane-1,2-diylbis(oxy)]diethanol

Details on test material:

purity: 99.74 - 99.9%

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female Fischer 344 rats were used. 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 2 w 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 66-77°F and relative humidity at 40-70%. A 12-h photoperiod was used.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 748, 1522, 3849 mg TEG/kg/day (= 0, 10000, 20000 or 50000 ppm) for males and 0, 848, 1699, 4360 mg TEG/kg/day (= 0, 10000, 20000, 50000 ppm) for females.
Basis:
nominal in diet

No. of animals per sex per dose:

30/sex/group in the control and high dose and 20/sex/group in the low and mid dose groups

Control animals:

yes, concurrent no treatment

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:

Observations for mortality wer emade twice daily. Detailed clinical observations were performed weekly, and observations for overt clinical signs were performed on other days. Opthalmic examinations were performed prior to the start of dosing and prior to interim (13 week) sacrifice). Body weight and food consumption data were collected for all animals weekly.
Blood was collected on day 30. Prior to termination, hematology ,clinical chemistry and urinalysis were performed.
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.
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, color, microscopy, blood, protein, ketones, glucose, bilirubin and urobilinogen.

Sacrifice and pathology:

Twenty 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.

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 Saftware. The fiducial limit of 0.05 was used as the critical level of significance for all tests.

Results and discussion

Results of examinations

Details on results:

Treatment of rats with TEG for 13 weeks did not result in abnormal or biologically significant clinical signs, ophthalmological changes, changes in food consumption, alterations in clinical chemistry measurements, necropsy findings, or histologic findings. 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. Hematology measurements, including decreased erythrocytes and hematocrit in males from the high and mid dose groups and decreased hemoglobin 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. Decrease in urine pH at all dose levels in males and the mid and high dose levels in females and an increase in urine volulme in males from the high dose group were considered to be related to TEG treatment. 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 also 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.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

20 000 ppm

Sex:

male/female

Basis for effect level:

other: overall effects

2

Dose descriptor:

NOAEL

Effect level:

1 522 mg/kg diet

Sex:

male

Basis for effect level:

other: overall effects

3

Dose descriptor:

NOAEL

Effect level:

1 699 mg/kg diet

Sex:

female

Basis for effect level:

other: overall effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In the currently reported study with TEG there was no evidence for any specific organ or tissue toxicity. TEG did not show the repeated exposure toxicity characteristic of the lower molecular weight homologues. In this present study, a NOAEL of 20,000 ppm of dietary TEG for the rat was observed.

Executive summary:

Fischer 344 rats (30/sex/group in the control and high dose groups and 20/sex/group in the low and mid dose groups) were exposed to triethylene glycol (TEG) in the diet at concentrations of 0, 10000, 20000, or 50000 ppm for 13 weeks. The doses corresponded to approximate mean consumption values of 748, 1522 and 3849 mg TEG/kg/day for the males from the 10000, 20000, and 50000 ppm groups, respectively. The extra 10 animals/sex in the control and high dose groups were monitored without additional treatment for a 6-week recovery period following the dosing phase of the study. Observations or measurements for clinical signs of toxicity, ophthalmologic changes, food consumption, body weight, clinical pathology (interim and final), organ weights, necropsy, and histology were made.

Treatment of rats with TEG at doses of 10000, 20000, or 50000 ppm for 13 weeks did not result in abnormal or biologically significant clinical signs, ophthalmologic changes, changes in food consumption, alterations in clinical chemistry measurements, necropsy findings, or histological findings. Body weight depression compared to controls occurred in males from the high dose group throughout the study in females during the latter weeks of the study (starting at approximately week 8) 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 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. Hematology measurements, including decreased erythrocytes and hematocrit in males from the high and mid dose groups and decreased hemoglobin 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 red cell indexes.

Decreases in urine pH at all dose levels in males and 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. 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 also 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. Due to the alterations in urine pH in the males from the 10000 ppm level and the abnormal body weight measurements, a clear NOEL could not be established.