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Repeated dose toxicity: oral

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Administrative data

Endpoint:
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: basic information given.
Justification for type of information:
Read across is based on the category approach. Please refer to attached category document.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1976
Report Date:
1976
Reference Type:
publication
Title:
Human Health Assessment for Long-term Oral Ingestion of Diethylene Glycol
Author:
WM Snellings, KE McMartin, MI Banton, F Reitman, J Klapcz, S Green
Year:
2016
Bibliographic source:
Manuscript under peer-review

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
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%.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals 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: ad libitum

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


Administration / exposure

Route of administration:
oral: feed
Duration of treatment / exposure:
98 days (first experiment)
225 days (second experiment)
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
First experiment: 0, 300, 1500 or 3000 mg/kg bw for 98 days (= 0, 0.4 , 2.0 or 4.0 %)
Basis:

Remarks:
Doses / Concentrations:
Second experiment: 0, 64, 128, 300, 1500 mg/kg bw for 225 days (= 0 %, 0.085 %, 0.17 %, 0.4 %, 2.0 %)
Basis:
nominal in diet
No. of animals per sex per dose:
15-20 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 15-20 rats of each sex were given diets containaing 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.

Examinations

Observations and examinations performed and frequency:
The animals were weighed initially, on days 1, 4 and 8 and then at approximately weekly intervals throughout the study.
Food and water intake over a 24-hr period were measured at the same intervals.
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, post mortem examinations, organ-weight analyses and collection of blood for haematological examination were carried out.
Sacrifice and pathology:
In the haematological examination the reticulocyte and differential leucocyte preparations were not examined. Histological examination was confined to the kidneys.

Results and discussion

Results of examinations

Details on results:
14 week study:
4% - deaths, dpressed body weight, increased water intake, increased urine volume, hematuria, increased kidney weight, abnormal gross/microscopic kidney findings, increased liver weight, and abnormal gross/microscopic liver findings noted
2% - kidney hydropic degeneration in the proximal tubule (1/15 rats)

32 week study:
2% - no hydropic degeneration of the kidneys observed; lower body weights in both males and females observed

Effect levels

open allclose all
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:
other: Based on renal hydropic degeneration.
Dose descriptor:
NOAEL
Remarks:
(225 days)
Effect level:
234 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Fifteen to twenty Wistar rats/sex/dose were fed 0, 0.4, 2.0, or 4.0% DEG (equivalent to 300, 1600, and 3000 mg/kg/day in males and 400, 1800 and 3700 mg/kg/day in females) for 14 weeks (phase 1) or ten male and ten female Wistar rats were fed 0, 0.085, 0.17, 0.4, or 2.0% DEG (equivalent to 50, 100, 230, and 1200 mg/kg/day in males and 60, 130, 290, and 1500 mg/kg/day in females) for 32 weeks (phase 2). Observations and measurements included body weights, food and water intake, urinalysis, hematology, clinical chemistry (14 week), and organ weight and histopathology (kidneys only in 32 week). In the 14 week study, effects included death, decreased body weight, and kidney hydropic degeneration at the high dose of 4% DEG. Oxalic acid observed in the urine in some animals of all dose groups was considered a biomarker and does not indicate toxicity. Since hydropic degeneration of the kidney was observed in one animal exposed to 2% DEG and decreased male and female body weights were observed, the LOAEL is considered 2% for the 14 week exposure. The 14 week NOAEL was therefore 0.4% (300 mg/kg/day). For the 32 week study, reduced body weight was observed at 2%, resulting in a NOAEL of 0.4% (234 mg/kg/day).
Executive summary:

Fifteen to twenty Wistar rats/sex/dose were fed 0, 0.4, 2.0, or 4.0% DEG (equivalent to 300, 1600, and 3000 mg/kg/day in males and 400, 1800 and 3700 mg/kg/day in females) for 14 weeks (phase 1) or ten male and ten female Wistar rats were fed 0, 0.085, 0.17, 0.4, or 2.0% DEG (equivalent to 50, 100, 230, and 1200 mg/kg/day in males and 60, 130, 290, and 1500 mg/kg/day in females) for 32 weeks (phase 2). Observations and measurements included body weights, food and water intake, urinalysis, hematology, clinical chemistry (14 week), and organ weight and histopathology (kidneys only in 32 week). In the 14 week study, effects included death, decreased body weight, and kidney hydropic degeneration at the high dose of 4% DEG. Oxalic acid observed in the urine in some animals of all dose groups was considered a biomarker and does not indicate toxicity. Since hydropic degeneration of the kidney was observed in one animal exposed to 2% DEG and decreased male and female body weights were observed, the LOAEL is considered 2% for the 14 week exposure. The 14 week NOAEL was therefore 0.4% (300 mg/kg/day). For the 32 week study, reduced body weight was observed at 2%, resulting in a NOAEL of 0.4% (234 mg/kg/day).