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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
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

Reference
Reference Type:
publication
Title:
Dosimetry considerations in the enhanced sensitivity of male Wistar rats to chronic ethylene glycol-induced nephrotoxicity.
Author:
Corley RA, Wilson DM, Hard GC, Stebbins KE, Bartels MJ, Soelberg JJ, Dryzga MD, Gingell R, McMartin KE, Snellings WM
Year:
2008
Bibliographic source:
Toxicol Appl Pharmacol 228: 165-178

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
12 months
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
400 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20
Control animals:
yes, plain diet

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality occurred in 5 of 20 rats at 300 mg/kg bw/day (days 111-221) and 4 of 20 rats at 400 mg/kg bw/day (days 43-193), with remaining rats at this dose euthanized early (day 203) due to excessive weight loss.
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Increased water consumption and urine volume with decreased specific gravity occurred at 300 mg/kg bw/day presumably due to osmotic diuresis.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
No significant differences in kidney oxalate levels, the metabolite responsible for renal toxicity, were observed among control, 50 and 150 mg/kg bw/day groups. At 300 and 400 mg/kg bw/day, oxalate levels increased proportionally with the nephrotoxicity score supporting the oxalate crystal-induced nephrotoxicity mode of action. No treatment-related effects on the renal clearance of intravenously infused (3)H-inulin, a marker for glomerular filtration, and (14)C-oxalic acid were observed in rats surviving 12 months of exposure to ethylene glycol up to 300 mg/kg bw/day.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Calculi (calcium oxalate crystals) occurred in the bladder or renal pelvis at > = 300 mg/kg/day. Rats dying early at > = 300 mg/kg/day had transitional cell hyperplasia with inflammation and haemorrhage of the bladder wall. Crystal nephropathy (basophilic foci, tubule or pelvic dilatation, birefringent crystals in the pelvic fornix, or transitional cell hyperplasia) affected most rats at 300 mg/kg bw/day, all at 400 mg/kg bw/day, but none at < =150 mg/kg bw/day.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Details on results:
Mortality occurred in 5 of 20 rats at 300 mg/kg bw/day (days 111-221) and 4 of 20 rats at 400 mg/kg bw/day (days 43-193), with remaining rats at this dose euthanized early (day 203) due to excessive weight loss. Increased water consumption and urine volume with decreased specific gravity occurred at 300 mg/kg bw/day presumably due to osmotic diuresis. Calculi (calcium oxalate crystals) occurred in the bladder or renal pelvis at > = 300 mg/kg/day. Rats dying early at > = 300 mg/kg/day had transitional cell hyperplasia with inflammation and haemorrhage of the bladder wall. Crystal nephropathy (basophilic foci, tubule or pelvic dilatation, birefringent crystals in the pelvic fornix, or transitional cell hyperplasia) affected most rats at 300 mg/kg bw/day, all at 400 mg/kg bw/day, but none at < =150 mg/kg bw/day. No significant differences in kidney oxalate levels, the metabolite responsible for renal toxicity, were observed among control, 50 and 150 mg/kg bw/day groups. At 300 and 400 mg/kg bw/day, oxalate levels increased proportionally with the nephrotoxicity score supporting the oxalate crystal-induced nephrotoxicity mode of action. No treatment-related effects on the renal clearance of intravenously infused (3)H-inulin, a marker for glomerular filtration, and (14)C-oxalic acid were observed in rats surviving 12 months of exposure to ethylene glycol up to 300 mg/kg bw/day. In studies with naïve male Wistar and F344 rats (a less sensitive strain), a significant difference was observed in oxalate clearances between young rats (i.e. Wistar clearance < F344) but not in age-matched old rats. Regardless, the ratios of oxalate:inulin clearances in these two strains of rats, including those exposed to ethylene glycol, were all < 1, suggesting that a fraction of the filtered oxalate is reabsorbed. Other species, including humans, typically have clearance ratios >1 and are more effective at clearing oxalic acid by both glomerular filtration and active secretion. Thus, the lower renal clearance and kidney accumulation of oxalates in male Wistar rats enhances their sensitivity, which will be a factor in human risk assessments. The benchmark dose values (BMD05, BMDL05) were 170 mg/kg bw/day and 150 mg/kg bw/day for nephropathy, and 170 mg/kg bw/day and 160 mg/kg bw/day for birefringent crystals, using incidence times severity data in each case.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
System:
other: urogenital
Organ:
kidney
Treatment related:
yes

Applicant's summary and conclusion