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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Fully reported study performed under GLP and using a standard test method.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-[1,3-bis(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea
EC Number:
278-928-2
EC Name:
1-[1,3-bis(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea
Cas Number:
78491-02-8
Molecular formula:
C8H14N4O7
IUPAC Name:
1-[1,3-bis(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea
Test material form:
other: aqueous 50% solution

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
42 days old at start of treatment: bodyweights males 175-195g, females 145-178g. Individually housed; animal room 19-23C, 30-80% humidity, 12h dark/light cycle. Food and water provided ad lib.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
(distilled)
Details on oral exposure:
Gavage dosing at 5 ml/kg dose volume.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability (up to14 days) and homogeneity of formulated doses was confirmed. Achieved concentrations were confirmed by analysis of samples taken weekly to Week 4, then in Weeks 7, 10 and 13.
Analytical method: after addition of a colour reagent to diluted samples and heating (70C, 1h), absorbance at 492nm was determined.
Duration of treatment / exposure:
91 or 92 days (staggered termination).
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
200 mg/kg
Basis:
other: ingested dose (corrected for active ingredient)
Remarks:
Doses / Concentrations:
500 mg/kg
Basis:
other: ingested dose (corrected for active ingredient)
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
other: ingested dose (corrected for active ingredient)
No. of animals per sex per dose:
20 males, 20 females
Control animals:
yes, concurrent vehicle
Details on study design:
Samples from 10M, 10F/group taken for haematology, clinical chemistry and urinalysis.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
Twice daily cageside observations. Detailed weekly observations including bodyweight.
Opthalmoscopy: pretest and at termination.
Blood samples taken at termination, after fasting: full haematology and clinical chemistry.
Urinalysis: at termination.
Sacrifice and pathology:
Macroscopic observations at necropsy.
Organ weights: adrenals, brain, heart, kidneys, liver, lungs, ovaries, pituitary, spleen, testes with epididymides, thyroid/parathyroids, uterus.

Tissues collected: weighed organs plus aorta (thoracic), bone and bone marrow (sternum/femur), oesophagus, eyes with optic nerve, intestine (caecum, colon, ileum, jejunum, rectum), lacrymal gland, lymph nodes, mammary gland, sciatic nerve, pancreas, prostate, salivary glands, seminal vesicles, skeletal muscle, skin spinal cord (cervical, thoracic, lumbar), stomach, thymic region, trachea, urinary bladder, uterus with cervix, gross lesions.

Histopathology: all collected tissues from control and high-dose groups plus decedents. Kidneys, liver, lungs, stomach, adrenals, gross lesions for other test groups.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
2 males died at 1000 mg/kg/day. Excessive salivation seen at 500 and 1000 mg/kg/day.
Mortality:
mortality observed, treatment-related
Description (incidence):
2 males died at 1000 mg/kg/day. Excessive salivation seen at 500 and 1000 mg/kg/day.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased in males dosed at 1000 mg/kg/day.
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Haemoglobin, haematocrit and erythrocyte counts were significantly decreased, leucocyte counts increased at 1000 mg/kg/day (both sexes); erythrocytes were significantly decreased in males at 500 mg/kg/day.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
At 1000 mg/kg/day glucose, total protein, albumin and globulin significantly decreased, albumin/globulin ratio increased. Total protein, globulin and albumin/globulin ration were reduced at 500 mg/kg (and glucose decreased in males).
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative adrenal weights increased significantly at 1000 and at 500 (males only) mg/kg/day. In females absolute and relative liver weights increased significantly at 1000 and 500 mg/kg/day, pituitary weights decreased at 1000 mg/kg/day.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Stomach lesions (nodules, masses, swelling) seen at 1000 mg/kg/day.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Necrotising gastritis of forestomach and/or glandular stomach seen at 500 and 1000 mg/kg/day (severe at 1000 mg/kg/day).
Details on results:
Homogeneity and stability of test doses plus achieved concentrations (within 20% of nominal values) were confirmed by analysis.

Effect levels

Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Based on stomach lesions and associated clinical pathology parameters observed at 500 and 1000 mg/kg/day.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Daily oral dosing of rats at 200 mg/kg/day produced no effects considered treatment-related: this is concluded to be the NOEL.