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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:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(1,3-benzodioxol-5-ylamino)ethanol hydrochloride
EC Number:
303-085-5
EC Name:
2-(1,3-benzodioxol-5-ylamino)ethanol hydrochloride
Cas Number:
94158-14-2
Molecular formula:
C9H11NO3.ClH
IUPAC Name:
2-(1,3-benzodioxol-5-ylamino)ethanol hydrochloride
Test material form:
solid: particulate/powder
Details on test material:
beige, cryst. powder

Test animals

Species:
rat
Strain:
other: Wistar HanBrl: WIST (SPF)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Bi-distilled water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability, homogeneity and content of the solutions of HYDROXYETHYL-3,5-METHYLENEDIOXYANILINE HCL in the vehicle were analytically confirmed. Samples were freshly prepared once per week since stability in the vehicle for up to 7 days could be demonstrated (> 80 % of the nominal values). The mean concentrations of the homogeneity samples ranged between 94.8 and 101.6 % of the nominal values for the three dose groups. The content of the dosing solutions was within the range of +/- 20 % for all samples analysed. Thus, proper dosing was confirmed for the entire study period.
Duration of treatment / exposure:
Once daily over a period of 13 weeks
Frequency of treatment:
Once daily / 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
control group
Dose / conc.:
20 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
350 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Clinical signs, outside cage observation, food consumption and body weight gain were recorded periodically during pre-test and treatment period. Ophthalmoscopic examinations were performed before the start of the treatment and during week 13. The functional observational battery, and investigations of locomotor activity and grip strength were performed during week 13. At the end of the dosing period, blood samples were withdrawn for the clinical laboratory investigations (haematology and clinical biochemistry). Urine samples were collected for urinalyses.
Sacrifice and pathology:
All animals were killed, necropsied and examined post mortem. Histological examinations were performed on a large number of organs and tissues from all control and high dose animals. From the animals of the low and mid dose groups, the liver, kidneys, spleen and ovaries were also examined. Furthermore, all observed gross lesions from animals of all dose groups were examined histopathologically.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Sporadic clinical signs at the daily and weekly observation as well as at the FOB were observed. However, those effects were not considered as test-item related as they did not show any dose-dependency.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male treated with 350 mg/kg bw died spontaneously at treatment day 85. This death was not considered to be treatment related. All other animals survived until scheduled necropsy.
Body weight and weight changes:
no effects observed
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):
At 350 mg/kg bw:
Elevated mean absolute and relative reticulocyte counts were observed after 13 weeks treatment. This effect correlated with the splenic extramedullary haematopoesis which was observed during histopathology and was therefore considered as a test item related effect. In females, effects on blood chemistry (reduced red blood cell count, haematocrit and haemoglobin level) and elevated mean absolute and relative reticulocyte counts accompanied by a shift in the reticulocyte maturity index towards less mature reticulocytes was observed.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At 350 mg/kg bw:
Some clinical biochemistry parameters were elevated in both sexes (bilirubin, cholesterol, phospholipids, sodium and potassium concentrations), indicating changes in the liver and in the kidneys. Those changes were accompanied by an increased liver and kidney weight and an increased urinary volume.
At 100 mg/kg bw:
Increased bilirubin levels were noted in females (statistically significant, exceeding the historical control range). Elevated cholesterol (both sexes) and phospholipid levels were observed (females only).
At 20 mg/kg bw:
No adverse effects were noted.
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
At 350 mg/kg bw:
Statistically significantly reduced mean locomotor activity was seen in males.
At 100 mg/kg bw:
Locomotor activity was statistically significantly reduced in males.
At 20 mg/kg bw:
No adverse effects were noted.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At 350 mg/kg bw:
In females, ovary and spleen weights were elevated and thymus weights were reduced in addition.
At 100 mg/kg bw:
Absolute and relative liver weights were elevated in males.
At 20 mg/kg bw:
No adverse effects were noted.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
At 350 mg/kg bw:
The histopathological investigation revealed hepatocellular hypertrophy in both sexes, as well as renal tubular damage like cell degeneration. In females, extramedullary haematopoiesis was observed in the spleen and corpus luteum hypertrophy in the ovaries.
At 100 mg/kg bw:
Hepatocellular hypertrophy was observed (effect was most pronounced in males).
At 20 mg/kg bw:
No adverse effects were noted.

Effect levels

Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
behaviour (functional findings)
clinical biochemistry
histopathology: non-neoplastic
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
Based on the above described effects, a “No observed Adverse Effect Level” (NOAEL) of 20 mg/kg bw HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE HCL was deduced from this 90-day oral toxicity study in rats.
Executive summary:

The test item was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 0, 20, 100 and 350 mg/kg bw for a period of 13 weeks. The dose volume in treated and control groups was 10 ml/kg body weight. The groups comprised 10 animals per sex, which were sacrificed after 13 weeks of treatment. Clinical signs, outside cage observation, food consumption and body weight gain were recorded periodically during pre-test and treatment period. Ophthalmoscopic examinations were performed before the start of the treatment and during week 13. The functional observational battery, and investigations of locomotor activity and grip strength were performed during week 13. At the end of the dosing period, blood samples were withdrawn for the clinical laboratory investigations (haematology and clinical biochemistry). Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on a large number of organs and tissues from all control and high dose animals. From the animals of the low and mid dose groups, the liver, kidneys, spleen and ovaries were also examined. Furthermore, all observed gross lesions from animals of all dose groups were examined histopathologically. Based on the above described effects, a “No observed Adverse Effect Level” (NOAEL) of 20 mg/kg bw HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE HCL was deduced from this 90-day oral toxicity study in rats.