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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2002-12-03 until 2003-01-22
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD guideline, GLP compliance, read across substance
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
27-Jul-1995
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
30-Sep-1996
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 424 (Neurotoxicity Study in Rodents)
Version / remarks:
adopted on 21-Jul-1997
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
other: EPA, Guideline 799, 9620-62-158, 15 August 1997
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, I'Arbresle, France
- Age at study initiation: 6 weeks old
- Weight at study initiation: males mean body weight: 195 g, females mean body weight: 154 g
- Housing: individually, in suspended wire mesh cages
- Diet: The animals had free access to A04 C pelleted maintenance diet
- Water: filtered tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2°C
- Humidity: 50 ± 20%
- Air changes: approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod: 12h/12h (7:00-19:00)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 50% PEG 300 aqueous solution
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: no data

VEHICLE
- Justification for use and choice of vehicle (if other than water): standard vehicle for studies of this type
- Concentration in vehicle: 30, 80 or 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before the start of treatment, the suitability of the proposed preparation procedure was determined by the analysis of concentration, homogeneity and stability of dosage forms which were prepared using this procedure. During the treatment period, the concentration ofthe dosage forms prepared for use in the study
was checked.
Duration of treatment / exposure:
29 days
Frequency of treatment:
Once a day
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 150, 400, 1000 mg/kg bw /day
Basis:
other: gavage: 5 mL/kg bw/day
No. of animals per sex per dose:
5 females and 5 males per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dose-levels were selected on the basis of the results of a previous acute toxicity study by oral route performed in the same species in which neither clinical signs nor mortality were recorded at the dose-level of 500, 1000 or 1500 mg/kg bw/day. In addition, the body weight gain and food consumption remained unchanged during the study and no treatment-related necropsy findings were noted.
- Post-exposure recovery period in satellite groups:
On completion of the treatment period, designated animals were held for a 2-week treatment-free period (satellite groups (0 and 1000 mg/kg bw/day)) in order to evaluate the reversibility of any findings.
Positive control:
No positive control

Examinations

Observations and examinations performed and frequency:
- The animals were checked once/twice daily for clinical signs, morbidity and mortality
- Detailed clinical observations were carried out weekly and a functional observation battery was performed at the end of the treatment period
- The body weight and food consumption were recorded weekly
- Vaginal smears were performed daily in order to determine the stage of the estrous cycle and to check its regularity and length
- Hematology, blood biochemical and urinary investigations were performed at the end of the treatment period
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
- All the animals were subjected to a macroscopic post-mortem examination and designated organs weighed. Macroscopic lesions and selected tissues were preserved and examined microscopically

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
- Mortality
No unscheduled mortalities occurred during the study.
- General clinical signs
Ptyalism, with a dose-related incidence was the main clinical sign observed in all test-treated groups. It was no longer observed during the treatment-free period. Ptyalism is a common sign noted when test items are administered by gavage and it was therefore not considered as an adverse effect.
- Detailed clinical observation and functional observation battery
No perturbation of autonomic or physiological functions for the animals was noted at the end of the treatment period.
- Bodv weight and food consumption
No changes of toxicological relevance were seen during the study.
- Vaginal smears
No differences from controls were observed in the estrous cycle of any of the test-treated animals.
- Hematologv and blood biochemistry
No differences of toxicological importance from controls were observed in the hematological and blood biochemical parameters of any ofthe test-treated animals.
- Urinalysis
There were no treatment-related changes in any of the quantitative or qualitative urinary parameters examined.
- Organ weights
There were no treatment-related changes in organ weights at the end of treatment and treatment-free periods.
- Macroscopic post-mortem examination
No treatment-related macroscopic findings were observed at the end of the treatment and treatment-free periods.
- Microscopic examination
No microscopic findings, which were considered to be related to the treatment with the test item, were found at the end ofthe treatment period.
No toxicologically relevant effects were noted. Consequently, under the experimental conditions, the No Observable Adverse Effect Level (NOAEL) was established at 1000 mg/kg bw/day. No target organ was identified.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion