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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:
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:
2002
Report Date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 6 weeks
- Weight at study initiation: mean males: 217 g; females: 176
- Housing: in groups of 5. Singly during activity monitoring overnight.
- Diet: ad libitum starting at 4 hours after dosing
- Water: tap water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-3
- Humidity (%): 30-70
- Air changes/hour: 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations in vehicle were prepared daily within 4 hours prior to dosing.
Homogeneity and stability were checked.


VEHICLE
- Justification for use and choice of vehicle: based on results of a pre-test
- Concentration in vehicle: approx. 90-99.95%
- Amount of vehicle (if gavage): 5mL/kg bw/day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A GC/MS method was developed and evaluated
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily, 7 days per week
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.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on results of a pre-test using dose levels of 150 and 1000 mg/kg bw/day
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily


BODY WEIGHT: Yes
- Time schedule for examinations: on days 1, 8, 15, 22, and 28


FOOD CONSUMPTION AND COMPOUND INTAKE (no feeding study): yes
- Time schedule: weekly


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Anaesthetic used for blood collection: Yes (iso-flurane)
- Animals fasted: Yes


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Animals fasted: Yes
- How many animals: all


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4 of treatment
- Dose groups that were examined: all
- Battery of functions tested: sensory activity; grip strength; motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Dunnett-test and exact Fisher-test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
breathing difficulties in 1000 mg/kg bw/d group (non-adverse)
Mortality:
mortality observed, treatment-related
Description (incidence):
breathing difficulties in 1000 mg/kg bw/d group (non-adverse)
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
hyperplasia of squamous epithelium of forestomach in 1000 mg/kg bw/d group (non-adverse)
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No substance-related mortality occurred.
Slight to moderate breathing difficulties (rales and/or gasping) were seen in several high dose animals on some days during week 3. These signs subsided and were absent during week 4.
No signs were noted in the low and intermediate dose groups.


BODY WEIGHT AND WEIGHT GAIN
Body weight and body weight gain of treated animals remained in the same range as controls over the 4-week study period.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There was no effect on food consumption except from a slight transient reduction in high dose females during week 3.


HAEMATOLOGY
There was no effect on hematological parameters.


CLINICAL CHEMISTRY
There were no treatment-related differences between control and treated animals.


NEUROBEHAVIOUR
No changes were noted in hearing ability, pupillary reflex, static righting reflex and grip strength, or in motor activity.


ORGAN WEIGHTS
Absolute and relative organ weights were similar between control and treated animals.


GROSS PATHOLOGY
Finding No. 1: an irregular surface of the forestomach was noted in all high dose animals.
Finding No. 2: a thickened glandular mucosa of the stomach was observed among the treated animals. Since none of these cases could be confirmed microscopically, they were considered to be of no toxicological relevance.


HISTOPATHOLOGY: NON-NEOPLASTIC
No other findings than slight to marked hyperplasia of the squamous epithelium of the forestomach in all high dose animals, and at a minimal degree in 3 intermediate dose group animals.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of adverse effects. Rales and hunched posture in some rats at 1000 mg/kg bw/day were generally minimal to mild and only seen on some days during week 3 and subsided thereafter, and were, therefore, regarded as being of no biological relevance.
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Taking into account that there is no correlate for the rat’s forestomach in humans the NOAEL for systemic toxicity is considered to be 1000 mg/kg bw/day.