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Description of key information

A 7-day oral toxicity study (Carcia and Alumà, 2008) is available which is key study. The LOAEL was considered to be less than 150 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 21 to 28 January 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study run to a reliable method and to GLP
Qualifier:
according to
Guideline:
other: Repeated Dose Toxicity. CPMP/SWP/1042/99. 27 July 2000
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Interfauna Ibérica, S.L.
- Age at study initiation: Approximately 9 weeks
- Weight at study initiation: Males: 226-242 g Females: 151-169 g
- Fasting period before study:
- Housing: Groups of five rats at the most of the same sex during acclimatization and groups of three rats of the same sex from the same treatment group during treatment in Makrolon type-5 cages with sawdust bedding
- Diet (e.g. ad libitum): Pelleted, standard dry rodent diet, access ad libitum
- Water (e.g. ad libitum): Community tap water was offered to the animals ad libitum in bottles
- Acclimation period: 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25℃
- Humidity (%): 30-60%
- Air changes (per hr): More than 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light (7:00 am to 7:00 pm)/12 hours dark (7:00 pm to 7:00 am)

IN-LIFE DATES: From: 21 January 2008 To: 28 January 2008
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle was chosen based on the information in Study B65992 (Acute Oral Toxicity Study in Rats) performed in Harlan Laboratories Ltd.
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required): 2057KMR
- Purity:
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
7 days
Frequency of treatment:
Once daily
Remarks:
Doses / Concentrations:
0, 150, 300 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
3 males and 3 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment (if not random):
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):
Positive control:
None stated
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
Viability/mortality: Twice daily
Clinical signs: Cage-side clinical observations once daily during acclimatization.Three times on test day 1 and at least twice daily on days 2-7.
Food consumption: Once during acclimatization and on days 1 and 7.
Body weights: Once during acclimatization, at days 1, 3 and 7 during the treatment period (immediately before the administration), and before sacrifice.
- Time schedule: Once daily during acclamatization
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day:
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data:

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations:






Sacrifice and pathology:
GROSS PATHOLOGY: Yes
A full autopsy was performed on all animals. The autopsy included the examination of the external surface of the body, all orifices, cranial, thoracic and abdominal cavities and the observation of the organs both in situ and after evisceration.

HISTOPATHOLOGY: Yes
adrenal glands, aorta, bone marrow , brain-incluing sections of medulla/pons, cerebral and cerebellar cortex, ovaries, pancreas, rectum, prostate gland and seminal vesicles, skin, spinal cord-cervical, midthoracic
Statistics:
The following statistical methods were used to analyze the body weight, food consumption, clinical laboratory, organ weights, all ratios and macroscopic findings:
The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables can be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data can not be assumed to follow a normal distribution.
Fisher's exact-test was applied to the macroscopic findings.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Clinical signs and mortality:
In all test item treated groups, muscular hypotonus, hunched back, abnormal gait and ruffled fur were recorded. Three animals (1 male + 2 females) from group 4 died. These deaths were treatment-related.

Body weight and weight gain:
A decrease in body weight and body-weight gain was observed in males from group 3 and 4 and in females from groups 2, 3 and 4. This decrease was dose-related.

Food consumption and compound intake (if feeding study):
A lower dose-related food consumption was recorded in all test item treated groups, with the exception of males from group 2 in which the food consumption was similar to Control group.

Haematology:
A dose-related increase in red blood cells, hemoglobin and hematocrit and a decrease in reticulocyte count was recorded in all test item treated groups in comparison to the Control group.

Clinical chemistry:
In males from group 4 and females from group 3 lower values of creatinine and higher values of proteins and globulin or albumin were recorded in comparison to Control group.

Organ weights: Animals from all groups treated with the test item showed a dose-related decrease of absolute and relative weight of the thymus and spleen.

Histopathology: non-neoplastic:
There were histopathological changes in the heart, spleen, thymus and adrenal glands.
Dose descriptor:
LOAEL
Effect level:
<= 150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Conclusions:
The LOAEL was considered to be less than 150 mg/kg bw/day.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
2 (reliable with restrictions)

Additional information

A 7-day oral toxicity study was conducted using rats (Carcia and Alumà, 2008). Key study.

The LOAEL was considered to be less than 150 mg/kg bw/day.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This study was conducted according to a reliable method under GLP.

Justification for classification or non-classification