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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
07 March 2007 to 04 April 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
1995
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
466-080-8
EC Name:
-
Molecular formula:
C23H31N3O4
IUPAC Name:
466-080-8
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Test material: LFC 2098
Manufactured on: 05/29/2006
Common name: Aminoester
Declared concentration: 100%.
Analysed concentration: 100%
Stability: Stable under normal conditions

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
Wistar(albinos rats)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animal source: Tecam (Sao Roque, SP)
Sex and number: The study was conducted with 10 animals (five males and five female) in each group (test and control groups). Females were nulliparous and non pregnant.
Body weight range and age: Healthy young adult rats were used which were 9 weeks old at the initial date of treatment; the weight variation of each animal was not greater than 20 percent of the mean weight for each sex.
Housing: Animals were housed using suitable rodent cages with 5 animals per cage.
Environment: The environmental conditions in the animal room were controlled and were recorded daily five days a week. Temperature during the test ranged from 20 to 22°C, average relative humidity was 64% and light cycles of 12 hours/day were maintained.
Feeding: Filtered water and pelleted commercial diet for the species (Biobase Biotec - Biotecnicas) were provided ad libitum throughout acclimatization and test period. A pre-anesthetic fasting of approximately 12 hours occurred before blood collection. Results of the monitoring of the food and water by TECAM/SP for environmental contaminants were maintained by the laboratory during this period.

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
The chosen route of administration was orai gavage, since test substance added in the diet caused an alteration in the food consumption in the preliminary diet test.
Vehicle:
corn oil
Details on oral exposure:
Animals were dosed by oral gavage using avsuitable gastric tube with the test substance diluted in corn oil 5 days per week for 28days.
Doses: 0 mg/kg bw/day, 50 mg/kg bw/day, 200 mg/kg bw/day and 1000 mg/kg bw/day
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
Preliminary: exposed to treated diet
Dose / conc.:
5 000 ppm
Remarks:
Preliminary: exposed to treated diet
Dose / conc.:
10 000 ppm
Remarks:
Preliminary: exposed to treated diet
Dose / conc.:
20 000 ppm
Remarks:
Preliminary: exposed to treated diet
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Preliminary: dosed by oral gavage using asuitable gastric tube with the test substance diluted in corn oil
Dose / conc.:
50 mg/kg bw/day (nominal)
Remarks:
Preliminary: dosed by oral gavage using asuitable gastric tube with the test substance diluted in corn oil
Dose / conc.:
200 mg/kg bw/day (nominal)
Remarks:
Preliminary: dosed by oral gavage using asuitable gastric tube with the test substance diluted in corn oil
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
Preliminary: dosed by oral gavage using asuitable gastric tube with the test substance diluted in corn oil
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
dosed by oral gavage using asuitable gastric tube with the test substance diluted in corn oil 5 days per week for 28 days
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
dosed by oral gavage using asuitable gastric tube with the test substance diluted in corn oil 5 days per week for 28 days
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
dosed by oral gavage using asuitable gastric tube with the test substance diluted in corn oil 5 days per week for 28 days
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
dosed by oral gavage using asuitable gastric tube with the test substance diluted in corn oil 5 days per week for 28 days
No. of animals per sex per dose:
4 groups with 8 animals each (4 maies and 4 females) preliminary: LFC 2098 in the diet to set concentrations for the main test
4 groups with 8 animals each (4 males and 4 females) preliminary: LFC 2098 administered by oral gavage
4 groups with 10 animals each (5 males and 5 female) full study: test and control groups
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: The main test dose selection was based on the results of the preliminary 5-day repeated dose oral test

Justification of test system selection: The rat is a preferred species for acute oral toxicity testing by various regulatory agencies; the Wistar rat has been shown to be sensitive to the toxic effects of a variety of drugs and chemicals.

Fasting period before blood sampling for clinical biochemistry: A pre-anesthetic fasting of approximately 12 hours occurred before blood collection.

Examinations

Observations and examinations performed and frequency:
1. Clinical and mortality signs observed for were: Death, fur alterations, eyes alterations, prostration, pupil size alteration, tremors, piloerection, lacrimation, diarrhoea, salivation, gait alterations, posture alterations, dyspnoea, convulsion, stereotypic behaviour, bizarre behaviour, mucous membranes alteration, coma, skin alterations

2. Body weight measured weekly

3. Food consumption measured weekly during 28 days

4. Functional Observational Battery (FOB) was assessed in the fourth exposure week (day 26), tests were: Hearing Test (auditory assessment), Pupil response (Visual assessment), Positive geotropism (proprioceptive stimuli assessment), Grip strength assessment, Motor activity assessment,

5. Haematological examination: blood clotting time, haematocrit, haemoglobin concentration, erythrocyte count, leucocyte count and platelet count

6. Clinical biochemistry determination: sodium, potassium, glucose, total cholesterol, urea, creatinine, total protein and albumin, alanine aminotrasferase and aspartate aminotransferase
Sacrifice and pathology:
1. Necropsy: absolute and relative organ weights

2. Histopathology: Histopathological examination of the brain (cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines, liver, kidney, adrenal, spleen, heart, thymus, thyroid, trachea, lung, gonads (testis or ovaries), accessory sex organs (uterus or prostate), urinary bladder, lymph nodes, peripheral nerve and bone marrow
Statistics:
All statistical analyses were carried out separately for males and females
Analysesof variance were performed by Student’s ‘t’ test for a dose-related response.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No important treatment - related clinical signs were observed in the daily examinations throughout the study except for one female (number 7) treated at 10 mg/kg bw/day that presented tremors on 9th day of observation. No other alterations were observed in all animals during the 28 days of testing at doses 0 mg/kg bw/day, 10 mg/kg bw/day, 100 mg/kg bw/day and 1000 mg/kg bw/day.
Mortality:
no mortality observed
Description (incidence):
No mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight measured weekly, no significant differences were found comparing body weight of the female rats and the control at any time. Although the dose groups were randomised, body weights of the male rats of the 1000 mg/kg bw/day dose group were significantly lower than in the other dose groups from day 0 onwards.
Reductions of body weight gain were observed in two males treated at 10 and 1000 mg/kg and one female of control group in the first week. This was possibly a consequence of the gavage treatment. In the second and third week of testing, all groups showed body weight gain. However it was lower at the highest dose. Loss of body weight in the fourth week observed in all groups was possibly a consequence of the 12-hour pre-anaesthetic fasting.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
All tested animals presented contraction of the pupil in response to light stimulation of the retina. Those responses were considered to be indicative of no alteration in the visual sensory reactivity.
Haematological findings:
no effects observed
Description (incidence and severity):
No statistical difference to the control was observed in haematological parameters for any of the treated groups. Results are within the range of physiological variability.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Significant statistical increases of the levels of sodium at 100 mg/kg bw/day and urea at 1000 mg/kg bw/day were found in males. Total protein in males treated at 100 mg/kg bw/day was found to be significantly decreased. Glucose at 10 mg/kg bw/day was found to be significantly decreased in females. Significant statistical decreases of the levels of total protein and albumin at 10 mg/kg bw/day and 100 mg/kg bw/day were found to be decreased in females. All the differences found for clinical biochemistry were considered to be within the normal expected range and were considered to be of no toxicological significance.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Relative liver weight at the highest dose group is significantly increased for both male and females.
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Lower testis absolute weight was detected and could be associated to the atrophy described in the histopathology.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
Full details of all the results can be seen in the full study report attached

Effect levels

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The repeated dose 28-day oral toxicity study with LFC 2098 at 0 mg/kg bw/day, 10 mg/kg bw/day, 100 mg/kg bw/day and 1000 mg/kg bw/day revealed a statistical significant difference in the body weight of male rats treated at 1000 mg/kg bw/day compared to the control group. Although the dose groups were randomised, body weights of the male rats of the 1000 mg/kg bw/day dose group were significantly lower than in the other dose groups from day 0 onwards. No statistical significance was observed in food consumption in this group nor in body weight gain.
No mortality or evident signs of toxicity were observed in any group except for one female treated at 10 mg/kg bw/day that presented tremors on day 9 of observation.
FOB assessed on day 26 showed no alteration in the sensory reactivity to auditory, visual and proprioceptive stimuli nor were any alteration in the assessment of grip strength. Significant alterations in motor activity were detected in male rats but not in female rats. Some minor differences were observed in haematological and biochemical parameters when the groups were compared. However these differences were within the normal expected range and were considered to be of no toxicological significance.
Relative liver weight at the highest dose group is significantly increased for both male and females. Lower testis absolute weight was detected and could be associated to the atrophy described in the histopathology. Based on these results it is concluded that the NOAEL for LFC 2098 is 100 mg/kg bw/day.
Executive summary:

Based on the results it is concluded that the NOAEL for LFC 2098 is 100 mg/kg bw/day.