SILATRIZOLE

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Subchronic 26-weeks

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 March 1998 to 12 November 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP study conducted similarly to OECD Guideline 408 with few deviations that did not affect the reliability of the study: no neurological investigations were performed and the free-treatment period was performed at the end of the 26-weeks instead of being done at the end of the 13-weeks intermediate point.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: EEC Recommendation No. 83/571/EEC, 26th October 1983

Deviations:

yes

Remarks:

(minor and transient deviations of relative humidity, food consumption recorded in weeks 27 and 29 instead of every 4 weeks, no food consumption recorded in week 30: not considered to compromise the validity of the study)

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: USA/FDA guideline for the Format and Content of the Nonclinical/Pharmacology/Toxicology Section of an Application. US Department of Health and Human Services, Public Health Service, Food and Drug Administration. February 1987

Deviations:

yes

Remarks:

(minor and transient deviations of relative humidity, food consumption recorded in weeks 27 and 29 instead of every 4 weeks, no food consumption recorded in week 30: not considered to compromise the validity of the study)

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Japanese guideline; Notification No. 88 of the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, 10th August 1993.

Deviations:

yes

Remarks:

(minor and transient deviations of relative humidity, food consumption recorded in weeks 27 and 29 instead of every 4 weeks, no food consumption recorded in week 30: not considered to compromise the validity of the study)

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

422-940-4

EC Name:

-

Cas Number:

155633-54-8

Molecular formula:

C24H39N3O3Si3

IUPAC Name:

2-(2H-1,2,3-benzotriazol-2-yl)-4-methyl-6-[2-methyl-3-(2,2,4,6,6-pentamethyl-3,5-dioxa-2,4,6-trisilaheptan-4-yl)propyl]phenol

Test material form:

other: solid

Details on test material:

- Name of test material (as cited in study report): G4375
- Physical state: whitish solid
- Analytical purity: > 98.5%
- Lot/batch No.: DEF/C 95004/B
- Date of receipt: 15 January 1998
- Expiration date of the lot/batch: 20 November 2001
- Stability under test conditions: the chemical purity determined before the start of the treatment period and in week 13 were higher than 98.5% and confirmed the stability of the test substance.
- Storage condition of test material: At room temperature and protected from light.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Wistar rats of the Ico: WI (TOPS AF/Han) strain from Charles River (Iffa Credo, l'ArbresIe, France)
- Age at study initiation: approximately 6 weeks old
- Weight at study initiation: mean 158 g (139-171 g) for the males and mean 143 g (129-155 g) for the females
- Fasting period before study: no
- Housing: The animals were housed in suspended wire-mesh cages (43,0 x 21.5 x 18.0 cm) and each cage contained two rats of the same sex and group.
A metallic tray, containing autoclaved sawdust (SÎCSA, Alfortvilie, France), was placed under
each cage.
- Diet (e.g. ad libitum): A04 C pelleted maintenance diet, batch Nos. 71203, 80128, 80327, 80507, 80609 and 80729 (UAR, Villemoisson-sur-Orge, France), ad libitum.
- Water (e.g. ad libitum): tap water, filtered using a 0.22 micron filter, ad libitum.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ±2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately l2 cycles/hour of filtered,non-recycled air.
- Photoperiod (hrs dark / hrs light): 12h dark/ 12h light

IN-LIFE DATES: From: 7 April 1998 To: 12 November 1998

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 4% aqueous methycellulose with 1 % Tween 80

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test substance was administered as a suspension in the vehicle. The test substance was ground to fine powder using a mortar and pestle. suspended in the vehicle in order to achieve the concentrations of 20, 60 and 200 (until day 11) and 12.5, 37.5 and 125 mg/ml (from day 12 until the end of treatment) and then homogenized using a magnetic stirrer. The test substance formulations were made to allow treatment up to a maximum of 9 days and were stored at +4 °C and protected from light prior to use. Each day they were delivered protected from light to the animal room.

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 12.5, 20 and 200 mg/mL
- Amount of vehicle (if gavage): 5 ml/kg bw/day was used from day 1 to day 11. Then due to the texture of formulations and following complementary chemical analyses, a constant dosage-volume of 8 ml/kg bw/day was used until the end of the study.
- Lot/batch no. (if required):
. methylcellulose (Methocel® MC, réf. 64605; 10-25 mPAS), batch Nos. 366101/1 34597 and 366101/1 61 Î98, supplied by Fluka (St Quentin-Fallavier, France),
. Tween 80, batch Nos. 37H01641 and 44H0121 supplied by Sigma (St Quentin-Fallavier, France),
. purified water, obtained by reverse osmosis using a Milli-Ro apparatus (Millipore S.A., Saint-Quentin en Yvelines, France).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of a sample taken from each suspension (including the control) prepared for use in weeks 1, 3, 4, 13 and 26 was determined.
The results of the analyses demonstrated a good homogeneity of each suspension analysed before and during the study (concentration range: 12,5 mg/ml to 200 mg/ml). Furthermore, there was a good correspondence between the nominal and the measured concentrations of the test material in the vehicle.
Throughout the study, a satisfactory agreement was observed between the nominal and measured concentrations of the test material in the suspensions administered since the deviations from nominal concentrations were in an acceptable range of ±7%.

Duration of treatment / exposure:

13 weeks (92 days for satellite 2 animals) or 26 weeks (182, 183 or 184 days for principal, satellite 1 and 3 animals).

Frequency of treatment:

once a day seven days a week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Principal group: 12 animals/sex/dose
Satellite group 1: 8 animals/sex/dose
Satellite group2: 6 animals/sex/dose
Satellite group 3: 6 animals/sex/dose (only dosed at 0 and 1000 mg/kg bw/day)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): allocated, by sex to the groups, according to a computerized procedure.
- Rationale for selecting satellite groups: no data
- Post-exposure recovery period in satellite group 3: 4-weeks

Positive control:

Not applicable

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
Time schedule:
- Mortality and morbidity: at least twice a day (during treatment period) or at least once a day (during treatment-free period).
- Clinical signs: once daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: once before allocation of the animals into groups, on the first day of treatment and then once a week.

FOOD CONSUMPTION (principal, satellite 2 and 3 animals):
- Time schedule: once a week during the first 13 weeks, and then once every four weeks until the end of the study and then in week 27 and 29 (treatment-free period).
- Food intake per animal and per day was calculated.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

FOOD EFFICIENCY (principal, satellite 2 and 3 animals):
- Body weight gain (in g/animal/week) / food consumption (in g/animal/week) X 100 calculated : Yes, calculated on a weekly basis for each sex and each group, during the maximal growth period (i.e. the first 13 weeks of the treatment period) using body weight and food consumption means

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: Yes (principal and satellite 3 animals)
- Time schedule for examinations: before the beginning of the treatment period and in weeks 12 and 25.
- Dose groups that were examined: control and high-dose groups

HAEMATOLOGY: Yes (principal and satellite 2 animals)
- Time schedule for collection of blood: Blood samples were taken (before the daily treatment) from the orbital sinus of the animals under isoflurane anaesthesia and collected into tubes containing the appropriate anticoagulant. Blood samples were then taken for principal animals during weeks 6, 13 and 26 and for satellite 2 animals during week 12. In the absence of relevant abnormalities in haematology parameters at the end of the treatment period, no parameters were determined at the end of the treatment-free period in satellite 3 animals.
- Anaesthetic used for blood collection: Yes ( isoflurane)
- Animals fasted: Yes, the animals were deprived of food and placed in metabolism cages for an overnight period of at least 14 hours.
- How many animals: principal (12 animals/sex/dose), satellite 2 (6 animals/sex/dose) animals
- Parameters checked: Erythrocytes (RBC), Haemoglobin (HB), Mean Cell Volume (MCV), Packed Cell Volume (PCV), Mean Cell Haemoglobin Concentration (MCHC), Mean Cell Haemoglobin (MCH), Thrombocytes (PLAT), Leucocytes (WBC), Differential White Cell count with cell morphology (neutrophils (N), eosinophils (E), basophils(B), lymphocytes (L), monocytes (M)), Reticulocytes (RETIC), Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), Fibrinogen (FIB)

CLINICAL CHEMISTRY: Yes (principal, satellite 2 and 3 animals)
- Time schedule for collection of blood: Blood samples were taken (before the daily treatment) from the orbital sinus of the animals under isoflurane anaesthesia and collected into tubes containing the appropriate anticoagulant. Blood samples were then taken for principal animals during weeks 6, 13 and 26 and for satellite 2 animals during week 12. In addition, glucose levels were determined at the end of the treatment-free period in satellite 3 animals.
- Animals fasted: Yes, the animals were deprived of food and placed in metabolism cages for an overnight period of at least 14 hours.
- How many animals: principal (12 animals/sex/dose), satellite 2 (6 animals/sex/dose) and satellite 3 animals (6animals/sex/dose)
- Parameters checked: Sodium (Na+), Potassium (K+), Chloride (Cl-), Calcium (Ca++), Inorganic phosphorus (I.PHOS), Glucose (GLUC), Urea (UREA), Creatinine (CREAT), Total Bilirubin (TOT.BIL), Total Proteins (PROT), Albumin (ALB), Albumin/globulin ratio (A/G) Cholesterol (CHOL), Triglycerides (TRIG), Alkaline phosphatase (ALP), Aspartate aminotransferase (ASAT), Alanine aminotransferase (ALAT), Gamma-glutamyl transferase (GGT)

URINALYSIS: Yes (principal and satellite 2 animals)
- Time schedule for collection of urine: Urine samples were taken for principal animals during weeks 6, 13 and 26 and for satellite 2 animals during week 12. In absence of relevant qualitative and quantitative changes at the end of the treatment period, no parameters were determined at the end of the treatment-free period in satellite 3 animals.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes, the animals were deprived of food and placed in metabolism cages for an overnight period of at least 14 hours.
- Parameters checked: Volume (VOLUME), pH(PH), Specific gravity (SP.GRAV), Proteins (PROT), Glucose (GLUC), Ketones (CETO), Bilirubin (BILI), Nitrites (NITR), Blood (BLOOD), Urobilinogen (UROB), Cytology of sediment (leucocytes (WBC), erythrocytes (RBC), cylinders (CYLIN), magnesium ammonium phosphate crystals (AMM.PH), calcium phosphate crystals (CAL.PH), calcium oxalate crystals (CAL.OX.), cells (CELLS)), Appearance (APP), Color (COLOR)

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY (principal, satellite 2 and 3): Yes
On completion of the treatment or treatment-free periods, after at least 14 hours fasting, the designated animals were weighted and killed by carbon dioxide asphyxiation and exsanguination. Selected tissues and macroscopic lesions were retained.
A complete macroscopic post-mortem examination was performed on all animals. This included physical examination of the external surfaces, all orifices, the cranial cavity, the external surface of the brain and spinal cord, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues.

ORGAN WEIGHTS (principal, satellite 2 and 3): The organs specified in the table 7.5.1/2 were weighed. Paired organs were weighed separately (except for thyroids and parathyroids and seminal vesicles).

HISTOPATHOLOGY (principal, satellite 2 and 3): Yes, Samples of tissues and organs specified in the table 7.5.1/2 were collected from all animals at necropsy and were preserved in 10% buffered formalin, except for the eyes with Harderian glands and optic nerve which were fixed in Davidson's fixative and the testes and epididymes which were preserved in Bouin's fluid. All tissues required for microscopic examination were embedded in paraffinwax, sectioned at approximately four microns in thickness and stained with hematoxylin-eosin. A microscopic examination was performed on:
- all tissues listed in the table 7.5.1/2 for animals of the control and high-dose groups killed at the end of the treatment periods and for all animals that died during the study
- all macroscopic lesions for the animals of the low- and intermediate-dose groups killed on completion of the treatment periods.

Other examinations:

- PLASMA LEVELS OF THE TEST SUBSTANCE (satellite 1 animals):
Blood sampling was performed in weeks 4. 13 and 26 as follows;
. on four animals of each sex and group; 30 minutes after dosing (tmax),
. on the four remaining animals of each sex and group: 24 hours after dosing.
Blood (at least 2 ml) was taken into a tube containing lithium heparinate from the orbital sinus of the animal under isoflurane anaesthesia.

- BONE MARROW: Bone marrow smears were prepared from the femoral bone or all animals killed on completion of the 13 or 26-week treatment period (satellite 2 and principal animals, respectively). As no abnormalities were observed in the haemogram, the bone marrow differentia! cell count was not determined.

Statistics:

A sequence was used for the statistical analysis of body weight, food consumption, haematology, blood biochemistry, urinalysis and organ weight data: Test for Normality of the distribution of data: Kolmogorov-Lilliefors' test followed by Bartlett'stest or a Fisher's test for a normal distribution. Dunn's test, Student's test, Dunnett's test or Mann-Whitney's test are then performed based on the homogeneity of variance between groups.

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

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No death related to treatment with the test substance occurred during the first 13 weeks of treatment.
Since the incidence of mortality was low (two females in the control group and one male and one female in the high-dose group) and the histopathological examination did not pointed out any evidence of toxic manifestations, the mortality occurring during the treatment period was considered to be without relationship to treatment with the test substance.
No clinical signs related to the test substance were noted during the treatment period. The only clinical signs observed (including areas of hair loss, cutaneous lesions or scabs and in a few rare cases, signs of poor condition) were not dose-related and/or seen with a low incidence. Consequently, they were considered without relationship to treatment with the test substance.

BODY WEIGHT AND WEIGHT GAIN
The only statistically significant differences from controls in mean body weight during the treatment period were slight (not exceeding 7%), transient (only noted for females in weeks 2, 3, 4 and 5). In addition, the mean overall body weight gain was considered to be similar between control and treated groups. Since the differences were not dose-related and did not exceed 8%. Consequently, they were considered to be without relationship to treatment with the test substance. During the treatment-free period, there were no notable differences in body weight between control and treated animals.

FOOD CONSUMPTION AND COMPOUND INTAKE
The mean food consumption during the treatment period was considered to be similar in control and treated animals. The only statistically significant differences from controls were slight and not dose-related. Consequently, they were considered to be without relationship to treatment with the test substance.

FOOD EFFICIENCY
The efficiency of food utilization was considered to be similar between control and treated animals.

OPHTHALMOSCOPIC EXAMINATION
No abnormality related to treatment with the test substance was observed in weeks 12 and 25.
The only findings observed were:
- variation of corneal thickness seen with a similar incidence in control and treated animals,
- dry keratitis associated with exophthalmia seen in week 25 for one control male,
- corneal opacity noted in week 25 for another control male,
- opacification of the lens in week 25 for one male given 1000 mg/kg bw/day.
This latter lesion was considered to be without relationship to treatment with me test substance since it was noted in a single animal and can be seen spontaneously in the rats of this age and strain.

HAEMATOLOGY
In weeks 6, 12/13 and 26, no changes attributed to the treatment with the test substance were noted. The few differences from controls (namely in erythrocyte count, mean cell hemoglobin, activated partial thromboplastin time and lymphocyte count) were slight, not dose-related and/or all the individual values were within the range of historical background data. Consequently, they were considered to be without relationship to treatment with the test substance.

CLINICAL CHEMISTRY
In weeks 6 and 12/13, no changes attributed to the treatment with the test substance were noted. the few statistically significant differences from controls (including electrolyte and cholesterol levels) were slight, not dose-related, without similar trend in weeks 6 and 12/13, and/or all the individual values were within the range of historical background data. Consequently, they were considered to be without relationship to treatment with the test substance.
In week 26, statistically significant lower mean glucose level was noted in males given 1000 mg/kg bw/day (-20% when compared to controls) and in females given 300 and 1000 mg/kg bw/day (-20% and -26%, respectively, when compared to controls). In week 13, no relevant differences in glucose levels were noted in control and treated animals. In addition, the mean glucose levels are similar in control and treated animals at the end of the reversibility period (week 30). Consequently, and without corresponding histopathological findings, the differences in glucose levels noted in week 26 were considered to be toxicologically insignificant. The other few differences from controls in weeks 13 and 26 (including electrolyte and urea levels) were slight, not dose-related, and/or al! the individual values were within the range of historical background data. Consequently, they were considered to be of no toxicological importance.

URINALYSIS
In weeks 6, 12/13 and 26, no test substance-related quantitative or qualitative changes were noted. The few statistically significant differences from controls, namely in volume and specific gravity were slight and not dose-related. Consequently, they were considered to be without relationship to treatment with the test substance.

ORGAN WEIGHTS
As the differences were not dose-related and/or lacked similar trend in both sexes and in times of sacrifice, and without corresponding microscopic findings, they were considered to be of no toxicological importance.

GROSS PATHOLOGY
After 13 weeks of treatment, all findings were those which are commonly seen in the untreated laboratory rat of this strain and age, and their incidence was considered to be of no toxicological importance.
After 26 weeks of treatment, a greyish mass in the subcutaneous tissue was seen in one female given 1000 mg/kg bw/day; at microscopic examination, a mammary ductular carcinoma was found. All other findings seen after 26 weeks of treatment and the findings noted after the treatment-free period were those which are commonly seen in the untreated laboratory rat of this strain and age and their incidence was considered to be of no toxicological importance.

HISTOPATHOLOGY: NON-NEOPLASTIC
After 13 and 26 weeks of treatment, no treatment-related findings were detected.

HISTOPATHOLOGY: NEOPLASTIC
A mammary ductular carcinoma was seen in one female given 1000 mg/kg bw/day killed after 26 weeks of treatment. This finding can be found spontaneously in the untreated rat of this strain and age and consequently the reported incidence was considered to be unrelated to treatment with the test substance.
All other findings were those which are commonly seen in the laboratory rat of this strain and age and were considered to be of no toxicological importance.

HISTORICAL CONTROL DATA: no data available

OTHER FINDINGS
Systemic exposure to the test substance was observed in all animals at all test treated dose levels in weeks 4, 13 and 26, at both 30 minutes and 24 hours after treatment. For the control animals, the plasma levels of G4375 were below the limit of quantification (BLQ: < 50 ng/ml). The absorption of the test substance (as measured by C30min and C24h) at all dose-levels and for both sexes showed a low inter-animal variability. The mean plasma levels were generally slightly higher 24 hours after dosing than 30 minutes after treatment at all dose-levels, indicating a slow and sustained absorption (or reabsorption) of the test substance. In addition, at all time-points, the levels were moderately to markedly higher in females than in males, except in week 4 at 100 mg/kg bw/day where the plasma levels were considered to be similar, suggesting a gender difference in the pharmacokinetic of the test substance. Specifically, with respect to both C30min and C24h, the values increased linearly (but not proportionally) with the dose-Ievel and the extent of absorption of the test substance remained relatively constant:
- between week 4 and week 26 for males given 100 mg/kg bw/day,
- between week 4 and week 13 for females given 100 mg/kg bw/day and for males given 300 mg/kg bw/day.
However, the plasma levels seen in weeks 13 and 26 were greater than those of week 4 (time effect) for females given 300 mg/kg bw/day and for all animals given 1000 mg/kg bw/day, suggesting a dose- and sex-dependent accumulation of the test substance.

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The only treatment-related changes observed were considered to be of no toxicological relevance.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:

Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of Silatrizole (encoded "G4375") was considered to be 1000 mg/kg bw/day for male and female rats.

Executive summary:

In a repeated dose oral toxicity study, Silatrizole (encoded "G4375") was administered by gavage as a suspension in 4% aqueous methycellulose with 1 % Tween 80 to Wistar rats (12/sex/dose) at daily doses of 0, 100, 300 and 1000 mg/kg bw/day for approximately 13 weeks or 26 weeks. The animals of this principal group were used to investigate ophthalmology before treatment period and in weeks 12 and 25 and to perform laboratory investigations in weeks 6, 13 and 26. Additional 6 rats per group and sex were used to obtain toxicokinetics data at 4, 13 and 26 weeks of treatment (group satellite 1). Additional 6 rats per group and sex were used to obtain laboratory investigations at 12 weeks of treatment (group satellite 2). Further 6 rats per group and sex at 0 and 1000 mg/kg bw (group satellite 3) were treated for at least 26 weeks and then allowed a 4 weeks treatment-free recovery period.

 

Plasma levels of the test substance showed that systemic exposure to the test substance was seen at all test treated dose-levels. The plasma levels increased linearly (but not proportionally) with the dose. The absorption was greater in females than in males, and generally greater in weeks 13 and 26 than in week 4, indicating both time and gender effects. There was no death related to the treatment with the test substance. There were no clinical signs related to the treatment with the test substance. The body weight gain was similar in control and treated animals. The food consumption and the efficiency of food utilization were unaffected by treatment with the test substance. There was no abnormality in the ophthalmology investigations due to treatment with the test substance. There were no changes in hematology attributed to the treatment with the test substance. Slightly lower glucose levels were noted in females given 300 mg/kg/day and in males and females given 1000 mg/kg/day. Since there was no corresponding histopathological finding, these effects were considered to be toxicologically insignificant. There were considered to be of no toxicological significance. There were no test substance-related quantitative or qualitative changes of urine. There were no differences in organ weights attributed to the treatment with the test substance. No findings related to treatment with the test substance were found with macroscopic and microscopic examinations.

 

Based upon these results, the No Observed Adverse Effect Level (NOAEL) for Silatrizole in this study is considered to be 1000 mg/kg bw/day.