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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28 Feb - 29 May 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the appropriate OECD test guideline and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
(1998)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
The Department of Health of the Government of the United Kingdom
Limit test:
no

Test material

Constituent 1
Reference substance name:
Didocosyl sebacate
EC Number:
255-730-4
EC Name:
Didocosyl sebacate
Cas Number:
42233-75-0
Molecular formula:
Not applicable (UVCB substance)
IUPAC Name:
Decanedioic acid, diesters with Fatty alcohols C20-22 (even numbered)
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): only trade name given
- Physical state: white solid
- Storage condition of test material: room temperature in the dark
- Expiration date of the lot/batch: 30 Nov 2014

Test animals

Species:
rat
Strain:
other: Wistar Han(TM):RccHan(TM)WIST
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Oxon, UK
- Age at study initiation: 6 – 8 weeks
- Weight at study initiation: 153 – 210 g (males), 135 – 168 g (females)
- Housing: animals were housed in groups of three or four by sex in solid floor propylene cages with stainless steel mesh lids and softwood flake bedding with environmental enrichment in the form of wooden chew blocks and cardboard fun tunnels (Datesand Ltd., Cheshire, UK)
- Diet: pelleted Rodent 2014C Teklad Global Certified Diet (Harlan Laboratories U.K. Ltd., Oxon, UK), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 – 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 28 Feb 2013 To: 29 May 2013

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The analytical validation of the test item was previously determined using an earlier batch of ST1797KS in Harlan Study No. 41203177. In this earlier study, verification work carried out by Harlan Laboratories Ltd., Shardlow, UK Analytical Services established that due to the chemical characteristics of the test item a chromatographic method of analysis could not be developed due to the test items limited solubility in typical HPLC/GC solvents (for this reason there was no alternative but to use the gravimetric approach which involves weighing a set amount of test item into arachis oil (vehicle) to make the required formulation concentration and then analyzing by taking an aliquot onto a glass sintered crucible and then rinsing with a solvent ie acetone to remove the oil. The insoluble test item is then retained on the crucible and weighed to confirm the concentration present. For continuity with the earlier study (41203177) the test formulations in this study (41206796) were prepared daily and analyzed at regular intervals during the study for concentration of ST1797KS.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Due to the chemical characteristics of the test item and its limited solubility in organic and aqueous media, arachis oil was chosen as the vehicle.
- Concentration in vehicle: 7.5, 25 and 250 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Due to the chemical characteristics of the test item and its limited solubility in organic and aqueous media, a substance specific quantitative method of analysis could not be developed. The concentration of the test item in the formulations was determined using a gravimetric technique. The test item formulations were weighed into tared glass sintered crucibles and then rinsed with acetone to leave a test item residue. The samples were then dried in an oven at approximately 105 °C before allowing to cool over silica gel in a desiccator and re-weighed. The formulations during the study were found to comprise test item in the range of 89% to 102% and, thus, the required content limit of ± 11% with reference to the nominal content was met. In conclusion, the results indicate the accurate use of the test item and Arachis Oil as vehicle during this study. The formulations were found to be homogeneously prepared.
Duration of treatment / exposure:
13 weeks and 4 weeks post-exposure observation period (satellite control and test group)
Frequency of treatment:
once daily, 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 100, 1000 mg/kg bw/day
Basis:
other: nominal dose
No. of animals per sex per dose:
10 (main study)
10 (satellite control and high-dose group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected following review of the results from a previous toxicity study (Harlan Laboratories Ltd., Project No: 41203177). The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item, and the results of the study are believed to be of value in predicting the likely toxicity of the test item to man.
- Post-exposure recovery period in satellite groups: 4 weeks
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were examined for overt signs of toxicity, ill-health, mortality or behavioural change immediately before dosing, up to thirty minutes post dosing one and five hours after dosing during the working week. Animals were observed immediately before and after dosing and one hour after dosing at weekends and public holidays. During the treatment-free period, animals were observed daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Prior to the start of treatment and at weekly intervals thereafter, all non-recovery animals were observed for signs of functional/behavioural toxicity. During Week 12 functional performances tests were also performed on all animals together with an assessment of sensory reactivity to different stimuli.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on Day 1 (prior to dosing) and at weekly intervals thereafter. Body weights were also recorded at terminal kill.

FOOD CONSUMPTION: YES
- Food consumption per housing group determined weekly and mean daily diet consumption calculated as g food/animal/day for each sex: Yes

WATER CONSUMPTION: YES
- Time schedule for examinations: Water intake was observed daily, for each cage group, by visual inspection of the water bottles for any overt changes.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: The eyes of all non-recovery control and test group animals were examined pre-treatment and for all non-recovery control and high dose animals before termination of treatment (during Week 12). Examinations included observation of the anterior structures of the eye, pupillary and corneal blink reflex. Following pupil dilation with 0.5% Tropicamide solution detailed examination of the internal structure of the eye using a direct ophthalmoscope was performed.
- Dose groups that were examined: all non-recovery and test group animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Hematological investigations were performed on all non-recovery animals from each test and control group at the end of the study (Day 90) and on all surviving recovery group animals at the end of the treatment-free period (Day 118). Blood samples were obtained from the lateral tail vein.
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: all animals
- Parameters examined: hemoglobin (Hb), erythrocyte count (RBC), hematocrit (Hct), erythrocyte indices (mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC)), total leukocyte count (WBC), differential leukocyte count (neutrophils (Neut), lymphocytes (Lymph), monocytes (Mono), eosinophils (Eos), basophils (Bas)), platelet count (PLT), reticulocyte count (Retic). Prothrombin time (CT) was assessed by “Innovin” and Activated partial thromboplastin time (APTT) was assessed by “Actin FS” using samples collected into sodium citrate solution (0.11 mol/L).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood chemical investigations were performed on all non-recovery animals from each test and control group at the end of the study (Day 90) and on all surviving recovery group animals at the end of the treatment-free period (Day 118). Blood samples were obtained from the lateral tail vein.
- Animals fasted: No
- How many animals: all animals
- Parameters examined: urea, glucose, total protein (Tot. Prot.), albumin, albumin/globulin (A/G) ratio (by calculation), sodium (Na+), potassium (K+), chloride (Cl-), calcium (Ca++), inorganic phosphorus (P), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase (AP), creatinine (Creat), total cholesterol (Chol), total bilirubin (bili), bile acids.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Prior to the start of treatment and at weekly intervals thereafter, all non-recovery animals were observed for signs of functional/behavioural toxicity. During Week 12 functional performances tests were also performed on all animals together with an assessment of sensory reactivity to different stimuli.
- Dose groups that were examined: all non-recovery animals
- Battery of functions tested: sensory activity / forelimb/hindlimb grip strength / motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- On completion of the dosing period or in the case of recovery group animals, at the end of the treatment-free period all surviving animals were killed by intravenous overdose of sodium pentobarbitone followed by exsanguination. All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.

HISTOPATHOLOGY: Yes
- Samples of the following tissues were removed from all animals and preserved in buffered 10% formalin, except where stated: adrenals, aorta (thoracic), bone/bone marrow (femur including stifle joint/sternum), brain (including cerebrum, cerebellum and pons), caecum, colon, duodenum, epididymides, eyes, gross lesions, heart, ileum (including Peyer´s patches), jejunum, kidneys, liver, lungs (with bronchi), lymph nodes (mandibular and mesenteric), mammary tissue, muscle (skeletal), oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary glands (submaxillary), sciatic nerve, seminal vesicles, skin (hind limb), spinal cord (cervical, mid thoracic and lumbar), spleen, stomach, testes, thymus, thyroid/parathyroid, tongue, trachea, urinary bladder, uterus, vagina. All tissues were dispatched to the histology processing Test Site (Propath UK Ltd., Willow Court, Netherwood Road, Rotherwas, Hereford, HR2 6JU) for processing. All tissues from non-recovery control and 1000 mg/kg bw/day dose group animals were prepared as paraffin blocks, sectioned at a nominal thickness of 5 µm and stained with Hematoxylin and Eosin for subsequent microscopic examination. Any macroscopically observed lesions were also processed.
Other examinations:
ORGAN WEIGHT:
The following organs, removed from animals that were killed either at the end of the dosing period or at the end of the treatment-free period, were dissected free from fat and weighed before fixation: adrenals, brain, epididymides, heart, kidneys, liver, ovaries, spleen, testes, thymus, uterus.
Statistics:
Where considered appropriate, quantitative data was subjected to statistical analysis to detect the significance of intergroup differences from control; statistical significance was achieved at a level of p<0.05. Statistical analysis was performed on the following parameters: Grip Strength, Motor Activity, Body Weight Change, Haematology, Blood Chemistry, Urinalysis (Volume and Specific Gravity), Absolute Organ Weights, Body Weight-Relative Organ Weights. Data were analyzed using the decision tree from the ProvantisTM Tables and Statistics Module as detailed as follows: Where appropriate, data transformations were performed using the most suitable method. The homogeneity of variance from mean values was analyzed using Bartlett’s test. Intergroup variance were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covarities. Any transformed data were analyzed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for nonparametric data. If no dose response was found but the data shows non-homogeneity of means, the data were analyzed by a stepwise Dunnett’s (parametric) or Steel (non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).

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:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
One male from the 1000 mg/kg bw/day treatment group was terminated on humane grounds on Study Day 10 having been observed at this time to display exophthalmia, abnormal posture and loss of righting reflex. However, no abnormalities were detected at necropsy and while the aetiology is uncertain it is reasonable given the isolated nature of this finding to consider that these findings were not related to test item toxicity. There were no further unscheduled deaths in this study. Clinical observations were confined to one incident of post dose increased salivation that was detected in one 1000 mg/kg bw/day male and one female on Study Day 86 or 85 respectively. The isolated nature of this finding would suggest it to be associated with the gavage procedure and not test item toxicity. One control male was noted to have damage to one digit on the left forepaw between Days 19 and 38. This did not appear to cause the animal any distress and clearly was not related to treatment.

BODY WEIGHT AND WEIGHT GAIN
There were no adverse treatment-related changes detected in body weight development between test animals of either sex in comparison with controls throughout the study. Incidental findings involved a slight reduction (p<0.05) in weight gain in all male test groups during Week 7 and in all female test groups at Week 3 and in 30 mg/kg bw/day females (p<0.01) at Week 11. However, these were isolated changes lacking a dose dependent trend.

FOOD CONSUMPTION AND COMPOUND INTAKE
No treatment-related adverse effect on food consumption or food efficiency (the ratio of bodyweight gain to dietary intake) was detected in test animals of either sex in comparison with controls throughout the study.

WATER CONSUMPTION AND COMPOUND INTAKE
Daily visual inspection of water bottles did not reveal any overt intergroup differences in water intake for treated animals when compared to controls.

OPHTHALMOSCOPIC EXAMINATION
No treatment-related ocular abnormalities were detected in the test or control animals examined.

HAEMATOLOGY
There were no convincing treatment-related changes identified in the haematological parameters measured. Non-recovery males treated with 100 and 1000 mg/kg bw/day showed a slight elevation (p<0.05) for hemoglobin when compared with controls. Males treated at 1000 mg/kg bw/day also showed an increase (p<0.01) in mean corpuscular hemoglobin concentration. However, these findings were unsupported by other evidence of an effect on haemopoiesis and as such were considered spurious. Males from the non-recovery 100 and 1000 mg/kg bw/day test groups showed a statistically significant increase (p<0.01) in prothrombin time when compared with the controls. The individual values for all but one male from each test group were within the anticipated historical ranges. Furthermore, in the absence of any supporting evidence of impaired liver function this isolated finding was considered attributable to biological variability and not a result of exposure to the test item. A small elevation (p<0.05) in total leucocyte count resulting from a minor increase in circulating neutrophils was apparent in non-recovery males treated at 1000 mg/kg bw/day. This isolated change in the absence of evidence to the contrary was considered to have arisen fortuitously. Females from all the non-recovery test groups were observed to have slight elevations (p<0.05) for erythrocyte and hematocrit compared with controls. However, the majority of individual values remained similar to those of the concurrent control and in the absence of any histopathological correlates or other evidence to suggest an anaemia, these increases were considered to have arisen fortuitously. At the end of the treatment free period recovery 1000 mg/kg bw/day males showed an increase (p<0.05) in platelet counts in comparison with the concurrent control. However, as there were no other indications of an inhibitory effect on one or more of the intrinsic coagulation factors and as a similar finding was absent in non-recovery 1000 mg/kg bw/day males this finding was considered fortuitous. A slight but statistically significant reduction for total leucocyte (p<0.05) and lymphocyte (p<0.01) counts was identified for recovery 1000 mg/kg bw/day females in comparison with the recovery control females. While the aetiology is uncertain there was no supporting evidence to suggest this finding was associated with treatment.

CLINICAL CHEMISTRY
There were no treatment-related adverse effects identified for the biochemistry profile. A statistically significant reduction (p<0.05) for plasma calcium levels was detected in males from the 1000 mg/kg bw/day non-recovery test group in comparison with controls. However, as all but one value was within the normal ranges for rats of this strain and age used and there was no other evidence of renal impairment this finding was considered spurious. Females from all the non-recovery test groups showed a reduction (p<0.05 or<0.01) in plasma glucose levels when compared with controls. However, there was no dose dependent trend or any other supporting evidence to suggest impaired liver function; it is therefore reasonable to assume this finding arose fortuitously. Females treated at 100 mg/kg bw/day showed a small but statistically significant increase for plasma potassium concentration compared to controls. However, there was no convincing dose related trend and on this basis this isolated finding was considered to have arisen fortuitously. Recovery 1000 mg/kg bw/day males showed an increase (p<0.05) for plasma chloride in comparison with controls. A similar trend for plasma cholesterol was observed in 1000 mg/kg bw/day females together with reductions for inorganic phosphate and alanine aminotransferase in comparison with controls. There was no supporting verification to suggest a treatment-relationship and on this basis these isolated findings were considered not to be a result of test item toxicity.

NEUROBEHAVIOUR
There were no treatment-related changes in the behavioural assessments observed. Non-recovery 1000 mg/kg bw/day males showed a statistically significant increase (p<0.05) in one of three hind limb grip strength tests in comparison with the concurrent control. It is reasonable to assume this was attributable to biological variability given the isolated nature of this change and absence of similar effects in any of the forelimb or remaining hind limb tests in these animals. Males treated at 100 mg/kg bw/day showed a reduction (p<0.01) in one of three hind limb tests with these and males from the 30 mg/kg bw/day test group both exhibiting an increase (p<0.01) in overall activity. In the absence of a dose dependent trend these findings were considered fortuitous and not to be associated with neurotoxicity. All inter and intra group differences in sensory scores were considered to be a result of normal variation for rats of the species and strain used and therefore, were considered to be of no toxicological significance.

ORGAN WEIGHTS
There were no treatment-related changes in the organ weights measured. Incidental findings were confined to recovery 1000 mg/kg bw/day males that showed a slight but statistically significant reduction (p<0.05) in absolute and relative (to terminal bodyweight) liver weight. No such organ weight changes were detected among non-recovery 1000 mg/kg bw/day males following ninety days of treatment and there were no histopathological correlates; accordingly this intergroup difference was considered a result of natural biological variability and no test item toxicity.

GROSS PATHOLOGY
No treatment-related macroscopic abnormalities were observed in any test or control animal. Incidental findings included one control male observed to have small epididymides and small and flaccid testes while the left horn of the uterus of one 100 mg/kg bw/day female was noted to be enlarged and fluid filled and appeared to be detached from the surrounding tissues (albeit this latter finding may have resulted from damage during dissection). Such abnormalities represent commonly detected, low incidence findings of a congenital or incidental nature for laboratory rats of the strain and age used in the study, and were therefore considered not to be associated with treatment. Two 100 mg/kg bw/day females and two 1000 mg/kg bw/day females were observed to have reddened lungs at necropsy. Isolated changes of this nature may be considered associated with the exsanguination procedure.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related histopathological changes were detected. All findings recorded were considered to be within the range of normal background lesions which may be recorded in animals of this strain and age.

Effect levels

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no relevant treatment related effects were observed

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 Table 1: Group Mean Haematological Values (Males, Non-recovery)

Dose Group [mg/kg bw/day]

 

Hb [g/dL]

MCHC [g/dL]

WBC [10^9/L]

CT [seconds]

 

0

Mean

S.D.

N

16.88

0.60

10

34.41

0.55

10

6.54

1.35

10

9.70

0.43

10

 

30

Mean

S.D.

N

17.13

0.55

10

34.50

0.35

10

7.05

1.03

10

10.05

0.36

10

 

100

Mean

S.D.

N

17.56*

0.49

10

34.78

0.81

10

7.16

1.36

10

10.36**

0.61

10

 

1000

Mean

S.D.

N

17.34*

0.49

10

35.30**

0.75

10

7.78*

0.97

10

10.43**

0.74

10

* p<0.05

** p<0.01

S.D.: standard deviation

N: number of animals examined

Table 2: Group Mean Haematological Values (Females, Non-recovery)

Dose Group [mg/kg bw/day]

 

RBC [10^12/L]

Hct [%]

 

0

Mean

S.D.

N

7.428

1.272

10

40.46

7.18

10

 

30

Mean

S.D.

N

8.289

0.523

10

45.41*

2.83

10

 

100

Mean

S.D.

N

8.436*

0.195

10

45.60*

0.94

10

 

1000

Mean

S.D.

N

8.268*

0.585

10

45.62*

2.65

10

* p<0.05

** p<0.01

S.D.: standard deviation

N: number of animals examined

Table 3: Group Mean Haematological Values (Males/Females, Recovery)

Dose Group [mg/kg bw/day]

 

PLT [10^9/L]

WBC [10^9/L]

Lymph [10^9/L]

M

F

M

F

M

F

 

0

Mean

S.D.

N

552.3

115.6

10

644.1

59.7

10

7.00

1.26

10

4.24

1.08

10

5.754

0.929

10

3.519

0.911

10

 

1000

Mean

S.D.

N

640.9*

43.0

9

604.6

75.2

10

6.47

1.24

9

3.16*

0.66

10

5.179

1.087

9

2.506**

0.530

10

* p<0.05

** p<0.01

S.D.: standard deviation

N: number of animals examined

M: males

F: females

Table 4: Group Mean Blood Chemical Values (Males/Females, Non-recovery)

Dose Group [mg/kg bw/day]

 

Ca++ [mmol/L]

K+ [mmol/L]

Glucose [mg/dL]

M

F

M

F

M

F

 

0

Mean

S.D.

N

2.738

0.063

10

101.6

1.3

10

4.499

0.339

10

4.268

0.221

10

169.8

14.3

10

187.7

31.6

10

 

30

Mean

S.D.

N

2.776

0.084

10

102.0

2.6

10

4.665

0.332

10

4.534

0.477

10

158.9

23.9

10

163.9*

19.4

10

 

100

Mean

S.D.

N

2.671

0.118

10

101.3

1.9

10

4.655

0.174

10

4.742*

0.332

10

165.7

24.4

10

148.8**

19.5

10

 

1000

Mean

S.D.

N

2.631*

0.146

10

102.0

1.8

10

4.421

0.471

10

4.378

0.392

10

180.0

36.7

10

154.9**

17.5

10

* p<0.05

** p<0.01

S.D.: standard deviation

N: number of animals examined

M: males

F: females

Table 5: Group Mean Blood Chemical Values (Males/Females, Recovery)

Dose Group [mg/kg bw/day]

 

Cl- [mmol/L]

P [mmol/L]

ALAT [IU/L]

Chol [mg/dL}

M

F

M

F

M

F

M

F

 

0

Mean

S.D.

N

100.4

1.3

10

102.9

2.0

10

1.84

0.45

10

1.48

0.30

10

60.6

17.9

10

78.9

22.2

10

97.1

18.9

10

79.4

8.7

10

 

1000

Mean

S.D.

N

102.3**

1.6

9

102.6

2.4

10

1.66

0.34

9

1.18*

0.19

10

84.6

60.6

9

62.9*

8.6

10

100.1

16.9

9

91.8*

13.3

10

* p<0.05

** p<0.01

S.D.: standard deviation

N: number of animals examined

M: males

F: females

Table 6: Group Mean Organ Weights With Corresponding Relative (% of Body Weight) Organ Weights (Males/Females, Recovery)

Dose [mg/kg bw/day]

 

M

F

0

1000

0

1000

 

 

 

Liver

Mean (g)

S.D.

N

12.2444

0.99570

10

11.5138*

1.04105

9

8.20709

0.71255

10

7.82322

0.62153

10

Mean (%)

S.D:

N

3.094

0.203

10

2.920*

0.169

9

3.142

0.227

10

3.128

0.245

10

* p<0.05

** p<0.01

S.D.: standard deviation

N: number of animals examined

M: males

F: females

Applicant's summary and conclusion

Conclusions:
Oral administration of the test item, ST1797KS, to rats for a period of ninety consecutive days, at dose levels of 30, 100 and 1000 mg/kg bw/day followed in selected control and 1000 mg/kg bw/day animals by a twenty-eight day treatment free period did not produce any convincing treatment-related changes and on this basis under the conditions of this study the No Observed Effect Level was considered to be greater than 1000 mg/kg bw/day.