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EC number: 271-843-1 | CAS number: 68609-93-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From September 19, 2016 to February 17, 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 9-Octadecenoic acid (Z)-, sulfonated, potassium salts
- EC Number:
- 271-843-1
- EC Name:
- 9-Octadecenoic acid (Z)-, sulfonated, potassium salts
- Cas Number:
- 68609-93-8
- Molecular formula:
- A generic formula cannot be provided for this UVCB substance. The alkyl chain length of the sulfonated fatty acids range from C12-C22, however the major alkyl chain is C18.
- IUPAC Name:
- 9-Octadecenoic acid (Z)-, sulfonated, potassium salts
- Test material form:
- solid
- Details on test material:
Purity/Composition: UVCB (100%);
Appearance: orange-brown crystalline powder with lumps.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- SPF-bred Wistar Han rats
- Details on species / strain selection:
- Rationale: Recognized by international guidelines as the recommended test system (e.g. EPA, FDA, OECD and EC).
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Test system Rat: Crl:WI(Han), (outbred, SPF-Quality).
Source: Charles River Deutschland, Sulzfeld, Germany.
Total number of animals: 40 males, 40 females (females were nulliparous and nonpregnant).
Age at start of treatment: Approximately 6 weeks.
Identification: Earmark and tattoo.
Randomization: By computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean.
Acclimatization period: At least 5 days before the start of treatment under laboratory conditions.
Health inspection: Upon receipt of the animals.
Conditions: Environmental controls for the animal room were a mean daily temperature range of 21 to 22°C, a mean daily relative humidity range of 44 to 63%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. The light/dark cycle was interrupted for study related activities.
Accommodation: Group housing of 5 animals per sex in Macrolon cages (MIV type, height 18 cm) with sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG) and paper as cage-enrichment (Enviro-dri, Wm. Lilico & Son (Wonham Mill Ltd)). During locomotor activity monitoring, animals were housed individually in a Hi-temp polycarbonate cage (Ancare corp).
Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF Spezialdiäten). During motor activity measurements, animals did not have access to food for a maximum of 1 hour and 43 minutes. Water: tap water. During motor activity measurements, animals did not have access to water for a maximum of 1 hour and 43 minutes.
Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- Method: Oral gavage, using a plastic feeding tube. Formulations were placed on a magnetic stirrer during dosing. A dose control system (DCS) was used as additional check to verify the dosing procedure according to Standard Operating Procedures.
Dose volume: 5 mL/kg body weight. Actual dose volumes were calculated weekly according to the latest body weight.
Frequency: Once daily, 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Sampling: Samples (0.5 mL) were taken using a pipette, and were weighed on an analytical balance at 4 decimals precision. During sampling, formulations were placed on a magnetic stirrer. Immediately after sampling (accuracy and homogeneity samples) or after 5 hours at room temperature under normal laboratory light conditions (stability samples), samples were stored on dry ice until receipt.
Analysis: Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 5 hours at room temperature under normal laboratory light conditions was also determined (highest and lowest concentration). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. Formulations were considered stable if the relative difference before and after storage was maximally 10%. - Duration of treatment / exposure:
- 90 d
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 males and 10 females
- Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- Mortality / Viability: At least twice daily.
Clinical signs: At least once daily from start of treatment onwards, detailed clinical observations were made in all animals at least immediately after dosing. The grade and duration of any observed signs were recorded. Signs were graded for severity and the maximum grade was predefined at 3 or 4. In the data tables, the scored grades as well as the percentage of animals affected were recorded.
Functional observations: during week 13 of treatment, functional observation tests were performed on the first 5 animals/sex/group. Tests were performed after dosing at no specific time point, but within a similar time period after dosing. The following tests were performed: hearing ability, pupillary reflex, static righting reflex, fore- and hind-limb grip strength, locomotor activity.
Body weights: weekly.
Food consumption: weekly.
Water consumption: subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
Ophthalmoscopic examination: following instillation of tropicamide solution both eyes were examined by means of an ophthalmoscope: at pretest: all animals (including spare animals), at week 13: groups 1 and 4 animals.
Blood samples were collected under anaesthesia using isoflurane between 7.00 and 10.30 a.m. at the end of the treatment. Animals were deprived of food overnight (for a maximum of 24 hours), but water was available.
Blood samples were drawn from the retro-orbital sinus and collected into tubes prepared with K3-EDTA for haematological parameters (0.5 mL), with citrate for clotting tests (0.45 mL) and Li-heparin treated tubes for clinical biochemistry parameters (0.5 mL). An additional blood sample (0.25 mL) was collected into serum tubes for determination of bile acids.
The following parameters were determined: white blood cells, differential leucocyte count neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cells, reticulocytes, red blood cell distribution width, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
Clotting Potential: prothrombin time, activated partial thromboplastin time.
Clinical Biochemistry: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total Protein, albumin, total bilirubin, urea, creatinine, glucose, cholesterol, sodium, potassium, chloride, calcium, inorganic phosphate. - Sacrifice and pathology:
- Animals surviving to the scheduled day of necropsy and all moribund animals were deeply anaesthetized using isoflurane and subsequently exsanguinated and subjected to a full post mortem examination.
The following organ weights and terminal body weight were recorded from the surviving animals on the scheduled day of necropsy: adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries, prostate, seminal vesicles including coagulating glands, spleen, testes, thymus, thyroid (including parathyroid), uterus (including cervix).
- Pathology examinations:
The numbers of corpora lutea and former implantation sites were recorded for all paired females. Samples of the following tissues and organs were collected and fixed in 10% buffered formalin for further histophatological examinations: ovaries, adrenal glands, pancreas, aorta, peyer's patches, brain (cerebellum, mid-brain, cortex), pituitary gland, caecum, preputial gland, cervix, prostate gland, clitoral gland rectum, colon, salivary glands (mandibular, sublingual), coagulation gland sciatic nerve, duodenum seminal vesicles, epididymide skeletal muscle, eyes, skin, female mammary gland area, spinal cord (cervical, midthoracic, lumbar), femur including joint, spleen, heart, sternum with bone marrow, ileum, stomach, jejunum, testes, epididymides, kidneys, thymus, lacrimal gland, exorbital, thyroid including parathyroid, larynx, tongue, liver, trachea, lung, urinary bladder lymph nodes, uterus, vagina, oesophagus, all gross lesions.
Histopathology
The following slides were examined by a pathologist:
- all tissues collected at the scheduled sacrifice from all Group 1 and 4 animals,
- all tissues from all animals of all dose groups which died spontaneously or were terminated in extremis,
- adrenal glands, pancreas, kidneys and mesenteric lymph nodes of all animals of Groups 2 and 3 (males and/or females) and spleen of all females of Groups 2 and 3, based on (possible) treatment-related changes in these organs in Group 4,
- all gross lesions.
All abnormalities were described and included in the report. An attempt was made to correlate gross observations with microscopic findings. - Statistics:
- The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- The Kruskal-Wallis nonparametric ANOVA test was applied to motor activity data to determine intergroup differences.
All tests were two-sided and in all cases p <0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In the surviving animals, diarrhoea was observed on single occasions in seven 1000 mg/kg animals towards the end of the treatment period. Swelling/gas distention of the abdomen was observed in three 1000 mg/kg and two 300 mg/kg animals, each for single short and transient bouts. Rales were also observed for single short and transient bouts in five 1000 mg/kg animals and two 100 mg/kg animals. No findings were noted during the arena observations in this study.
A dose-related increase in salivation seen after dosing among treated groups was not considered toxicologically relevant, taking into account the nature and minor severity of the effect and its time of occurrence (i.e. after dosing). This sign was considered to be a physiological response related to taste of the test substance rather than a sign of systemic toxicity.
Any other clinical signs noted during the treatment period occurred within the range of background findings. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- There were two death males treated at 1000 mg/kg.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Slight (not statistically significant) trends towards a lower body weight and body weight gain were seen in 1000 mg/kg treated animals during a large proportion of the study.
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A statistically significant increase in the incidence of focal corneal edema was observed in 100 mg/kg females at Week 13, however this finding was not considered treatment-related as it occurred in a non-dose related manner.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The following (statistically significant) changes in haematology parameters distinguished treated from control animals:
- White blood cell count was increased in 1000 mg/kg females, lymphocyte levels were reduced in 1000 mg/kg males and 1000 mg/kg females, and neutrophil levels were increased in 300 mg/kg males and 1000 mg/kg males and females (males not statistically significant).
- Red blood cell distribution width (%RDW) was increased in 1000 mg/kg females, and haemoglobin levels, mean red blood cell volume (MCV), and mean cell haemoglobin concentration (MCH) were reduced in 1000 mg/kg males and females.
Any other statistically significant changes in haematology parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The following (statistically significant) changes in clinical biochemistry parameters distinguished treated from control animals:
- Alanine aminotransferase (ALAT) levels were significantly increased in both male and female 1000 mg/kg animals, and aspartate transaminase (ASAT) levels were increased in 1000 mg/kg females.
- Total protein and albumin levels were increased in 1000 mg/kg, and 100/300/1000 mg/kg males, respectively. Total bilirubin levels were increased in 100, 300 and 1000 mg/kg males.
- Urea levels were increased in 1000 mg/kg males and females, and creatinine levels were increased in 100 and 1000 mg/kg males and 1000 mg/kg females.
- Glucose and cholesterol levels both reduced in 1000 mg/kg males and females.
- Inorganic phosphate levels were increased in 1000 mg/kg males and females. Sodium levels were increased in 100 and 300 mg/kg males and females, however these findings occurred in the absence of a dose-related trend and therefore considered not toxicologically relevant.
Any other statistically significant changes in clinical biochemistry parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Foregrip strength was reduced in 300 and 1000 mg/kg males and 1000 mg/kg females in a statistically significant manner. And a slight (not statistically significant) reduction in total movement and ambulatory behavior was observed in 1000 mg/kg females.
Further observations, hearing ability, pupillary reflex, static righting reflex and hindgrip strenght were normal in all examined animals. Motor activity was similar between treated and control males. And all groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related higher liver weights (relative to body weights) were noted in the 1000 mg/kg group females and increased kidney weights (absolute and/or relative to body weights) were noted in 1000 mg/kg group males and females. The increased kidney weight was related to the microscopic findings of tubular vacuolation with pigmented material.
Some organ weight differences were statistically significant when compared to the control group but were considered to be the result of a test substance-related effect on final body weight (including the liver weight change in males). There were no other test substance-related organ weight changes. - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related microscopic findings were noted, starting at 300 mg/kg in the kidneys and mesenteric lymph nodes of males and females, and at 1000 mg/kg in the adrenal glands of males and females, the pancreas of males, and the spleen of females.
Kidney findings included an increased incidence and severity of tubular vacuolation, with pigmented material in the cortex, which was present in males and females starting at a dose of 300 mg/kg. Tubular degeneration and an increased severity and/or incidence in tubular basophilia was observed at 1000 mg/kg.
In the mesenteric lymph node, an increased incidence and severity of macrophage foci was recorded, starting at 300 mg/kg in both sexes.
In the adrenal gland, vacuolation of the zona glomerulosa was recorded at an increased incidence and/or severity in both sexes at 1000 mg/kg.
In the pancreas, increased apoptosis of acinar cells was recorded in males treated at 1000 mg/kg. One female at 1000 mg/kg with minimal increased apoptosis was considered to be within background levels.
In the spleen, increased incidence and severity of extramedullary hematopoiesis and increased severity of pigmentation was recorded in females treated at 1000 mg/kg.
The remaining histological changes were considered to be incidental findings or within the range of background pathology encountered in rats of this age and strain. There were no test substance-related alteration in the prevalence, severity, or histological character of those incidental tissue alterations. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased macrophages in male and female mesenteric lymph nodes starting at 300 mg/kg/day, vacuolation of the zona glomerulosa of male and female adrenal glands at1000 mg/kg/day and increased apoptosis in male pancreas at 1000 mg/kg/day were also considered to be non-adverse since these findings were slight in nature.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- mortality
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Results
(A) Body weight
Body weights (gms) - Male
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
|
TREATMENT DAY 1 |
MEAN |
168 |
163 |
166 |
169 |
WEEK 1 |
ST.DEV |
8.8 |
8.8 |
8.5 |
6.4 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
217 |
210 |
210 |
216 |
WEEK 2 |
ST.DEV |
13.6 |
12.6 |
12.5 |
10.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 15 |
MEAN |
262 |
250 |
255 |
258 |
WEEK 3 |
ST.DEV |
17.6 |
13.9 |
17.2 |
14.6 |
|
N |
10 |
10 |
10 |
10 |
DAY 22 |
MEAN |
300 |
283 |
291 |
295 |
WEEK 4 |
ST.DEV |
21.8 |
15.2 |
22.2 |
16.8 |
|
N |
10 |
10 |
10 |
10 |
DAY 29 |
MEAN |
325 |
310 |
313 |
321 |
WEEK 5 |
ST.DEV |
28.9 |
13.1 |
28.2 |
21.1 |
|
N |
10 |
10 |
10 |
10 |
DAY 36 |
MEAN |
346 |
328 |
331 |
332 |
WEEK 6 |
ST.DEV |
35.7 |
15.3 |
32.4 |
41.3 |
|
N |
10 |
10 |
10 |
10 |
DAY 43 |
MEAN |
364 |
346 |
349 |
355 |
WEEK 7 |
ST.DEV |
36.3 |
14.8 |
33.5 |
23.3 |
|
N |
10 |
10 |
10 |
9 |
DAY 50 |
MEAN |
378 |
359 |
363 |
361 |
WEEK 8 |
ST.DEV |
38.1 |
15.9 |
36.7 |
30.6 |
|
N |
10 |
10 |
10 |
9 |
DAY 57 |
MEAN |
389 |
373 |
375 |
369 |
WEEK 9 |
ST.DEV |
40.0 |
16.7 |
38.8 |
32.0 |
|
N |
10 |
10 |
10 |
9 |
DAY 64 |
MEAN |
402 |
386 |
386 |
382 |
WEEK 10 |
ST.DEV |
41.9 |
17.3 |
39.3 |
26.8 |
|
N |
10 |
10 |
10 |
9 |
DAY 71 |
MEAN |
412 |
394 |
394 |
381 |
WEEK 11 |
ST.DEV |
44.2 |
17.9 |
39.7 |
29.1 |
|
N |
10 |
10 |
10 |
9 |
DAY 78 |
MEAN |
418 |
399 |
401 |
392 |
WEEK 12 |
ST.DEV |
45.4 |
19.3 |
41.4 |
31.0 |
|
N |
10 |
10 |
10 |
8 |
DAY 85 |
MEAN |
425 |
406 |
407 |
397 |
WEEK 13 |
ST.DEV |
48.5 |
19.3 |
41.3 |
32.0 |
|
N |
10 |
10 |
10 |
8 |
DAY 91 |
MEAN |
428 |
409 |
411 |
404 |
WEEK 13 |
ST.DEV |
48.6 |
17.9 |
42.2 |
34.2 |
|
N |
10 |
10 |
10 |
8 |
Body weight gain (%) - Male
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
TREATMENT DAY 1 |
MEAN |
0 |
0 |
0 |
0 |
WEEK 1 |
ST.DEV |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
29 |
28 |
26 |
28 |
WEEK 2 |
ST.DEV |
1.9 |
3.3 |
3.1 |
5.6 |
|
N |
10 |
10 |
10 |
10 |
DAY 15 |
MEAN |
56 |
53 |
53 |
53 |
WEEK 3 |
ST.DEV |
3.9 |
5.4 |
5.5 |
9.6 |
|
N |
10 |
10 |
10 |
10 |
DAY 22 |
MEAN |
78 |
74 |
75 |
75 |
WEEK 4 |
ST.DEV |
6.4 |
9.9 |
8.9 |
11.2 |
|
N |
10 |
10 |
10 |
10 |
DAY 29 |
MEAN |
93 |
90 |
88 |
90 |
WEEK 5 |
ST.DEV |
10.9 |
10.9 |
11.9 |
14.6 |
|
N |
10 |
10 |
10 |
10 |
DAY 36 |
MEAN |
105 |
102 |
99 |
96 |
WEEK 6 |
ST.DEV |
14.4 |
13.5 |
14.7 |
24.6 |
|
N |
10 |
10 |
10 |
10 |
DAY 43 |
MEAN |
116 |
113 |
110 |
110 |
WEEK 7 |
ST.DEV |
14.7 |
15.3 |
14.5 |
16.8 |
|
N |
10 |
10 |
10 |
9 |
DAY 50 |
MEAN |
124 |
121 |
118 |
113 |
WEEK 8 |
ST.DEV |
15.8 |
16.9 |
16.1 |
20.8 |
|
N |
10 |
10 |
10 |
9 |
DAY 57 |
MEAN |
130 |
129 |
125 |
118 |
WEEK 9 |
ST.DEV |
16.5 |
18.2 |
17.3 |
21.1 |
|
N |
10 |
10 |
10 |
9 |
DAY 64 |
MEAN |
139 |
137 |
132 |
126 |
WEEK 10 |
ST.DEV |
17.7 |
19.2 |
18.0 |
18.3 |
|
N |
10 |
10 |
10 |
9 |
DAY 71 |
MEAN |
145 |
142 |
136 |
125 |
WEEK 11 |
ST.DEV |
18.6 |
20.1 |
18.2 |
16.5 |
|
N |
10 |
10 |
10 |
9 |
DAY 78 |
MEAN |
148 |
146 |
141 |
131 |
WEEK 12 |
ST.DEV |
18.5 |
21.0 |
18.8 |
19.5 |
|
N |
10 |
10 |
10 |
8 |
DAY 85 |
MEAN |
152 |
150 |
145 |
133 |
WEEK 13 |
ST.DEV |
20.8 |
20.5 |
19.8 |
20.1 |
|
N |
10 |
10 |
10 |
8 |
DAY 91 |
MEAN |
154 |
151 |
147 |
137 |
WEEK 13 |
ST.DEV |
20.9 |
19.4 |
20.4 |
21.9 |
|
N |
10 |
10 |
10 |
8 |
Body weight (gms) - Female
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
TREATMENT DAY 1 |
MEAN |
132 |
133 |
133 |
134 |
WEEK 1 |
ST.DEV |
6.4 |
7.4 |
8.3 |
7.4 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
152 |
156 |
153 |
157 |
WEEK 2 |
ST.DEV |
9.3 |
10.6 |
11.8 |
10.0 |
|
N |
10 |
10 |
10 |
10 |
DAY 15 |
MEAN |
175 |
174 |
174 |
180 |
WEEK 3 |
ST.DEV |
9.8 |
13.0 |
13.6 |
12.9 |
|
N |
10 |
10 |
10 |
10 |
DAY 22 |
MEAN |
189 |
188 |
190 |
196 |
WEEK 4 |
ST.DEV |
8.4 |
14.1 |
14.8 |
9.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 29 |
MEAN |
202 |
199 |
200 |
203 |
WEEK 5 |
ST.DEV |
10.1 |
13.9 |
17.4 |
11.2 |
|
N |
10 |
10 |
10 |
10 |
DAY 36 |
MEAN |
208 |
210 |
208 |
207 |
WEEK 6 |
ST.DEV |
11.7 |
17.4 |
19.3 |
17.9 |
|
N |
10 |
10 |
10 |
10 |
DAY 43 |
MEAN |
218 |
217 |
216 |
219 |
WEEK 7 |
ST.DEV |
10.6 |
19.4 |
18.1 |
17.1 |
|
N |
10 |
10 |
10 |
10 |
DAY 50 |
MEAN |
224 |
222 |
222 |
221 |
WEEK 8 |
ST.DEV |
8.7 |
17.6 |
18.8 |
14.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 57 |
MEAN |
229 |
227 |
228 |
225 |
WEEK 9 |
ST.DEV |
10.6 |
18.5 |
20.2 |
14.8 |
|
N |
10 |
10 |
10 |
10 |
DAY 64 |
MEAN |
232 |
235 |
231 |
228 |
WEEK 10 |
ST.DEV |
12.9 |
22.9 |
21.1 |
15.6 |
|
N |
10 |
10 |
10 |
10 |
DAY 71 |
MEAN |
237 |
239 |
235 |
233 |
WEEK 11 |
ST.DEV |
12.1 |
23.1 |
19.2 |
17.8 |
|
N |
10 |
10 |
10 |
10 |
DAY 78 |
MEAN |
241 |
242 |
239 |
235 |
WEEK 12 |
ST.DEV |
10.6 |
23.2 |
19.6 |
16.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 85 |
MEAN |
243 |
244 |
241 |
233 |
WEEK 13 |
ST.DEV |
11.4 |
22.1 |
21.5 |
19.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 91 |
MEAN |
245 |
249 |
242 |
235 |
WEEK 13 |
ST.DEV |
12.9 |
24.9 |
21.2 |
16.5 |
|
N |
10 |
10 |
10 |
10 |
Body weight gain (%) - Female
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
TREATMENT DAY 1 |
MEAN |
0 |
0 |
0 |
0 |
WEEK 1 |
ST.DEV |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
15 |
17 |
15 |
17 |
WEEK 2 |
ST.DEV |
3.5 |
4.1 |
4.1 |
4.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 15 |
MEAN |
32 |
31 |
31 |
34 |
WEEK 3 |
ST.DEV |
3.5 |
5.5 |
6.0 |
8.9 |
|
N |
10 |
10 |
10 |
10 |
DAY 22 |
MEAN |
43 |
42 |
43 |
46 |
WEEK 4 |
ST.DEV |
3.6 |
7.6 |
7.6 |
5.8 |
|
N |
10 |
10 |
10 |
10 |
DAY 29 |
MEAN |
53 |
49 |
51 |
51 |
WEEK 5 |
ST.DEV |
3.9 |
5.3 |
7.0 |
6.4 |
|
N |
10 |
10 |
10 |
10 |
DAY 36 |
MEAN |
57 |
58 |
57 |
54 |
WEEK 6 |
ST.DEV |
6.1 |
9.3 |
8.7 |
13.1 |
|
N |
10 |
10 |
10 |
10 |
DAY 43 |
MEAN |
65 |
63 |
63 |
63 |
WEEK 7 |
ST.DEV |
6.2 |
10.0 |
8.5 |
10.5 |
|
N |
10 |
10 |
10 |
10 |
DAY 50 |
MEAN |
70 |
67 |
67 |
65 |
WEEK 8 |
ST.DEV |
5.3 |
9.4 |
9.7 |
8.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 57 |
MEAN |
74 |
71 |
72 |
68 |
WEEK 9 |
ST.DEV |
6.4 |
8.8 |
9.4 |
9.3 |
|
N |
10 |
10 |
10 |
10 |
DAY 64 |
MEAN |
76 |
77 |
74 |
70 |
WEEK 10 |
ST.DEV |
9.0 |
12.1 |
9.6 |
9.9 |
|
N |
10 |
10 |
10 |
10 |
DAY 71 |
MEAN |
80 |
80 |
77 |
74 |
WEEK 11 |
ST.DEV |
8.2 |
12.8 |
9.1 |
11.8 |
|
N |
10 |
10 |
10 |
10 |
DAY 78 |
MEAN |
82 |
82 |
80 |
75 |
WEEK 12 |
ST.DEV |
8.6 |
13.0 |
8.8 |
10.2 |
|
N |
10 |
10 |
10 |
10 |
DAY 85 |
MEAN |
84 |
83 |
82 |
74 |
WEEK 13 |
ST.DEV |
8.1 |
11.9 |
9.3 |
11.8 |
|
N |
10 |
10 |
10 |
10 |
DAY 91 |
MEAN |
86 |
87 |
82 |
75 |
WEEK 13 |
ST.DEV |
10.4 |
14.0 |
9.7 |
9.7 |
|
N |
10 |
10 |
10 |
10 |
(B) Food consumption
Food consumption (g/animal/day) - Males
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
TREATMENT DAYS 1-8 |
MEAN |
22 |
21 |
21 |
23 |
WEEKS 1-2 |
ST.DEV |
0.2 |
0.7 |
0.6 |
0.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
26 |
24 |
25 |
26 |
WEEKS 2-3 |
ST.DEV |
0.4 |
0.6 |
0.2 |
0.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 15-22 |
MEAN |
25 |
24 |
25 |
27 |
WEEKS 3-4 |
ST.DEV |
0.1 |
0.4 |
0.6 |
0.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 22-29 |
MEAN |
25 |
24 |
25 |
26 |
WEEKS 4-5 |
ST.DEV |
0.5 |
0.4 |
1.0 |
0.0 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 29-36 |
MEAN |
25 |
24 |
24 |
25 |
WEEKS 5-6 |
ST.DEV |
0.7 |
0.3 |
2.0 |
3.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 36-43 |
MEAN |
25 |
24 |
24 |
26 |
WEEKS 6-7 |
ST.DEV |
0.1 |
0.0 |
1.5 |
0.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 43-50 |
MEAN |
24 |
23 |
23 |
26 |
WEEKS 7-8 |
ST.DEV |
0.3 |
0.1 |
0.8 |
0.2 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 50-57 |
MEAN |
23 |
23 |
23 |
23 |
WEEKS 8-9 |
ST.DEV |
0.4 |
0.7 |
1.2 |
2.2 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 57-64 |
MEAN |
23 |
23 |
22 |
25 |
WEEKS 9-10 |
ST.DEV |
0.5 |
0.8 |
0.9 |
2.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 64-71 |
MEAN |
23 |
22 |
22 |
23 |
WEEKS 10-11 |
ST.DEV |
0.2 |
1.6 |
1.3 |
3.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 71-78 |
MEAN |
22 |
21 |
22 |
22 |
WEEKS 11-12 |
ST.DEV |
0.7 |
1.6 |
1.6 |
1.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 78-85 |
MEAN |
22 |
21 |
21 |
23 |
WEEKS 12-13 |
ST.DEV |
0.5 |
0.8 |
1.0 |
1.4 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 85-91 |
MEAN |
23 |
22 |
21 |
25 |
WEEK 13 |
ST.DEV |
0.4 |
1.4 |
1.3 |
0.5 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER TREATMENT |
MEAN |
24 |
23 |
23 |
25 |
Relative food consumption (g/kg bw/day) - Males
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
TREATMENT DAYS 1-8 |
MEAN |
101 |
102 |
102 |
104 |
WEEKS 1-2 |
ST.DEV |
0.3 |
0.5 |
3.1 |
0.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
98 |
98 |
98 |
102 |
WEEKS 2-3 |
ST.DEV |
0.8 |
0.3 |
0.6 |
1.6 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 15-22 |
MEAN |
85 |
85 |
85 |
90 |
WEEKS 3-4 |
ST.DEV |
1.6 |
0.6 |
0.1 |
0.9 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 22-29 |
MEAN |
77 |
77 |
79 |
82 |
WEEKS 4-5 |
ST.DEV |
0.8 |
1.8 |
0.6 |
1.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 29-36 |
MEAN |
73 |
74 |
71 |
74 |
WEEKS 5-6 |
ST.DEV |
0.2 |
1.7 |
3.4 |
6.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 36-43 |
MEAN |
70 |
70 |
69 |
75 |
WEEKS 6-7 |
ST.DEV |
1.7 |
0.3 |
1.9 |
0.7 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 43-50 |
MEAN |
65 |
63 |
64 |
73 |
WEEKS 7-8 |
ST.DEV |
1.0 |
0.2 |
0.1 |
3.8 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 50-57 |
MEAN |
60 |
62 |
62 |
62 |
WEEKS 8-9 |
ST.DEV |
0.5 |
1.9 |
1.2 |
3.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 57-64 |
MEAN |
58 |
59 |
57 |
65 |
WEEKS 9-10 |
ST.DEV |
0.1 |
1.7 |
0.2 |
7.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 64-71 |
MEAN |
56 |
57 |
56 |
61 |
WEEKS 10-11 |
ST.DEV |
1.0 |
3.5 |
1.1 |
7.5 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 71-78 |
MEAN |
53 |
54 |
55 |
56 |
WEEKS 11-12 |
ST.DEV |
0.1 |
3.7 |
1.5 |
5.2 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 78-85 |
MEAN |
52 |
52 |
51 |
57 |
WEEKS 12-13 |
ST.DEV |
0.6 |
1.3 |
0.5 |
1.9 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 85-91 |
MEAN |
53 |
53 |
52 |
62 |
WEEK 13 |
ST.DEV |
0.7 |
2.6 |
1.0 |
3.0 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER TREATMENT |
MEAN |
69 |
70 |
69 |
74 |
Food consumption (g/animal/day) - Females
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
TREATMENT DAYS 1-8 |
MEAN |
15 |
15 |
15 |
16 |
WEEKS 1-2 |
ST.DEV |
0.1 |
1.0 |
0.3 |
0.4 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
17 |
17 |
17 |
18 |
WEEKS 2-3 |
ST.DEV |
0.3 |
1.3 |
0.1 |
0.2 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 15-22 |
MEAN |
16 |
16 |
16 |
16 |
WEEKS 3-4 |
ST.DEV |
0.5 |
1.2 |
0.1 |
0.7 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 22-29 |
MEAN |
16 |
16 |
16 |
17 |
WEEKS 4-5 |
ST.DEV |
0.4 |
1.3 |
0.0 |
0.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 29-36 |
MEAN |
16 |
17 |
17 |
16 |
WEEKS 5-6 |
ST.DEV |
0.5 |
0.6 |
0.1 |
1.2 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 36-43 |
MEAN |
17 |
17 |
17 |
17 |
WEEKS 6-7 |
ST.DEV |
0.4 |
0.7 |
0.0 |
0.9 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 43-50 |
MEAN |
16 |
17 |
16 |
16 |
WEEKS 7-8 |
ST.DEV |
0.6 |
0.4 |
0.2 |
0.2 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 50-57 |
MEAN |
16 |
16 |
17 |
16 |
WEEKS 8-9 |
ST.DEV |
0.5 |
0.2 |
0.2 |
0.8 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 57-64 |
MEAN |
16 |
16 |
16 |
15 |
WEEKS 9-10 |
ST.DEV |
0.8 |
0.6 |
0.2 |
0.4 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 64-71 |
MEAN |
16 |
16 |
16 |
16 |
WEEKS 10-11 |
ST.DEV |
1.0 |
0.3 |
0.3 |
0.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 71-78 |
MEAN |
15 |
16 |
16 |
15 |
WEEKS 11-12 |
ST.DEV |
1.1 |
0.4 |
0.7 |
0.4 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 78-85 |
MEAN |
15 |
15 |
15 |
15 |
WEEKS 12-13 |
ST.DEV |
1.1 |
0.1 |
0.5 |
0.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 85-91 |
MEAN |
16 |
15 |
15 |
14 |
WEEK 13 |
ST.DEV |
1.5 |
0.0 |
0.4 |
0.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER TREATMENT |
MEAN |
16 |
16 |
16 |
16 |
Relative food consumption (g/kg bw/day) - Females
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
TREATMENT DAYS 1-8 |
MEAN |
96 |
95 |
96 |
99 |
WEEKS 1-2 |
ST.DEV |
0.9 |
4.4 |
1.0 |
0.7 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
96 |
96 |
96 |
99 |
WEEKS 2-3 |
ST.DEV |
0.7 |
5.1 |
0.1 |
4.0 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 15-22 |
MEAN |
85 |
85 |
84 |
81 |
WEEKS 3-4 |
ST.DEV |
3.0 |
3.6 |
0.3 |
5.7 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 22-29 |
MEAN |
81 |
82 |
80 |
81 |
WEEKS 4-5 |
ST.DEV |
2.3 |
3.9 |
0.3 |
1.4 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 29-36 |
MEAN |
79 |
79 |
79 |
76 |
WEEKS 5-6 |
ST.DEV |
1.9 |
1.2 |
0.3 |
2.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 36-43 |
MEAN |
78 |
76 |
78 |
76 |
WEEKS 6-7 |
ST.DEV |
2.0 |
1.0 |
0.5 |
0.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 43-50 |
MEAN |
73 |
75 |
74 |
73 |
WEEKS 7-8 |
ST.DEV |
3.2 |
0.6 |
0.4 |
4.5 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 50-57 |
MEAN |
68 |
72 |
73 |
72 |
WEEKS 8-9 |
ST.DEV |
2.4 |
1.1 |
1.1 |
0.4 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 57-64 |
MEAN |
68 |
69 |
67 |
68 |
WEEKS 9-10 |
ST.DEV |
3.0 |
0.0 |
1.0 |
1.5 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 64-71 |
MEAN |
66 |
65 |
67 |
68 |
WEEKS 10-11 |
ST.DEV |
3.8 |
1.7 |
0.7 |
5.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 71-78 |
MEAN |
64 |
65 |
66 |
66 |
WEEKS 11-12 |
ST.DEV |
4.1 |
1.4 |
3.0 |
1.5 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 78-85 |
MEAN |
63 |
63 |
63 |
63 |
WEEKS 12-13 |
ST.DEV |
3.5 |
2.0 |
2.1 |
1.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 85-91 |
MEAN |
63 |
62 |
63 |
60 |
WEEK 13 |
ST.DEV |
5.1 |
3.1 |
1.5 |
1.4 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER TREATMENT |
MEAN |
75 |
76 |
76 |
76 |
(C) Opthalmic observations
MALES |
|
|
|
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
PRE-TEST No Findings |
4/10 |
4/10 |
4/10 |
4/10 |
Corneal Edema |
1/10 |
0/10 |
0/10 |
0/10 |
Focal Corneal Edema |
3/10 |
1/10 |
0/10 |
0/10 |
Focal Corneal Opacity |
5/10 |
6/10 |
6/10 |
6/10 |
Haemorrhage From Hyaloid Vessel |
1/10 |
0/10 |
0/10 |
0/10 |
Pinpoint Corneal Opacities AT WEEK13 NoFindings |
1/10
4/10 |
0/10 |
1/10 |
1/10
5/8 |
Focal Corneal Edema |
1/10 |
|
|
1/8 |
Focal Corneal Opacity |
4/10 |
|
|
3/8 |
Pinpoint Corneal Opacities |
2/10 |
|
|
0/8 |
FEMALES |
|
|
|
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
PRE-TEST No Findings |
7/10 |
2/10 |
4/10 |
7/10 |
Focal Corneal Edema |
0/10 |
6/10 # |
2/10 |
0/10 |
Focal Corneal Opacity |
2/10 |
7/10 |
4/10 |
3/10 |
Haemorrhage From Hyaloid Vessel |
1/10 |
0/10 |
0/10 |
0/10 |
Pinpoint Corneal Opacities AT WEEK13 NoFindings |
0/10
5/10 |
2/10 |
2/10 |
2/10
6/10 |
Focal Corneal Edema |
1/10 |
|
|
1/10 |
Focal Corneal Opacity |
5/10 |
|
|
4/10 |
Pinpoint Corneal Opacities |
0/10 |
|
|
1/10 |
# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level
(D) Haematology summary
Males
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
|
END OF TREATMENT WBC |
MEAN |
7.1 |
6.9 |
6.5 |
7.4 |
10E9/L |
ST.DEV |
1.4 |
1.0 |
1.1 |
1.4 |
|
N |
10 |
10 |
10 |
8 |
Neutrophils |
MEAN |
14.6 |
18.6 |
20.2 ++ |
20.8 |
%WBC |
ST.DEV |
3.1 |
4.2 |
2.9 |
7.5 |
|
N |
10 |
10 |
10 |
8 |
Lymphocytes |
MEAN |
82.4 |
77.5 |
76.5 ++ |
75.7 ++ |
%WBC |
ST.DEV |
3.3 |
5.1 |
2.7 |
8.2 |
|
N |
10 |
10 |
10 |
8 |
Monocytes |
MEAN |
1.8 |
2.2 |
1.9 |
2.1 |
%WBC |
ST.DEV |
0.5 |
1.0 |
0.6 |
0.8 |
|
N |
10 |
10 |
10 |
8 |
Eosinophils |
MEAN |
1.1 |
1.6 + |
1.3 |
1.3 |
%WBC |
ST.DEV |
0.3 |
0.4 |
0.7 |
0.6 |
|
N |
10 |
10 |
10 |
8 |
Basophils |
MEAN |
0.1 |
0.1 |
0.1 |
0.2 |
%WBC |
ST.DEV |
0.0 |
0.1 |
0.1 |
0.1 |
|
N |
10 |
10 |
10 |
8 |
Red blood cells |
MEAN |
9.01 |
9.20 |
9.02 |
9.21 |
10E12/L |
ST.DEV |
0.41 |
0.33 |
0.45 |
0.35 |
|
N |
10 |
10 |
10 |
8 |
Reticulocytes |
MEAN |
2.1 |
2.1 |
2.0 |
2.0 |
%RBC |
ST.DEV |
0.3 |
0.2 |
0.2 |
0.3 |
|
N |
10 |
10 |
10 |
8 |
RDW |
MEAN |
13.7 |
12.5 |
14.0 |
14.0 |
% |
ST.DEV |
3.6 |
0.5 |
3.3 |
0.8 |
|
N |
10 |
10 |
10 |
8 |
Haemoglobin |
MEAN |
10.0 |
10.1 |
9.9 |
9.5 * |
mmol/L |
ST.DEV |
0.4 |
0.2 |
0.5 |
0.3 |
|
N |
10 |
10 |
10 |
8 |
Haematocrit |
MEAN |
0.481 |
0.490 |
0.486 |
0.469 |
L/L |
ST.DEV |
0.013 |
0.015 |
0.019 |
0.023 |
|
N |
10 |
10 |
10 |
8 |
MCV |
MEAN |
53.4 |
53.3 |
53.9 |
50.9 ** |
fL |
ST.DEV |
1.9 |
1.1 |
1.8 |
1.0 |
|
N |
10 |
10 |
10 |
8 |
MCH |
MEAN |
1.10 |
1.09 |
1.10 |
1.03 * |
fmol |
ST.DEV |
0.06 |
0.03 |
0.07 |
0.02 |
|
N |
10 |
10 |
10 |
8 |
MCHC |
MEAN |
20.67 |
20.54 |
20.39 |
20.18 |
mmol/L |
ST.DEV |
0.48 |
0.35 |
0.63 |
0.41 |
|
N |
10 |
10 |
10 |
8 |
Platelets |
MEAN |
726 |
769 |
692 |
686 |
10E9/L |
ST.DEV |
121 |
121 |
83 |
63 |
|
N |
10 |
10 |
10 |
8 |
PT |
MEAN |
16.7 |
15.6 * |
15.2 ** |
16.3 |
s |
ST.DEV |
0.6 |
0.5 |
0.6 |
1.4 |
|
N |
10 |
10 |
9 |
8 |
APTT |
MEAN |
19.2 |
20.7 |
18.9 |
18.9 |
s |
ST.DEV |
2.0 |
0.9 |
2.2 |
2.1 |
|
N |
10 |
10 |
9 |
8 |
+/++ Steel-test significant at 5% (+) or 1% (++) level
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Females
END OF TREATMENT |
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
WBC |
MEAN |
3.9 |
3.6 |
4.6 |
5.9 ** |
10E9/L |
ST.DEV |
0.9 |
0.8 |
0.8 |
1.3 |
|
N |
10 |
10 |
10 |
10 |
Neutrophils |
MEAN |
13.8 |
21.3 |
17.6 |
21.1 ++ |
%WBC |
ST.DEV |
2.4 |
13.8 |
8.9 |
4.9 |
|
N |
10 |
10 |
10 |
10 |
Lymphocytes |
MEAN |
82.4 |
73.1 |
78.9 |
75.7 ++ |
%WBC |
ST.DEV |
2.6 |
16.4 |
9.3 |
4.4 |
|
N |
10 |
10 |
10 |
10 |
Monocytes |
MEAN |
2.3 |
2.2 |
2.2 |
2.2 |
%WBC |
ST.DEV |
0.5 |
0.7 |
0.4 |
0.8 |
|
N |
10 |
10 |
10 |
10 |
Eosinophils |
MEAN |
1.4 |
3.3 + |
1.2 |
0.9 |
%WBC |
ST.DEV |
0.6 |
3.2 |
0.5 |
0.2 |
|
N |
10 |
10 |
10 |
10 |
Basophils |
MEAN |
0.1 |
0.1 |
0.1 |
0.1 |
%WBC |
ST.DEV |
0.1 |
0.1 |
0.1 |
0.1 |
|
N |
10 |
10 |
10 |
10 |
Red blood cells |
MEAN |
8.19 |
8.12 |
8.17 |
8.37 |
10E12/L |
ST.DEV |
0.40 |
0.36 |
0.24 |
0.48 |
|
N |
10 |
10 |
10 |
10 |
Reticulocytes |
MEAN |
2.9 |
2.9 |
2.6 |
2.6 |
%RBC |
ST.DEV |
0.4 |
0.3 |
0.3 |
1.5 |
|
N |
10 |
10 |
10 |
10 |
RDW |
MEAN |
11.4 |
11.6 |
11.2 |
12.8 ** |
% |
ST.DEV |
0.6 |
0.4 |
0.4 |
1.0 |
|
N |
10 |
10 |
10 |
10 |
Haemoglobin |
MEAN |
9.3 |
9.1 |
9.3 |
9.0 * |
mmol/L |
ST.DEV |
0.3 |
0.2 |
0.2 |
0.4 |
|
N |
10 |
10 |
10 |
10 |
Haematocrit |
MEAN |
0.455 |
0.452 |
0.456 |
0.444 |
L/L |
ST.DEV |
0.015 |
0.015 |
0.008 |
0.022 |
|
N |
10 |
10 |
10 |
10 |
MCV |
MEAN |
55.6 |
55.7 |
55.9 |
53.1 ** |
fL |
ST.DEV |
1.3 |
1.5 |
1.5 |
1.7 |
|
N |
10 |
10 |
10 |
10 |
MCH |
MEAN |
1.14 |
1.12 |
1.14 |
1.07 ** |
fmol |
ST.DEV |
0.04 |
0.03 |
0.03 |
0.04 |
|
N |
10 |
10 |
10 |
10 |
MCHC |
MEAN |
20.49 |
20.13 |
20.35 |
20.18 |
mmol/L |
ST.DEV |
0.31 |
0.28 |
0.37 |
0.41 |
|
N |
10 |
10 |
10 |
10 |
Platelets |
MEAN |
785 |
750 |
815 |
711 |
10E9/L |
ST.DEV |
100 |
96 |
95 |
175 |
|
N |
10 |
10 |
10 |
10 |
PT |
MEAN |
17.2 |
16.2 |
16.5 |
16.6 |
s |
ST.DEV |
1.4 |
0.8 |
1.1 |
1.6 |
|
N |
10 |
10 |
10 |
10 |
APTT |
MEAN |
19.4 |
19.2 |
20.0 |
18.5 |
s |
ST.DEV |
1.4 |
1.8 |
1.0 |
1.4 |
|
N |
10 |
10 |
10 |
10 |
+/++ Steel-test significant at 5% (+) or 1% (++) level
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
(E) Clinical biochemistry summary
Males
END OF TREATMENT |
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
ALAT |
MEAN |
43.0 |
45.1 |
46.6 |
83.6 ** |
U/L |
ST.DEV |
7.1 |
13.5 |
11.8 |
17.2 |
|
N |
10 |
10 |
10 |
8 |
ASAT |
MEAN |
76.0 |
69.4 |
73.2 |
81.7 |
U/L |
ST.DEV |
7.8 |
6.8 |
9.0 |
5.8 |
|
N |
10 |
10 |
10 |
8 |
ALP |
MEAN |
126 |
132 |
124 |
147 |
U/L |
ST.DEV |
38 |
50 |
25 |
49 |
|
N |
10 |
10 |
10 |
8 |
Total protein |
MEAN |
65.7 |
67.9 |
67.9 |
69.7 ** |
g/L |
ST.DEV |
1.4 |
2.6 |
3.0 |
3.0 |
|
N |
10 |
10 |
10 |
8 |
Albumin |
MEAN |
32.0 |
33.3 * |
33.6 ** |
34.5 ** |
g/L |
ST.DEV |
1.0 |
0.8 |
1.2 |
0.9 |
|
N |
10 |
10 |
10 |
8 |
Total bilirubin |
MEAN |
1.9 |
2.4 * |
2.8 ** |
2.8 ** |
umol/L |
ST.DEV |
0.3 |
0.3 |
0.6 |
0.6 |
|
N |
10 |
10 |
10 |
8 |
Urea |
MEAN |
7.0 |
7.1 |
7.6 |
8.3 |
mmol/L |
ST.DEV |
1.0 |
0.9 |
1.5 |
1.4 |
|
N |
10 |
10 |
10 |
8 |
Creatinine |
MEAN |
41.5 |
45.2 ** |
42.2 |
45.8 ** |
umol/L |
ST.DEV |
2.9 |
2.6 |
1.7 |
2.5 |
|
N |
10 |
10 |
10 |
8 |
Glucose |
MEAN |
10.42 |
10.39 |
9.32 |
9.03 * |
mmol/L |
ST.DEV |
1.10 |
1.16 |
1.04 |
1.27 |
|
N |
10 |
10 |
10 |
8 |
Cholesterol |
MEAN |
2.37 |
2.04 |
2.06 |
1.67 ** |
mmol/L |
ST.DEV |
0.42 |
0.34 |
0.35 |
0.17 |
|
N |
10 |
10 |
10 |
8 |
Bile Acids |
MEAN |
19.8 |
34.4 ** |
23.7 |
11.3 |
umol/L |
ST.DEV |
9.8 |
14.8 |
8.0 |
2.7 |
|
N |
10 |
10 |
10 |
8 |
Sodium |
MEAN |
138.8 |
141.0 ** |
142.6 ** |
138.7 |
mmol/L |
ST.DEV |
1.5 |
1.4 |
1.0 |
1.5 |
|
N |
10 |
10 |
10 |
8 |
Potassium |
MEAN |
3.88 |
3.79 |
3.90 |
3.96 |
mmol/L |
ST.DEV |
0.11 |
0.19 |
0.22 |
0.24 |
|
N |
10 |
10 |
10 |
8 |
Chloride |
MEAN |
101 |
101 |
103 * |
102 |
mmol/L |
ST.DEV |
2 |
1 |
1 |
2 |
|
N |
10 |
10 |
10 |
8 |
Calcium |
MEAN |
2.55 |
2.56 |
2.56 |
2.56 |
mmol/L |
ST.DEV |
0.04 |
0.05 |
0.04 |
0.08 |
|
N |
10 |
10 |
10 |
8 |
Inorg.Phos |
MEAN |
1.49 |
1.39 |
1.60 |
1.99 ** |
mmol/L |
ST.DEV |
0.16 |
0.15 |
0.12 |
0.15 |
|
N |
10 |
10 |
10 |
8 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Females
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
ALAT |
MEAN |
31.3 |
29.0 |
32.7 |
94.2 ** |
U/L |
ST.DEV |
7.9 |
6.1 |
5.2 |
24.1 |
|
N |
10 |
10 |
10 |
10 |
ASAT |
MEAN |
73.0 |
69.4 |
70.0 |
88.2 * |
U/L |
ST.DEV |
11.0 |
12.7 |
15.5 |
11.9 |
|
N |
10 |
10 |
10 |
10 |
ALP |
MEAN |
43 |
45 |
47 |
53 |
U/L |
ST.DEV |
19 |
20 |
15 |
22 |
|
N |
10 |
10 |
10 |
10 |
Total protein |
MEAN |
68.4 |
67.2 |
69.9 |
70.6 |
g/L |
ST.DEV |
2.4 |
3.6 |
2.1 |
3.6 |
|
N |
10 |
10 |
10 |
10 |
Albumin |
MEAN |
35.4 |
35.0 |
36.2 |
35.5 |
g/L |
ST.DEV |
1.3 |
1.9 |
1.6 |
1.8 |
|
N |
10 |
10 |
10 |
10 |
Total bilirubin |
MEAN |
2.2 |
2.5 |
3.0 |
3.3 ** |
umol/L |
ST.DEV |
0.3 |
0.5 |
0.7 |
1.3 |
|
N |
10 |
10 |
10 |
10 |
Urea |
MEAN |
7.3 |
6.1 |
6.9 |
10.0 ** |
mmol/L |
ST.DEV |
1.1 |
0.9 |
0.9 |
1.5 |
|
N |
10 |
10 |
10 |
10 |
Creatinine |
MEAN |
45.1 |
45.8 |
46.6 |
52.0 ** |
umol/L |
ST.DEV |
2.3 |
5.3 |
2.5 |
4.8 |
|
N |
10 |
10 |
10 |
10 |
Glucose |
MEAN |
7.32 |
7.86 |
7.92 |
7.10 |
mmol/L |
ST.DEV |
0.78 |
1.16 |
0.85 |
0.94 |
|
N |
10 |
10 |
10 |
10 |
Cholesterol |
MEAN |
1.75 |
1.84 |
1.73 |
1.57 |
mmol/L |
ST.DEV |
0.23 |
0.53 |
0.29 |
0.35 |
|
N |
10 |
10 |
10 |
10 |
Bile Acids |
MEAN |
18.8 |
16.1 |
15.4 |
13.3 |
umol/L |
ST.DEV |
12.6 |
4.0 |
6.6 |
7.5 |
|
N |
10 |
10 |
10 |
10 |
Sodium |
MEAN |
140.0 |
141.5 ** |
141.8 ** |
139.8 |
mmol/L |
ST.DEV |
0.7 |
0.9 |
0.9 |
1.1 |
|
N |
10 |
10 |
10 |
10 |
Potassium |
MEAN |
3.52 |
3.45 |
3.45 |
3.67 |
mmol/L |
ST.DEV |
0.20 |
0.16 |
0.20 |
0.29 |
|
N |
10 |
10 |
10 |
10 |
Chloride |
MEAN |
102 |
102 |
102 |
102 |
mmol/L |
ST.DEV |
1 |
2 |
1 |
2 |
|
N |
10 |
10 |
10 |
10 |
Calcium |
MEAN |
2.58 |
2.56 |
2.56 |
2.56 |
mmol/L |
ST.DEV |
0.05 |
0.07 |
0.06 |
0.07 |
|
N |
10 |
10 |
10 |
10 |
Inorg.Phos |
MEAN |
1.37 |
1.30 |
1.35 |
1.79 ** |
mmol/L |
ST.DEV |
0.15 |
0.12 |
0.18 |
0.13 |
|
N |
10 |
10 |
10 |
10 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
(F) Organ weight and organ/body weight ratio summary
Males - organ weight
ORGAN WEIGHTS MALES |
(GRAM) SUMMARY |
|
|||
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
END OF TREATMENT BODY W. |
MEAN |
408 |
388 |
388 |
367 * |
(GRAM) |
ST.DEV |
44 |
18 |
38 |
29 |
|
N |
10 |
10 |
10 |
8 |
BRAIN |
MEAN |
2.07 |
2.05 |
2.03 |
2.06 |
(GRAM) |
ST.DEV |
0.06 |
0.06 |
0.07 |
0.06 |
|
N |
10 |
10 |
10 |
8 |
HEART |
MEAN |
1.055 |
0.978 |
0.992 |
0.945 * |
(GRAM) |
ST.DEV |
0.122 |
0.089 |
0.079 |
0.061 |
|
N |
10 |
10 |
10 |
8 |
LIVER |
MEAN |
9.72 |
8.72 |
8.89 |
9.57 |
(GRAM) |
ST.DEV |
1.15 |
0.73 |
1.10 |
1.34 |
|
N |
10 |
10 |
10 |
8 |
THYROIDS |
MEAN |
0.017 |
0.016 |
0.016 |
0.015 * |
(GRAM) |
ST.DEV |
0.002 |
0.003 |
0.003 |
0.001 |
|
N |
10 |
10 |
10 |
8 |
THYMUS |
MEAN |
0.317 |
0.319 |
0.288 |
0.233 * |
(GRAM) |
ST.DEV |
0.053 |
0.069 |
0.065 |
0.025 |
|
N |
10 |
10 |
10 |
8 |
KIDNEYS |
MEAN |
2.40 |
2.24 |
2.32 |
2.57 |
(GRAM) |
ST.DEV |
0.22 |
0.14 |
0.23 |
0.20 |
|
N |
10 |
10 |
10 |
8 |
ADRENALS |
MEAN |
0.058 |
0.056 |
0.053 |
0.060 |
(GRAM) |
ST.DEV |
0.009 |
0.008 |
0.008 |
0.009 |
|
N |
10 |
10 |
10 |
8 |
SPLEEN |
MEAN |
0.581 |
0.557 |
0.551 |
0.615 |
(GRAM) |
ST.DEV |
0.080 |
0.076 |
0.081 |
0.120 |
|
N |
10 |
10 |
10 |
8 |
TESTES |
MEAN |
3.71 |
3.71 |
3.60 |
3.55 |
(GRAM) |
ST.DEV |
0.19 |
0.28 |
0.19 |
0.23 |
|
N |
10 |
10 |
10 |
8 |
PROSTATE GLAND |
MEAN |
0.870 |
0.779 |
0.844 |
0.865 |
(GRAM) |
ST.DEV |
0.158 |
0.132 |
0.192 |
0.123 |
|
N |
10 |
10 |
10 |
8 |
EPIDIDYMIDES |
MEAN |
1.279 |
1.303 |
1.243 |
1.226 |
(GRAM) |
ST.DEV |
0.128 |
0.284 |
0.099 |
0.181 |
|
N |
10 |
10 |
10 |
8 |
SEMINAL VESICLES |
MEAN |
1.338 |
1.338 |
1.344 |
1.321 |
(GRAM) |
ST.DEV |
0.219 |
0.294 |
0.209 |
0.179 |
|
N |
10 |
10 |
10 |
8 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Males - organ/body weight ration (%) summary
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
END OF TREATMENT BODY W. |
MEAN |
408 |
388 |
388 |
367 * |
(GRAM) |
ST.DEV |
44 |
18 |
38 |
29 |
|
N |
10 |
10 |
10 |
8 |
BRAIN |
MEAN |
0.51 |
0.53 |
0.53 |
0.56 |
(%) |
ST.DEV |
0.05 |
0.02 |
0.05 |
0.05 |
|
N |
10 |
10 |
10 |
8 |
HEART |
MEAN |
0.260 |
0.252 |
0.256 |
0.258 |
(%) |
ST.DEV |
0.033 |
0.019 |
0.018 |
0.015 |
|
N |
10 |
10 |
10 |
8 |
LIVER |
MEAN |
2.38 |
2.25 |
2.29 |
2.60 ** |
(%) |
ST.DEV |
0.10 |
0.15 |
0.13 |
0.18 |
|
N |
10 |
10 |
10 |
8 |
THYROIDS |
MEAN |
0.004 |
0.004 |
0.004 |
0.004 |
(%) |
ST.DEV |
0.001 |
0.001 |
0.001 |
0.000 |
|
N |
10 |
10 |
10 |
8 |
THYMUS |
MEAN |
0.078 |
0.082 |
0.074 |
0.064 |
(%) |
ST.DEV |
0.014 |
0.017 |
0.014 |
0.006 |
|
N |
10 |
10 |
10 |
8 |
KIDNEYS |
MEAN |
0.59 |
0.58 |
0.60 |
0.70 ** |
(%) |
ST.DEV |
0.05 |
0.03 |
0.03 |
0.06 |
|
N |
10 |
10 |
10 |
8 |
ADRENALS |
MEAN |
0.014 |
0.014 |
0.014 |
0.016 |
(%) |
ST.DEV |
0.002 |
0.002 |
0.001 |
0.002 |
|
N |
10 |
10 |
10 |
8 |
SPLEEN |
MEAN |
0.143 |
0.144 |
0.142 |
0.168 |
(%) |
ST.DEV |
0.020 |
0.020 |
0.019 |
0.031 |
|
N |
10 |
10 |
10 |
8 |
TESTES |
MEAN |
0.92 |
0.96 |
0.94 |
0.97 |
(%) |
ST.DEV |
0.12 |
0.08 |
0.12 |
0.07 |
|
N |
10 |
10 |
10 |
8 |
PROSTATE GLAND |
MEAN |
0.214 |
0.201 |
0.217 |
0.235 |
(%) |
ST.DEV |
0.036 |
0.036 |
0.045 |
0.017 |
|
N |
10 |
10 |
10 |
8 |
EPIDIDYMIDES |
MEAN |
0.318 |
0.335 |
0.323 |
0.334 |
(%) |
ST.DEV |
0.056 |
0.067 |
0.040 |
0.049 |
|
N |
10 |
10 |
10 |
8 |
SEMINAL VESICLES |
MEAN |
0.330 |
0.345 |
0.351 |
0.360 |
(%) |
ST.DEV |
0.055 |
0.075 |
0.074 |
0.043 |
|
N |
10 |
10 |
10 |
8 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Females - organ weight
ORGAN WEIGHTS FEMALES |
(GRAM) SUMMARY |
|
|
|
|
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
END OF TREATMENT BODY W. |
MEAN |
231 |
231 |
226 |
210 * |
(GRAM) |
ST.DEV |
12 |
22 |
21 |
16 |
|
N |
10 |
10 |
10 |
10 |
BRAIN |
MEAN |
1.91 |
1.87 |
1.87 |
1.85 |
(GRAM) |
ST.DEV |
0.09 |
0.09 |
0.07 |
0.07 |
|
N |
10 |
10 |
10 |
10 |
HEART |
MEAN |
0.683 |
0.692 |
0.659 |
0.645 |
(GRAM) |
ST.DEV |
0.052 |
0.074 |
0.059 |
0.053 |
|
N |
10 |
10 |
10 |
10 |
LIVER |
MEAN |
5.64 |
5.76 |
5.36 |
6.27 |
(GRAM) |
ST.DEV |
0.37 |
0.94 |
0.42 |
0.51 |
|
N |
10 |
10 |
10 |
10 |
THYROIDS |
MEAN |
0.014 |
0.014 |
0.014 |
0.013 |
(GRAM) |
ST.DEV |
0.003 |
0.003 |
0.002 |
0.002 |
|
N |
10 |
10 |
10 |
10 |
THYMUS |
MEAN |
0.269 |
0.299 |
0.285 |
0.215 |
(GRAM) |
ST.DEV |
0.038 |
0.061 |
0.067 |
0.048 |
|
N |
10 |
10 |
10 |
10 |
KIDNEYS |
MEAN |
1.57 |
1.56 |
1.59 |
1.72 * |
(GRAM) |
ST.DEV |
0.08 |
0.14 |
0.15 |
0.11 |
|
N |
10 |
10 |
10 |
10 |
ADRENALS |
MEAN |
0.068 |
0.063 |
0.066 |
0.069 |
(GRAM) |
ST.DEV |
0.011 |
0.011 |
0.008 |
0.010 |
|
N |
10 |
10 |
10 |
10 |
SPLEEN |
MEAN |
0.443 |
0.432 |
0.436 |
0.465 |
(GRAM) |
ST.DEV |
0.044 |
0.078 |
0.029 |
0.053 |
|
N |
10 |
10 |
10 |
10 |
OVARIES |
MEAN |
0.139 |
0.147 |
0.134 |
0.128 |
(GRAM) |
ST.DEV |
0.017 |
0.017 |
0.019 |
0.026 |
|
N |
10 |
10 |
10 |
10 |
UTERUS |
MEAN |
0.684 |
0.822 |
0.611 |
0.607 |
(GRAM) |
ST.DEV |
0.244 |
0.287 |
0.293 |
0.282 |
|
N |
10 |
10 |
10 |
10 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
Female - organ/body weight ratio (%) summary
|
|
GROUP 1 CONTROL |
GROUP 2 100 MG/KG |
GROUP 3 300 MG/KG |
GROUP 4 1000 MG/KG |
END OF TREATMENT BODY W. |
MEAN |
231 |
231 |
226 |
210 * |
(GRAM) |
ST.DEV |
12 |
22 |
21 |
16 |
|
N |
10 |
10 |
10 |
10 |
BRAIN |
MEAN |
0.83 |
0.82 |
0.83 |
0.88 |
(%) |
ST.DEV |
0.05 |
0.08 |
0.06 |
0.06 |
|
N |
10 |
10 |
10 |
10 |
HEART |
MEAN |
0.296 |
0.299 |
0.292 |
0.307 |
(%) |
ST.DEV |
0.016 |
0.015 |
0.009 |
0.016 |
|
N |
10 |
10 |
10 |
10 |
LIVER |
MEAN |
2.44 |
2.49 |
2.38 |
2.98 ** |
(%) |
ST.DEV |
0.12 |
0.34 |
0.10 |
0.16 |
|
N |
10 |
10 |
10 |
10 |
THYROIDS |
MEAN |
0.006 |
0.006 |
0.006 |
0.006 |
(%) |
ST.DEV |
0.001 |
0.001 |
0.001 |
0.001 |
|
N |
10 |
10 |
10 |
10 |
THYMUS |
MEAN |
0.117 |
0.129 |
0.125 |
0.102 |
(%) |
ST.DEV |
0.015 |
0.020 |
0.021 |
0.019 |
|
N |
10 |
10 |
10 |
10 |
KIDNEYS |
MEAN |
0.68 |
0.68 |
0.70 |
0.82 ** |
(%) |
ST.DEV |
0.04 |
0.07 |
0.05 |
0.07 |
|
N |
10 |
10 |
10 |
10 |
ADRENALS |
MEAN |
0.029 |
0.027 |
0.029 |
0.033 |
(%) |
ST.DEV |
0.005 |
0.005 |
0.004 |
0.003 |
|
N |
10 |
10 |
10 |
10 |
SPLEEN |
MEAN |
0.192 |
0.187 |
0.194 |
0.222 * |
(%) |
ST.DEV |
0.018 |
0.031 |
0.016 |
0.029 |
|
N |
10 |
10 |
10 |
10 |
OVARIES |
MEAN |
0.060 |
0.064 |
0.060 |
0.061 |
(%) |
ST.DEV |
0.008 |
0.011 |
0.008 |
0.011 |
|
N |
10 |
10 |
10 |
10 |
UTERUS |
MEAN |
0.294 |
0.358 |
0.269 |
0.284 |
(%) |
ST.DEV |
0.094 |
0.132 |
0.120 |
0.111 |
|
N |
10 |
10 |
10 |
10 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
For more parameters and data tables, kindly refer to the attached background material section of the IUCLID.
Applicant's summary and conclusion
- Conclusions:
- Under the study conditions, based on the early mortality and adverse microscopic findings in the kidneys of 1000 mg/kg animals, a NOAEL for the test substance was established at 300 mg/kg bw/day.
- Executive summary:
A study was conducted to determine repeated dose toxicity of the test substance when administered to rats according to OECD Guideline 408, EU Method B.26 and EPA OPPTS 870.3100. The test substance, formulated in water, was administered daily for at least 90 days by oral gavage to SPF-bred Wistar Han rats. One control group and three treated groups were tested, each consisting of 10 males and 10 females, at the dose levels of 0, 100, 300 and 100 mg/kg bw/day. Chemical analyses of formulations were conducted on three occasions during the study to assess accuracy and homogeneity. The following parameters were evaluated: mortality and clinical signs daily; functional observation tests in week 13; body weight and food consumption weekly; ophthalmoscopy at pretest and in week 13; estrous cycle determination during the last 3 weeks; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues. Formulation analyses confirmed that formulations of test substance in water were prepared accurately and homogenously. Adverse test substance-related morphologic alterations were observed in the kidneys of males and females treated at 1000 mg/kg. These findings consisted of the accumulation of pigmented material in vacuolar structures in the cortical tubules. This pigmented material may well represent (parts of) test substance accumulated in the tubular organelles (lysosomes). At higher severity, the pigmented material most likely caused additional degeneration of the tubules and regenerative changes of the tubules, which was visible by the increased presence of basophilic tubules. The rather severe vacuolation with pigmented material, in combination with degeneration of tubules and increased tubular basophilia, is considered to be adverse. Furthermore, kidney weights were increased in 1000 mg/kg animals, an effect attributed to tubular vacuolation with pigmented material. The spontaneous death of a 1000 mg/kg male was also most likely attributed to the abovementioned test-substance related effects. At 300 mg/kg, in a few males and females, some small vacuoles containing a minimal amount of pigmented material were still present. This was not considered to be adverse based on severity and absence of the additional degenerative changes seen at 1000 mg/kg. Haematological alterations such as increased neutrophil levels in 300 mg/kg males, and 1000 mg/kg males and females, and increase in white blood cell counts in 1000 mg/kg females, and reductions of relative lymphocyte level in 1000 mg/kg males and females, and 300 mg/kg males do not seem to have any clear microscopic correlate. Also no clear correlation could be determined for changes in clinical biochemistry parameters, including increased urea, creatinine and inorganic phosphate levels in 1000 mg/kg males and females. In addition increased levels of total protein (1000 mg/kg), albumin (300/1000 mg/kg), and bilirubin (100/300/1000 mg/kg) were noted in males. At 1000 mg/kg, increases were observed in the levels of liver enzymes alanine aminotransferase and aspartate transaminase, and in other liver-related parameters including cholesterol and glucose levels. Although these occurred in correlation with increased liver weight, no corroborative microscopic correlates were noted. Haemoglobin, mean red blood cell volume, and mean cell haemoglobin concentration were all reduced in 1000 mg/kg animals, and red blood cell distribution width was increased in 1000 mg/kg females. These changes were small in scale and may be related to the marginally higher incidence of haematopoiesis (slight) observed in the spleen of 1000 mg/kg animals. Based on these slight changes and the histopathological evaluation this was considered to be non-adverse. Other test substance-related findings as increased macrophages in male and female mesenteric lymph nodes starting at 300 mg/kg/day, vacuolation of the zona glomerulosa of male and female adrenal glands at1000 mg/kg/day and increased apoptosis in male pancreas at 1000 mg/kg/day were also considered to be non-adverse since these findings were slight in nature. Clinical signs including diarrhoea, swelling/gas distention of the abdomen and rales were incidentally observed in individual surviving animals, mainly in 1000 mg/kg animals. These signs were most likely related to the test substance, however their respective durations were transient, and had no clear clinical pathology or microscopic correlate. The reduced foregrip strength in 300 mg/kg males and 1000 mg/kg males/females, and reduced motor activity in 1000 mg/kg females occurred in the absence of any clear correlation of clinical signs or morphological changes and therefore considered not adverse. No toxicologically significant changes were noted in any of the remaining parameters investigated in this study (i.e. ophthalmoscopy, body weight, food consumption, functional observations, and macroscopic examination). Under the study conditions, based on the early mortality and adverse microscopic findings in the kidneys of 1000 mg/kg animals, a NOAEL for the test substance was established at 300 mg/kg bw/day (Beerens-Heijnen, 2017).
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