Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006-05-15 to 2006-07-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented GLP-compliant study performed according to OECD Guideline 407 and EU Method B.7. No deviations were recorded.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2007

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanse Guidelines for Screening, Toxicity Testing of Chemicals: Testing Methods for new Substances, enacted July 13, 1974, amended December 5, 1986
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): T001624
- Physical state: solid
- Appearance: white powder
- CAS: 132961-05-8
- Molecular formula: C23H28F2N4O2
- Molecular weight: 430.5 g/mol
Specific details on test material used for the study:
Name of test material: T1624
- Physical state: white solid
- Analytical purity: 99.9% (assay base)
- Lot/batch No.: RT001624 IRA881
- Expiration date of the lot/batch: 2011-08-30
- Storage condition of test material: at room temperature (15-25 °C) away from direct sunlight
- Other:
- Stability of test item: stable under storage conditions

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: HanRcc:WIST (SPF) from RCC Ltd., Laboratory Animal Services, CH - 4414 Füllinsdorf, Switzerland
- Age at delivery: 6 weeks
- Weight at acclimatization: 132.5 - 154.6 grams (mean 143.7 grams) for males, 115.9 - 132.3 grams (mean 123.7 grams) for females
- Fasting period before study: no data
- Housing: standard laboratory conditions; groups of five rats in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz, Switzerland).
- Diet:ad libitum, Pelleted standard Provimi Kliba 3433 (batch no. 01/06 and 23/06) rat maintenance diet (Provimi Kliba AG)
- Water: ad libitum, Community tap-water from Itingen in water bottles
- Acclimation period: one week, under test conditions after health examination. Only animals without any visible signs of illness were used for the study

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity (%): 30-70 %
- Air changes: 10-15 air changes per hour
- Photoperiod: 12-hour fluorescent light/12-hour dark cycle with music during the light period

IN-LIFE DATES: from 2006-05-25 to 2006-07-28
From: 2006-05-25 to 2006-06-16 To: 2006-06-07 to 2006-07-28

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: PEG 300
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The dose formulations were prepared weekly. T1624 was weighed into a glass beaker on a tared Mettler balance and the vehicle was added. The mixtures were prepared using a magnetic stirrer and stored at room temperature (15-25 °C). Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

DIET PREPARATION: no data

VEHICLE
- Justification for use and choice of vehicle: no data
- Concentration in vehicle: 10, 30, 100, and 80 mg/kg body weight/day
- Amount of vehicle: 5 mL/kg body weight
- Lot/batch no.: no data
- Purity: no data
- Expiry date: 2011-02-02 and 2011-04-08
- Storage conditions: at room temperature (15-25°C) in the original container in the dark
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability, after 2 hours and 7 days, of the dose formulations were determined in samples taken after experimental start. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment. The analyses were performed by RCC Ltd., Environmental Chemistry & Pharmanalytics Division, according to an HPLC method supplied by the study owner.

This analytical phase was conducted at RCC Ltd., Itingen, Switzerland under GLP-compliant conditions to verify the identity of the test substance T1624 administered and to determine the content, homogeneity and stability of application formulations. Several application formulations were prepared at the test facility, and representative analytical samples were collected and dispatched to the test site internally. The test substance concentrations were determined by HPLC coupled to a UV detector and quantified with the area under the peak. The application formulations investigated during the study were found to comprise T1624 in the range of 94.7% to 114%. The distribution of T1624 in the dose preparation (±4.6%) was found to be homogenous. In addition, the test item as formulation was found to be when kept 7 days under storage conditions. In conclusion, the results obtained within this phase confirm the correct preparation and storage of application formulations during the conduct of this study.
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
10 mg/kg bw/day
Basis:
other: nominal daily dose
Remarks:
Doses / Concentrations:
30 mg/kg bw/day
Basis:
other: nominal daily dose
Remarks:
Doses / Concentrations:
100 mg/kg bw/day
Basis:
other: nominal daily dose
Remarks:
Doses / Concentrations:
80 mg/kg bw/day
Basis:
other: nominal daily dose
No. of animals per sex per dose:
5 animals per sex per dose. Two groups of five additional animals per sex were included at the 0 and 80 mg/kg dose levels.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based upon the results of a non-GLP, 5-day dose-range-finding study (RCC Study Number A71436) in which T1624 was administered by gavage to 2 rats per group and sex.
- Rationale for animal assignment: computer-generated random algorithm
- Rationale for selecting satellite groups: Two groups of five additional animals per sex at the 0 and 80 mg/kg dose groups were treated for 28 days and then allowed a 14-day treatment-free recovery period to assess reversibility of treatment-related changes. These animals were sacrificed after the 14-day recovery period.
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale: no data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed for clinical signs once before commencement of administration; twice daily on days 1-3; as well as once daily on days 4-28 and once daily during days 29-42 in recovery group animals.
- Cage side observations included: appearance (piloerection, salivation, hunched posture, hair loss (localized, left shoulder, & right shoulder)), motor function (ataxia, ventral recumbency, abnormal gait, tremor), behavior (hyperactivity, somnolence, sedated/dull), respiration (dyspnea, tachypnea, bradypnea, breathing noises), lacrimation, limbs cyanotic, and observations for mortality/viability were recorded twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were observed in their home cages, outside their home cages in a standard arena, and in the hand. These observations were performed in random sequence once before commencement of administration and once weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly during pretest, treatment and recovery and before
necropsy, using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer.

FOOD CONSUMPTION AND COMPOUND INTAKE : Yes
- Time schedule: once during the pretest period and weekly thereafter
- using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer. The food consumption was calculated per rat and per food consumption interval. It expresses the average food consumed per animal and per day over the food consumption interval. The relative food consumption was also calculated in grams of food per kg body weight and day.

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE:
- Water consumption was not monitored.
- Time schedule for examinations: not applicable

OPHTHALMOSCOPIC EXAMINATION:
- Ophthalmoscopic examinations were not conducted.
- Time schedule for examinations: not applicable
- Dose groups that were examined: not applicable

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after four and six weeks
- Anaesthetic used for blood collection: light isoflurane
- Animals fasted: 18 hours before blood sampling in metabolism cages but allowed access to water ad libitum
- How many animals: All remaining animals after the 100 mg/kg dose group was removed from the study (30 males and 30 females).
- Parameters examined: erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, red cell volume distribution width, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin concentration distribution width, platelet (thrombocyte) count, reticulocyte count, reticulocyte maturity index, methemoglobin, Heinz bodies (slides were prepared but evaluated only if changes were seen in the
methemoglobin levels), total leukocyte count, differential leukocyte count, coagulation: thromboplastin time, and activated partial thromboplastin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after four and six weeks
- Anaesthetic used for blood collection: light isoflurane
- Animals fasted: 18 hours before blood sampling in metabolism cages but allowed access to water ad libitum
- How many animals: All remaining animals after the 100 mg/kg dose group was removed from the study (30 males and 30 females).
- Parameters examined: glucose, urea, creatinine, bilirubin (total), cholesterol (total), triglycerides, phospholipids, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, creatine kinase, alkaline phosphatase, gamma-glutamyl-transferase, sodium, potassium, chloride, calcium, phosphorus inorganic, protein total, albumin, globulin, albumin/globulin ratio

URINALYSIS: Yes
- Time schedule for collection of urine: at four and six weeks
- Metabolism cages used for collection of urine: no data
- Animals fasted: urine was collected during the 18 hour fasting period in a specimen vial
- Parameters examined: volume (18 hours), specific gravity (relative density), color, appearance, pH, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, erythrocytes, leukocytes

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4
- Dose groups that were examined: all animals
- Battery of functions tested: modified Irwin screen test
- grip strength: forelimb and hind limb grip strength measurements were performed using a push-pull strain gauge (Mecmesin, AFG 25N). The animals were placed with the forepaws inside a triangular grasping ring and with the hind paws outside a triangular grasping ring. Using one hand, the animals were held towards the base of the tail and steadily pulled away or towards the ring until the grip was broken. Each measurement was repeated three times, the means were calculated and recorded.
- locomotor activity: locomotor (decreased or increased) activity was measured quantitatively with AMS Föhr Medical Instruments GmbH (FMI) and DeMeTec GmbH Acitivity Motor System. Animals were monitorid during the fourth treatment week for a 60-minute period and the total activity of this time period was recorded. Low beams count was reported in 10-minute intervals as well as the total activity of the measuring period.

OTHER:
MORTALITY/VIABILITY: Yes
- Observations for mortality/viability were recorded twice daily.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Group 4 (100 mg/kg ) was sacrificed and necropsied on 7 June 2006 due to unexpected serious symptoms and high mortality and was replaced by Group 5 at a lower dose level (80 mg/kg). All animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded.

All animals surviving to scheduled necropsy and all moribund animals were anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination. Samples of the following tissues and organs were collected from all animals at necropsy and fixed in neutral phosphate buffered 4% formaldehyde solution (unless otherwise indicated): adrenal glands, aorta, bone (sternum, femur including joint), bone marrow (femur), brain (4 levels), cecum, colon, duodenum, epididymides (fixed in Bouin's solution), esophagus, eyes with optic nerve (fixed in Davidson's solution), harderian gland (fixed in Davidson's solution), heart, ileum with Peyer's patches, jejunum with Peyer's patches, kidneys, larynx, lacrimal gland (exorbital), liver, lungs (infused with formalin at necropsy), lymph nodes (mesenteric, mandibular), mammary gland area, nasal cavity, ovaries, pancreas, pituitary gland, prostate gland (including coagulating gland), rectum, salivary glands (mandibular, sublingual), sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord (cervical, midthoracic, lumbar), spleen, stomach, testes (fixed in Bouin's solution), thymus, thyroid (including parathyroid gland), tongue, trachea, urinary bladder (infused with formalin at necropsy), uterus, vagina, gross lesions.

HISTOPATHOLOGY: Yes
Organ and tissue samples taken from animals which died spontaneously or which were killed in extremis were evaluated similarly to those organs taken from animals treated with 80 mg/kg/day. Because treatment-related morphologic changes were detected in the organs of high-dose animals, the same organs (kidneys) from animals of the mid- and low-dose groups were examined. All tissues were processed, embedded, and cut at an approximate thickness of 2 to 4 micrometers, and stained with hematoxylin and eosin.
Adrenal glands, bone marrow (femur), brain (4 levels), cecum, colon, duodenum, epididymides, heart, ileum, with peyer's patches, jejunum with peyer's patches, kidneys, liver, lungs, lymph nodes (mesenteric, mandibular), ovaries, prostate gland (including coagulating gland), rectum, sciatic nerve, seminal vesicles, spinal cord (cervical, midthoracic, lumbar), spleen, stomach, testes, thymus, thyroid (including parathyroid gland), trachea, urinary bladder (necropsy), uterus, vagina, and gross lesions that were collected at scheduled sacrifice from the animals of control and high dose groups were examined by a pathologist.

Other examinations:
Organ weights: recorded on the scheduled dates of necropsy: brain, thymus, spleen, ovaries, heart, kidneys, testes, liver, adrenals, and epididymides. The organ to terminal body weight ratios, as well as organ to brain weight ratios, were determined. The determination of the terminal body weight was performed immediately prior to necropsy.
Statistics:
The following statistical methods were used to analyze the grip strength, locomotor activity, body weight, organ weights and ratios, as well as clinical laboratory data:
- The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the treated groups and the control groups for each sex.
- The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
- Fisher's exact-test was applied to the macroscopic findings.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
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):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
MORTALITY:
The mortality was not influenced by treatment with T1624. Female no. 71 (80 mg/kg/day) was found dead on treatment day 25. No observed clinical signs were noted in female no. 71 until its death and therefore it was considered to be incidental. All other animals of dose groups 1, 2, 3, and 5 survived until their scheduled necropsy.

CLINICAL SIGNS AND MORTALITY
General cageside observations (daily):
- Audible breathing noises
- treatment days 19 and 20 in males treated with 80 mg/kg/day
- treatment day 5 in females treated with 80 mg/kg/day.
- Salivation: Males and females treated with 80 mg/kg/day from treatment day 18 until the end of the treatment or from treatment days 17 to 27, respectively.
- Soft feces
- treatment days 1, 18 to 20 and 26 to 28 in males treated with 80 mg/kg/day
- treatment days 1, 12 and 13, and 26 to 28 in females treated with 80 mg/kg/day with a high percentage of affected animals.
- ruffled fur: males treated with 80 mg/kg/day on treatment days 6 to 10.
- Hunched posture on treatment days 10 and 11 and dull behavior on treatment days 12 and 13 were noted in females treated with 80 mg/kg/day.
In animals treated with 80 mg/kg/day, soft feces were recorded during the first day of the recovery period. All other previously mentioned clinical signs disappeared during the recovery period. These findings were considered to be test item-related. Salivation in male control animals and localized hair loss (head) in female control animals and females treated with 80 mg/kg/day (cervical region and shoulders) occurred sporadically, but were considered to be incidental.

Detailed clinical observations (weekly):
In males and females treated with 80 mg/kg/day, audible breathing noises were noted in treatment weeks 1, 2 and 3 or in weeks 1 and 2, respectively. During week 1, hunched posture and trembling were noted in males treated with 80 mg/kg/day. In females treated with 80 mg/kg/day, trembling was recorded in treatment week 3. Males and females treated with 80 mg/kg/day showed sedated behavior and vocalization following tactile stimulation in week 3 of treatment. In females treated with 80 mg/kg/day, dull behavior was noted in week 2 of treatment. These findings were considered to be test item-related. Localized hair loss in control animals and females treated with 80 mg/kg/day were considered to be incidental and therefore of no toxicological relevance.

BODY WEIGHT AND WEIGHT GAIN
Test item-related reductions in mean body weight were noted in animals treated with 80 mg/kg/day. The differences were more clearly expressed in males, and attained statistical significance on days 8 and 22 of the treatment and on day 1 of the recovery period. In females, the body weight and body weight gain were moderately reduced on days 8, 15, 22, and 28 of the treatment. The mean body weight and body weight gain of animals treated with 10 and 30 mg/kg/day were unaffected by the treatment with T1624.

FOOD CONSUMPTION AND COMPOUND INTAKE
No findings of toxicological relevance were noted in rats of either sex.

HAEMATOLOGY
After week 4:
None of the observed differences were considered to be test item-related.
In males treated with 80 mg/kg/day, the hematocrit and the M reticulocytes count were significantly increased. The mean corpuscular hemoglobin concentration and the L reticulocyte count were significantly decreased. In females treated with 80 mg/kg/day, the hemoglobin concentration distribution width and the relative and absolute reticulocyte count were significantly increased. The leukocyte count, the absolute neutrophils, eosinophils, basophils, lymphocytes, monocytes, and large unstained cells were significantly increased in females treated with 80 mg/kg/day. Due to biological variance and no clear dose-response relationship, these findings were considered to be of no toxicological relevance.

After week 6:
No test item-related late effects were observed.
Males treated with 80 mg/kg/day showed a significant increase in absolute neutrophil and monocyte count. In the same animals, the partial thromboplastin time was significantly decreased. In females treated with 80 mg/kg/day, the hemoglobin and hematocrit were significantly decreased. The leukocyte count, the absolute basophils, lymphocytes, monocytes and large unstained cells were significantly increased in females treated with 80 mg/kg/day. The platelet count was significantly reduced in females treated with 80 mg/kg/day. Due to biological variance and no clear dose-response relationship, these findings were considered to be of no toxicological relevance.


CLINICAL CHEMISTRY
After week 4:
Test item-related effects were observed in blood protein levels.
The total blood protein, albumin and globulin levels were significantly decreased in animals treated with 80 mg/kg/day. The albumin/globulin ratio was significantly increased in males treated with 80 mg/kg/day and slightly increased in females treated with 80 mg/kg/day. In females treated with 80 mg/kg/day, the assessment of the blood glucose level revealed a significant decrease. In females treated with 30 and 80 mg/kg/day, the triglyceride level was significantly increased. These changes in the metabolism were considered not to be test item-related because there were no increases in liver enzymes and no correlative histopathological findings in the liver. In males treated with 80 mg/kg/day, the calcium level was significantly decreased. In females treated with 80 mg/kg/day, the chloride level was significantly reduced. In females treated with 30 and 80 mg/kg/day, the phosphorus level was significantly increased. Due to biological variance and no clear dose-response relationship, these findings in the electrolyte balance were considered to be of no toxicological relevance. In animals treated with 80 mg/kg/day, the lactate dehydrogenase (LDH) level was significantly increased. Differences in LDH were considered to be of no toxicological relevance.

After week 6:
In the recovery males, the total protein and albumin level were significantly increased. In the recovery females, the globulin level was significantly increased. The reversible effect to the changes in the total protein, albumin and globulin levels were more clear in males than in females. Therefore, these changes were considered to be not adverse. In males and females treated with 80 mg/kg/day, the blood glucose level was significantly decreased. These findings were considered not to be test item-related because no indication for liver damage was found. In the recovery animals, the sodium level was significantly increased. In the recovery males, the chloride level, and in the recovery females the phosphorus level, were significantly elevated. Due to biological variance and sex-specific effects, these findings were therefore considered to be of no toxicological relevance. In the male recovery animals, the urea was significantly lower. The lactate dehydrogenase was significantly decreased in female recovery animals. These findings were incidental and therefore considered to be of no toxicological relevance.


URINALYSIS
The assessment of the relative density of the urine revealed a significant increase in animals treated with 80 mg/kg/day at week 4. This finding was incidental and therefore considered to be of no toxicological relevance. No test item-related findings were observed.

NEUROBEHAVIOUR
During functional observational battery, the following test item-related findings were observed in animals treated with 80 mg/kg/day: ventral recumbency and abnormal gait was noted in 6/10 males and 5/10 females. Tremor was recorded in 3/10 males and 5/10 females. Further findings (localized hair loss in control females and in females treated with 80 mg/kg/day during week 4 of treatment) were considered to be incidental and therefore of no toxicological relevance.

Grip Strength:
Test item-related reductions in mean fore- and hind-limb grip strength were noted at 80 mg/kg/day. The mean fore- and hind-limb grip strength values in males were significantly decreased and moderately decreased in females. The mean fore- and hind-limb grip strength values of rats treated with 10 mg/kg/day and 30 mg/kg/day were unaffected.

Locomotor Activity:
The following test item-related findings were found in animals treated with 80 mg/kg/day: in males, the mean locomotor activity showed a significant reduction during the 20-30 min., 30-40 min. and 50-60 min. measurement intervals. The mean locomotor activity during the 10-20 min. and 40-50 min. measurement intervals and the total mean locomotor activity were moderately decreased in males. In females, significant reductions in mean locomotor activity during the 20-30 min. and 30-40 min. measurement intervals and in the total mean locomotor activity were observed. The mean locomotor activity during the 10-20 min., 40-50 min. and 50-60 min. measurement intervals in females were slightly decreased. Further findings were within the biological range and considered to be of no toxicological relevance. In males treated with 10 mg/kg/day, a significantly reduced mean locomotor activity during the 50-60 min. measurement intervals was recorded. In females treated with 10 mg/kg/day, the mean locomotor activity during the 10-20 min. measurement interval was significantly elevated.

ORGAN WEIGHTS
No test item-related effects of toxicological relevance were noted in absolute and relative organ weights in rats of either sex after treatment (after 4 weeks) and recovery (after 6 weeks) period.

After 4 Weeks:
In males, the mean absolute and relative organ weights of test item-treated rats compared favorably with those of control males. In females treated with 80 mg/kg/day, the mean absolute brain, heart and adrenal weight were significantly decreased. These differences in organ weights were not accompanied by microscopical changes and were therefore considered to be of no toxicological relevance. The absolute and relative organ weights of females treated with 10 and 30 mg/kg/day were unaffected by the treatment.

After 6 Weeks:
In males treated with 80 mg/kg/day, the absolute and relative liver organ weights were significantly reduced. The organ/body weight ratio of the kidney was significantly increased in males treated with 80 mg/kg/day. A significant increase in organ/body weight ratio of the brain, testes and epididymides was recorded in males treated with 80 mg/kg/day. In females treated with 80 mg/kg/day, the absolute and relative liver organ weights were significantly reduced. The organ/body weight ratio of the kidney was significantly increased and the organ/brain weight ratio of the adrenals significantly decreased in females treated with 80 mg/kg/day. Minor differences noted in organ weights and ratios were considered to be secondary effects of the differences in body weight. Therefore, these findings in the recovery animals were considered to be incidental and not test item-related.


GROSS PATHOLOGY
At the end of the treatment and the recovery periods, no test item-related gross lesions were observed. The findings recorded were considered to be within the range of normal background lesions, which may be seen in rats of this strain and age in oral toxicity studies and were considered incidental, reflecting the usual individual variability.


HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic findings consisted of increased severity of hyaline droplets in the kidneys of males treated with 80 mg/kg/day and increased incidence and severity of eosinophilic cytoplasm of tubular kidney cells in the cortical region in a few females treated with 80 mg/kg/day. Hyaline droplets in kidneys were increased in incidence and severity in the male recovery animals. Eosinophilic cytoplasm of tubular kidney cells in the cortical region in females previously treated with 80 mg/kg/day resolved after the recovery period. These findings in the kidneys in males and females treated with 80 mg/kg/day were not accompanied by signs of epithelial damage or further adverse findings and were reversible in female animals. In males, the hyaline droplets in the kidney were typical background lesions, specific to the male rat and therefore of no toxicological relevance or risk to man. In females, the finding in the kidney was considered to be test item-related, but not adverse. Further microscopical findings recorded were considered to be within the range of normal background lesions, which may be seen in rats of this strain and age in oral toxicity studies and were considered incidental, reflecting the usual individual variability.


HISTOPATHOLOGY: NEOPLASTIC
No data


HISTORICAL CONTROL DATA
no data


OTHER FINDINGS
no data

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
30 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Test substance related effects on clinical signs, functional observational battery, body weight, clincial biochemistry were observed at 80 mg/kg bw /day dose level.
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Test substance related effects on clinical signs, functional observational battery, body weight, clincial biochemistry were observed at 80 mg/kg bw /day dose level.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, 30 mg/kg body weight/day of T1624 was established as the no-observed-effect-level (NOEL) and as the no-observed-adverse-effect-level (NOAEL) based upon findings noted in the functional observational battery. Therefore the test item should be considered as STOT RE 2.