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Administrative data

chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 8, 1985 to July 17, 1985
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Per protocol and GLP.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
6-{[4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-[(5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-3,5,7,9,11,13-hexamethyloxacyclotetradecane-2,10-dione (non-preferred name)

Test animals

Details on species / strain selection:
Details on test animals or test system and environmental conditions:
- Source:Charles River Breeding Laboratories
- Age at study initiation:4 weeks old upon arrival and about 6 weeks old at the start of treatment.
- Fasting period before study: not noted
- Housing: throughout the study, animals were housed individually in hanging metal, mesh-bottom ca ges equipped with feeders and automatic waterers.Animal cages, racks and cage mats were changed regularly.The animal room was cleaned regularly .
- Diet (e.g. ad libitum): Certified Rodent Chow® pellet; were available ad libitum, except as noted elsewhere in this protocol.
Water (e.g. ad libitum): tap water were available ad libitum, except as noted elsewhere in this protoc ol.
- Acclimation period: 8days

- Temperature (°C):. Ambient temperature was maintained at 72 ± 5°F.
- Humidity (%):Temperature and humidity were monitored continuously with a temperature-h ygrometer unit.
- Air changes (per hr): not noted
- Photoperiod (hrs dark / hrs light):The room was on a 14-hour daily light cycle.
Racks within the room were rotated 180° and moved one rack space within the room each week. IN-LIFE DATES: - March 8, 1985 (day 0) through April 11, 1985

Administration / exposure

Route of administration:
oral: gavage
other: saline in 0.2% hydroxypropylmethylcellulose.
Details on oral exposure:

To - Vehicle control
Tl -15.0 mg/kg/day, as free base . T2 -37.5 mg/kg/day, as free base. T3 -75.0 mg/kg/day, as free base. T4 - 150.0 mg/kg/day, as free base.


- Concentration in vehicle:10 ml/kg.
- Amount of vehicle (if gavage):10 ml/kg.

Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Assayed values for samples of dosing formulations for all groups sent to Analytical Research for ana lysis during the first, fourth and twelfth weeks of the study corresponded closely to the theoretical values. In addition, assayed values of samples of both lots of bulk drug anayzed after the treatment period corresponded closely to the theoretical values.
Duration of treatment / exposure:
Each surviving rat received an oral dose by gavage each morning, seven days per week, for a period of approximately one or three months. During the treatment period each rat received a dose volume of 10 ml/kg based upon the most recent body weight data available.
Frequency of treatment:
Doses / concentrationsopen allclose all
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
37.5 mg/kg bw/day (actual dose received)
Dose / conc.:
75 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Two hundred and sixty-three Crl:Co®(SD)BR rats (132 males, 131 females)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:The acute oral LD50 of ABBOTT-56268 in rats is reported to be in excess o f 5 g/kg.Two preliminary 30-day male rat oral toxicity studies were conducted by Taisho Pharmaceuti cal Co., Ltd. (Tokyo). The apparent "no-toxic-effect" dosage was 50 mg/kg/day . In the second preli minary rat study. The "no-toxic-effect" dosage was 75 mg/kg/day.

The lowest dosage (15 mg/kg/day) approximated the anticipated human clinical dosage, while the highest dosage (150 mg/kg/day) represented a dosage which had previously been shown to be toxic and was expected to be toxic when administered for one and three months. The intermediate dos ages represented approximately equal log intervals between the 15 and 150 mg/kg/day dosages. The oral route was used because this is an intended clinical route.

Rationale for animal assignment (if not random):random

Toxicology (D-468) personnel prepared the T1, T2, T3 and T4 formulations daily.Stability data showed that 1.44 to 49.8 mg/ml concentrations of ABBOTT-56268 in 0.2% hydroxypropylmeth ylcellulose
were stable for up to 7 days.
Positive control:
None noted


Observations and examinations performed and frequency:
All rats were observed twice each day during the pretreatment and treatment periods for survival and general condition. In addition to the above twice daily observations, further examinations of physical condition and behavior were recorded approximately 2-4 hours after dosing five days each week during the 3-month treatment period.

Body weight and food consumption were measured twice during the pretreatment period and twice weekly during the first four weeks of treatment and weekly thereafter.

Ophthalmoscopic examinations (funduscopic and slit lamp) were performed by a veterinarian on each rat prior to treatment initiation, during the fourth treatment week, and at the end of the three-month treatment period.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
Anatomic Pathology
Eight rats (2 T0, 2 T1, 1 T2 and 3 T4) that died during the study were necropsied as soon as was p ractical.
The order in which the rats were necropsied was determined by a randomization schedule. The sched uled necropsies were conducted over several days.

Representative tissues from the organs listed below were assessed histologically from rats in groups To and T4 that were necropsied after three months of treatment as well as tissues from eight rats th at died during the treatment period.Because drug-related lesions were detected in the livers from the T4 rats, livers from the lower dosage groups were examined histologically.Other tissues from the T1
through T3 groups were however not examined microscopically, but were saved for future reference.

Bone (vertebra)
Bone marrow (vertebra) Brain
Cecum Epididymis Esophagus Eye
Gross lesions (at discretion of the pathologist) Heart
Intestine, small Intestine, large
Kidney Liver Lung
Lymph node,
cervical Lymph node, mesenteric Lymph node, thoracic Mammary gland Ovary
Peripheral nerve (sciatic) Pituitary
Prostate Rectum Salivary gland
Seminal vesicle Skeletal muscle Skin
Spinal cord Spleen Stomach Testis Thymus Thyroid Trachea
Urinary bladder

Other examinations:
Organ Weights
Adrenals, brain, gonads, heart, kidneys and liver from each surviving rat were weighed at scheduled necropsy and the percent of body weight of each organ was calculated.

Urinalysis involved evaluation of the following parameters: Color

Glucose Ketones Specific gravity pH
Protein Bilirubin Occult blood
Microscopic sediment


Red blood cell (RSC) count Erythrocytic indices Hematocrit
White blood cell (WBC) count Differential white blood]cell count Prothrombin time
Activated partial thromboplastin time

Clinical Chemistry Urea nitrogen Creatinine
Sodium Potassium Calcium Chloride Phosphorus
Alanine amino transferase (ALT) Aspartate amino transferase (AST) Alkaline phosphatase
Cholesterol Bilirubin Glucose Triglycerides Total protein Albumin
Globulin (calculated)
Albumin to globulin ratio (calculated) Gamma glutamyl transferase (GGT)
Organ weight, body weight, food consumption and selected clinical pathology parameters were analyzed.T1, T2, T3 and T4 sex group means were compared to To sex group means and each otheusing analysis of variance and a suitable multiple comparison test. All statistical comparisons were performed at the
0.05 level of significance.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
the body weight gain of the group T1 males was statistically greater than that of the group T4 males.
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increased mean relative liver and kidney weights that exhibited dose-related tendencies for males.
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related multinucleated hepato cytes of varying numbers were detected in the livers from t he mid-dose (37.5 and 75 mg/kg/day) and high-dose (150 mg/kg/day) rats
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: Eight deaths occurred during the study: None of these deaths was considered to be treatment-related.

- Increased salivation occurred in both male and female drug-treated rats, with an apparent increase in frequency with time and dosage.
-Dehydration was observed with greater frequency with time in the drug-treated female rats, primarily in the groups T3 and T4 animals.
-Aggressive behavior was seen in both sexes in all groups, but sporadically and in a non-dose-relate d manner. Hyperactivity was observed in both sexes, primarily in the drug-treated groups and, in ge neral, at the higher dosages.
-Decreased activity occurred sporadically in the drug-treated rats of both sexes from the 42-55 day observation period.

-Urine-staining of the genital/anal areas occurred primarily in the group T4 female rats.
-Non-treatment- related signs included ptosis of the eyes, discharges, scabs, tinted hair, hair loss and abnormal teeth

- Mean body weights of the T1 male rats were significantly greater than the group T0 males from day
20 through 59 (except day 52).
-Mean body weights of the T4 male rats were not significantly different from that o the To males on
any day. However, from day 31 onward, the mean weights of the T4 males were consistently lower th an those of the T0 males; this finding is considered to be of biological significance.
- From day 3 onward, the mean body weights of the group T1 males were statistically greater than that of the r4 males.
- The mean body weight gain of the T1 males over the 3-month treatment period was not statistically different from the group r0 males. However, the body weight gain of the group T1 males was statisti cally greater than that of the group T4 males.
-No significant differences were found among the mean body weights for female rats during the three- month treatment period.
FOOD CONSUMPTION: Food consumption in the T3 and T4 male and T4 female rats was significa ntly lower than in the T0 control rats, but only during isolated treatment periods.
- Food consumption in the T1 and T2 male rats was significantly higher than in the T0 control rats, but only during isolated treatment periods.Food consumption in the\T4 female rats was significantly less than in the T1 and To control rats on days 10-13.
- Thus, no consistent or dose-related pattern was seen in food consumption during the three-month treatment period.

OPHTHALMOSCOPIC EXAMINATION: - No ocular abnormalities, except for blepharitis in the right e ye of one rat which was not considered to be treatment related.

HAEMATOLOGY: No toxicologically significant differences between ABBOTT-56268-treated and control rats for hematologic parameters evaluated.

CLINICAL CHEMISTRYNo toxicologically significant differences between ABBOTT-56268-treated and control rats for clinical chemistry parameters evaluated

URINALYSIS: No toxicologically significant differences between ABBOTT-56268-treated and control rats for urinalysis.

NEUROBEHAVIOUR: not evaluated.

ORGAN WEIGHTS: Increased mean relative liver and kidney weights that exhibited dose-related te ndencies for males.


HISTOPATHOLOGY: NON-NEOPLASTIC: Treatment-related microscopic changes characterized by the presence of multinucleated cells (hepatocytes) were evident in the livers from T2 through T4 rats.The incidence and severity of the changes were greatest in the T4 males. -The incidence and a ppearance of the multinucleated hepatocytes in the mid-dose sex groups (T2 and T3) resembled the incidence and appearance in the T4 females


OTHER FINDINGS: Treatment-related multinucleated hepatocytes of varying numbers were detected in the livers from the mid-dose (37.5 and 75 mg/kg/day) and high-dose (150 mg/kg/day) rats."No-
toxic-effect" level was considered to be 15 mg/kg/day.

Effect levels

Dose descriptor:
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: see remark

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

This final three-month report describes the findings from a group of 100 rats randomly selected for
final necropsy. Treatment-related multinucleated hepatocytes of varying numbers were detected in the livers from the mid-dose (T2 = 37.5 mg/kg/day and T3 = 75 mg/kg/day) and high-
dose (T4 = 150 mg/kg/day) rats.The "no-observed toxic-effect" level was considered to be 15 mg/kg/