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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990-07-06 - 1990-11-02
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study with acceptable restrictions. Analytical purity of test material not specified.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity in Non-Rodents)
Deviations:
yes
Remarks:
analytical purity of test material not specified
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Kalamazoo, Michigan, on July 18, 1989.
- Age at study initiation: 5-6 months
- Weight at study initiation: 8.7-10.2 kg for males, 6.6-9.3 kg for females
- Housing: Individually in elevated, stainless-steel cages
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.7-25.6
- Humidity (%): 13-100%
- Air changes (per hr): 10/h
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: capsule
Vehicle:
other: Capsule
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 100%
- Amount of vehicle (if gavage): 1 capsule/day
- Purity: 100%
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Routine concentration analyses indicated that animals were generally dosed with formulations that were within ± 10% of the target range. In cases where the percent target was not within this range, formulations were remixed and reanalyzed during the study week.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily, 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
15, 30 and 100 mg/kg bw/day
Basis:
other: Nominal in capsule
No. of animals per sex per dose:
4
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once each day

DETAILED CLINICAL OBSERVATIONS: Yes,
- Time schedule: Twice each day

BODY WEIGHT: Yes
- Time schedule for examinations: Prior to treatment and weekly thereafter

FOOD CONSUMPTION
- Time schedule for examinations: Weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: On all dogs prior to treatment and on the control and high-dose dogs prior to termination of treatment

HAEMATOLOGY: Yes, cell morphology hemoglobin, corrected leukocyte count, leukocyte count, erythrocyte count, leukocyte differential, hematocrit, platelet count
- Time schedule for collection of blood: Prior to termination of dosing
- Animals fasted: Yes, overnight

CLINICAL CHEMISTRY: Yes, alanine aminotransferase, glucose, albumin, inorganic phosghorus, aspartate aminotransferase, potassium, calcium, sodium, chloride, total bilirubin, creatinine, total protein, ganrna glutamyltransferase, urea nitrogen
- Time schedule for collection of blood: Prior to termination of dosing
- Animals fasted: Yes, overnight

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
-Organ weights of adrenals, testes with epididymides, kidneys, thyroid (with parathyroids), liver (with gallbladder drained)
Sacrifice and pathology:
GROSS PATHOLOGY: external surface of the body, all orifices, cranial cavity, carcass, external surfaces of the brain and spinal cord and the cut surfaces of the spinal cord (at necropsy); the cut surfaces of the brain were examined at the time of tissue trimming nasal cavity and nasal turbinates, thoracic, abdominal and pelvic cavities and their viscera, cervical tissues and organs

HISTOPATHOLOGY: adrenals, aorta, brain with brainstem, (medulla/pons, cerebellar cortex, and cerebral cortex), cecum, colon, rectum, cervical spinal cord, duodenum, jejunum, iIeum, esophagus, eyes, gallbladder, heart, kidneys, lesions, liver, lumbar spinal cord, lung (with mainstem bronchi), mammary gland, mesenteric lymph node
mid-thoracic spinal cord, ovaries, pancreas, pituitary, prostate, salivary glands (mandibular), sciatic nerve wi h skeletal muscle, spleen,sternum with bone marrow, stomach, testes with epididymides, thymus, thyroid (parathyroids), trachea, urinary bladder, uterus with vagina and cervix
Other examinations:
Detailed physical examinations performed weekly
Statistics:
Group comparisons were analyzed at the 5% two-tailed probability level.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
no adverse effects
Mortality:
mortality observed, treatment-related
Description (incidence):
no adverse effects
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
no adverese effects
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
All animals survived until terminal sacrifice. Apparent treatment-related changes noted in the 100mg/kg bw/day group males and/or females consisted of an increased incidence of salivation and emesis. In addition, soft feces, noted with mucus alone or mucus and bile-like material, were noted with a greater incidence in the high-dose animals.

BODY WEIGHT AND WEIGHT GAIN
Statistical evaluation of mean absolute body weights and mean body weight gain values failed to reveal any significant differences when treatment groups were compared to respective control values.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Statistical evaluation of mean total food consumption values failed to reveal any significant differences when treatment groups were compared to respective control values.

OPHTHALMOSCOPIC EXAMINATION
There were no apparent compound-related ophthalmoscopic changes observed at termination.

HAEMATOLOGY
Statistical evaluation of clinical hematology values revealed a significantly elevated mean erythrocyte value in the 100 mg/kg bw/day group females.
Although the statistical significance was noted, the 100 mg/kg bw/day group female mean value is within the historical control range; therefore, the significance appears to be associated with an unusually low mean control value. The toxicological relevance of this finding is questionable.

CLINICAL CHEMISTRY
Statistical evaluation of mean blood chemistry values revealed an elevated alanine aminotransferase value in the 100 mg/kg bw/day group females, elevated mean calcium values in the 30 and 100 mg/kg bw/day group females, and a depressed mean blood urea nitrogen value in the 30mg/kg bw/day group males. In regard to the calcium and blood urea nitrogen values, the relatively low magnitude of change in the calcium value and the absence of a dose response for the urea nitrogen value also lend question as to their biological significance.

ORGAN WEIGHTS
Statistical evaluation of organ weight values failed to reveal any significant differences when the absolute or relative organ weights were compared to respective control values.

GROSS PATHOLOGY
There were no gross necropsy findings which were considered to be related to treatment with ATMER 163. Those observations which were noted were of the type commonly observed in this species of dog at this laboratory.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histomorphologic examination of protocol-specified tissues revealed an increased incidence of pigment accumulation in the Kupffer cells and bile canaliculi in the livers of the Group 4 females. There were no other apparent compound-related tissue changes noted.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: tissue alterations in the liver of females at 100 mg/kg bw/d
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects up to the limit dose of 100 mg/kg bw/d

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Based on the data generated from this study, the no-observable-adverse-effect level NOAEL of Atmer 163 when administered via capsule for approximately 13 weeks to male and female beagle dogs is 100 mg/kg bw/day for local effects and 30 mg/kg bw/d for systemic effects.

Applicant's summary and conclusion

Conclusions:
CLP: not classified