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Diss Factsheets

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Test material form:
liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
80% Polyethylene glycol 400 (PEG 400) in distilled water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples for homogeneity analysis were also analyzed for verification of dose level concentration. Results of dose formulation were 94.8, 91.1 and 104.5% at each dose levels of 25, 75 and 250 mg/mL. They were acceptable as the mean concentration was within ± 20% of the nominal concentration.
Duration of treatment / exposure:
Dosing of the males will begin 14 days prior to mating and continue through the day prior to sacrifice (at least 28 days). Dosing of the females will begin 14 days prior to mating and continue through lactation day (LD) 13. Animals in recovery group will not be mated and will be assigned to 2 weeks of recovery period after the completion of administration.
Frequency of treatment:
once a day
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw (total dose)
Dose / conc.:
100 mg/kg bw (total dose)
Dose / conc.:
300 mg/kg bw (total dose)
Dose / conc.:
1 000 mg/kg bw (total dose)
No. of animals per sex per dose:
control: 18 animals
100, 300 mg/kg: 12 animals
1000 mg/kg: 18 animals
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
1. Mortalilty observation
Mortality and morbidity observations were conducted twice daily except for the acclimation period. In addition, it was conducted once on necropsy day.
2. Clinical signs
Clinical signs including general appearance and behavior changes were recorded with date/time of finding, and duration. During the gestation period, dams were especially monitored for signs of abortion or premature delivery. In addition, nursing dams were carefully observed during the lactation period. Detailed clinical observations were made in all animals individually for abnormalities. Signs noted were included (but are not limited to) evaluation of fur, skin, eyes, mucous membranes, occurrence of secretions and excretions, autonomic nervous system activity (lacrimation, piloerection, pupil size, and unusual respiratory pattern), changes in gait, posture, clonic and tonic movements, stereotypical and bizarre behavior, and difficult and prolonged parturition. General clinical signs including observation after dosing were not additionally recorded in the day of detailed clinical signs observation.
3. Functional observation
Sensory function tests (approach and touch response, tail pinch, acoustic startle response and pupillary reflex), grip strength and motor activity were conducted in first six animals per sex in main group (if possible) and in all animals of the recovery group shortly before scheduled sacrifice.
Sacrifice and pathology:
1. Hematology
Approximately 1.5 mL of blood sample was collected for hematology. For the hematological test about 0.5 ml of blood was put into tubes containing potassium salt of EDTA. About 1.0 mL of blood was put into tubes containing 3.2% sodium citrate and then centrifuged (approximate 3000
rpm, 10 min, at room temperature) to obtain plasma to determine the clotting potential test.
2. Clinical chemistry
Approximately 1.5 mL of blood samples was collected for clinical chemistry. Blood was put into tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged (approximate 3000 rpm, 10 min, at room temperature) to obtain serum.
Other examinations:
1. Macroscopic findings
Complete necropsy was performed under the direct supervision of a veterinary pathologist. After blood sampling, the animals were sacrificed by exsanguination from the vena cava and aorta. The animals were examined carefully for external abnormalities. The abdominal, thoracic and cranial cavities were examined for abnormalities and the organs were removed and examined. Special attention was paid to the organs of the reproductive system.
2. Organ weights
Organs were weighed for all animals at terminal and recovery sacrifice and organ/body weight ratios using the terminal body weight (TBW) obtained prior to necropsy was calculated. Paired organs were weighed together unless gross abnormalities are present. However, paired reproductive organs were weighed separately.
3. Microscopic findings
All tissues except reproductive organs collected from first six animals per sex in main group were further processed to slides, stained with hematoxylin and eosin, and examined microscopically. All reproductive organs collected from the main groups were further processed to slides, stained with H&E, and examined microscopically.
Statistics:
Pristima system or SAS/STAS (Version 9.4 USA)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In males at 100, 300 and 1000 mg/kg, salivation was observed in 11, 12, and 18 animals, respectively. In females at 100, 300 and 1000 mg/kg, salivation was observed in 9, 11, and 18 animals, respectively. It was considered test item-related but not toxicologically statistically significant since it was considered to be attributed to the palatability of the test item.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes in body weight and body weight gain were observed in both sexes during the study.
Statistically significant changes in body weight gain during the study was not considered test item-related since it was transient.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes in food consumption were observed in both sexes during the study.
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
Description (incidence and severity):
Total red blood cell count (RBC) was significantly increased (1.07-fold over control, respectively) in males at 300 and 1000 mg/kg and mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were significantly increased (1.08 and 1.07-fold over control, respectively) in females at 1000 mg/kg. These changes were fully recovered after recovery period and considered not to represent meaningful toxicity as there were no histopathological
correlates.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Inorganic phosphorus (IP) was significantly decreased (85% of control) in males at 1000 mg/kg.
These changes were fully recovered after recovery period and considered not to represent meaningful toxicity as there were no histopathological correlates.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes in functional behavior examination were observed in both sexes during the study.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes in organ weights were observed in both sexes during the study.
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw (total dose)
Sex:
male/female
Basis for effect level:
clinical biochemistry
clinical signs
haematology

Target system / organ toxicity

Key result
Critical effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw (total dose)

Applicant's summary and conclusion