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Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: polyethylene glycol 400
Details on oral exposure:
The administration volume was 5 ml/kg body weight per day.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test item (test substance) was administered by gavage in Polyethylene glycol 400. The administration volume was 5 mL/kg body weight per day.
The formulations were prepared weekly. For the preparation of the formulations, a test item content of 100% was assumed for calculation. The preparation of the formulation is described in the raw data.
The stability of the formulations was analytically confirmed before the first treatment. Dosage forms for these analyses were prepared according to the procedure intended for this study. The dosage forms prepared for stability analysis were analyzed after 4 hours and 4 and 8 days thereafter. The analysis revealed that the test item was stable over 8 days within the defined limits.
The content of the test substance concentrations (control and dosed formulations) was verified twice during the study.
The test substance was administered as a solution in the vehicle. The formulations were stored at room temperature.

Duration of treatment / exposure:
29 days
Frequency of treatment:
once daily
Remarks:
Doses / Concentrations:
100, 300, 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
five
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:

The dose level was selected according to results obtained in a previous oral 2-weeks dose finding toxicity study performed in rats at Bayer Pharma AG, where 0, 100, 500 or 1000 mg/kg b.w. Ester PSA + DEG were administered in polyethylene glycol 400 to 3 male and 3 female rats per dose group.The administration volume was 5 ml/kg b.w..
In-life data revealed no treatment-related changes in mortality, clinical observations, body weight gain, food intake, water intake and necropsy.
In conclusion, the NOAEL in this 2-weeks dose finding toxicity study was found to be 1000 mg/kg bw.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes (incl. Open Field Observations (OFO))
- Time schedule: once before start and once weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: once, day 30, 31
- How many animals: all dose groups incl. controls

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: once, day 230, 31
- How many animals: all dose groups incl. controls

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: FOB: once, day 27-28 ); MA: once, day 27-28
- Dose groups that were examined: all dose groups incl. controls
- Battery of functions tested: Functional Observational Battery (FOB); Motor Activity (MA)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (all dose groups and controls)

ORGAN Weights:
Brain, heart, liver, spleen, kidneys (both), thymus, adrenal glands (both), epididymides (both), testes (both), prostate, seminal vesicles with coagulation glands, ovaries/oviducts (both) and uterus/cervix.

Fixed organs:
Adrenals, aorta, brain (cerebrum, cerebellum, ponslmedulla), epididymides, esophagus, eyes, eyelids, extraorbital lachrymal glands, femur, harderian glands, head (with nasal and paranasal cavities), heart, intestine (duodenum, jejunum, ileum, cecum, colon, rectum and remaining intestine), kidneys, larynx, liver, lymph nodes (mandibular, bronchial/hilus, and mesenteric), lung, mamma, optical nerves, ovaries, oviducts, pancreas, pharynx, pituitary, prostate, salivary glands, sciatic nerve, seminal vesicles (incl. coagulating glands), skeletal muscle (thigh), skin (mammary and muzzle), spinal cord (cervical, thoracic, lumbar), spleen, sternum, stomach (forestomach and glandular stomach), testes, thymus, thyroids (including parathyroid glands), tongue, trachea, ureter, urethra, urinary bladder, uterus with uterine cervix, vagina, Zymbal’s glands and all organs or tissues with macroscopic findings.

HISTOPATHOLOGY: Yes (high dose group and controls)
- Microscopic: Adrenals, aorta, brain (cerebrum, cerebellum, brain stem), epididymides, eyes, femur, heart, intestine (duodenum, jejunum, ileum, cecum, colon, rectum and remaining intestine), kidneys, lung, ovaries, oviducts, prostate, sciatic nerve, skeletal muscle (thigh), spinal cord (cervical, thoracic, lumbar), sternum with bone marrow, testes, seminal vesicles (incl. coagulating glands), stomach, trachea and thyroids glands, urinary bladder, uterus with uterine cervix, vagina and all organs or tissues with macroscopic findings.

HISTOPATHOLOGY: Yes (all dose groups and controls)
-Microscopic: thyroids
Statistics:
Statistical tests on FOB, body weights and weight gain as well as on absolute organ weights were done using the Dunnett Exact Homogeneous Test. For relative organ weights the Dunnett Exact Homogeneous Test after log. Transformation was used.
If primary food and water intake data were recorded, the calculated food/water intake per animal was evaluated using adjusted Mann-Whitney U-tests.
The Dunnett Exact Homogeneous or Heterogeneous Test, the Dunnett Exact Homogeneous Test after log. Transformation or the Bonferroni/Mann-Whitney U-test was used for clinical pathology parameters. Descriptive statistics were provided per sex, dose group and time point for all parameters that were recorded with a specified unit. This included measures of general tendency (mean and median (median not given for food and water intake)) and general variability (standard deviation, minimum and maximum) as appropriate.
Clinical signs:
no effects observed
Mortality:
no mortality observed
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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
FOOD INTAKE:

A minimal statistically significant increase of food intake was observed in females starting at the dose of 100 mg/kg b.w., but not found to be of any toxicological relevance.
The minimal statistically significant decrease observed in males at the dose of 1000 mg/kg b.w. was too small and too inconsistent to be of toxicological relevance.

WATER INTAKE:

A statistically significant decrease of water intake was observed in females at the dose of 1000 mg/kg b.w.. As this decrease very small, it was not found to be of any toxicological relevance. Other statistically significant changes of water intake observed were too small and/or too inconsistent to be of toxicological relevance.

ORGAN WEIGHTS:

At the high dose of 1000 mg/kg b.w., relative ovaries weights were statistically increased and the same trend could be observed in absolute ovaries weights at the high dose (not statistically significant). As histopathology did not reveal an effect on ovaries, this is not regarded as an adverse effect.


HAEMATOLOGY:

Hematological investigations on red blood parameters revealed a statistically significant decrease in hemoglobin concentration (HB) and hematocrit (HCT) in males at the dose of 1000 mg/kg b.w.. As these effects were only slight and based on the much lower values of one single animal (No. 19) these findings were not found to be of any toxicological relevance. Additionally a slight increase of thrombocyte count could be observed in both sexes at the dose of 1000 mg/kg b.w., being only statistically significant in males.


CLINICAL CHEMISTRY in the BLOOD:

Creatinine (CREA) was significantly decreased in males at the doses of 100 and 1000 mg/kg b.w. and a decrease in total bilirubin (Bili-t) in females at the doses of 100 and 1000 mg/kg b.w. was observed. These findings were considered of no toxicological relevance, as a dose-relationship was missing.



Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No test item related effects on the parameter investigated
Critical effects observed:
no
Executive summary:

In a repeated dose oral toxicity study in rats (Wistar, OECD TG 407), the substance was adimistered via gavage to 5 rats/sex/dose at 0, 100, 300, 1000 mg/kg bw in PEG 400 for 4 weeks. Up to and including 1000 mg/kg bw no mortality occured. The behavior and clinical appearance of the rats were not influenced by the treatment up to and including 1000 mg/kg in both sexes. The body weight gain, the food, water intake, clinical chemistry, hematology and organ weights were not affected up to and including 1000 mg/kg in males and females. The results from Functional Observational Battery (FOB) measurements in males and females receiving up to and including 1000 mg/kg bw did not differ from the control animals. Motor and Locomotor Activity (MA/LMA) tests did not indicate neurotoxicity up to and including 1000 mg/kg. There was no toxicological relevant effect on organ weights observed and histopathological investigations revealed no test item-related changes up to and including 1000 mg/kg b.w. in both sexes.

Therefore, under the condition of the present study, the NOAEL (no-observed-adverse-effect-level) for the test item after 4-week daily oral treatment by gavage is 1000 mg/kg b.w. for male and female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a repeated dose oral toxicity study in rats (Wistar, OECD TG 407), the substance was adimistered via gavage to 5 rats/sex/dose at 0, 100, 300, 1000 mg/kg bw in PEG 400 for 4 weeks. Up to and including 1000 mg/kg bw no mortality occured. The behavior and clinical appearance of the rats were not influenced by the treatment up to and including 1000 mg/kg in both sexes. The body weight gain, the food, water intake, clinical chemistry, hematology and organ weights were not affected up to and including 1000 mg/kg in males and females. The results from Functional Observational Battery (FOB) measurements in males and females receiving up to and including 1000 mg/kg bw did not differ from the control animals. Motor and Locomotor Activity (MA/LMA) tests did not indicate neurotoxicity up to and including 1000 mg/kg. There was no toxicological relevant effect on organ weights observed and histopathological investigations revealed no test item-related changes up to and including 1000 mg/kg b.w. in both sexes.

Therefore, under the condition of the present study, the NOAEL (no-observed-adverse-effect-level) for the test item after 4-week daily oral treatment by gavage is 1000 mg/kg b.w. for male and female rats.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
only one study available

Justification for classification or non-classification

No classification is required for repeated dose toxicity according to Regulation (EC) No 1272/2008, Annex I