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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From Jun. 28, 2002 to Dec. 23, 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to EU Method B.7. OECD Guideline 407, OPPTS 870.3050 in compliance with GLP
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EPA: OPPTS 870.3050(Repeated dose 28-day oral toxicity study in rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MITI: Guidelines for Screening Toxicity Testing of Chemicals
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): Reaktiv-Scharlach F01-0467

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HARLAN WINKELMANN Gartenstr. 27, D-33178 Borchen, SPF breeding colony
- Age at study initiation: Approximately 6 wk
- Housing: Macrolon cages (type 4) on soft wood granulate in groups of 5 animals
- Diet: ssniff R/M (V1534), ad libitum, except for the period in which the animals were kept in diuresis cages
- Water: Tap water in plastic bottles, ad libitum, except for the period in which the animals were kept In diuresis cages
- Acclimation period: At least 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3 °C
- Humidity (%): 50±20 °C
- Photoperiod (hrs dark / hrs light): 12 h dark/12 h light

IN-LIFE DATES: From Jun. 28, 2002 to Aug. 09, 2002

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Test substance was suspended in the concentrations of 1.25, 5.0 and 20 % in sesame oil. After each measurement of the body weight, the calculation of the application volume was repeated. The final dosing volume was 5 mL/kg bw

VEHICLE
- Concentration in vehicle: 1.25, 5.0 and 20 % w/v
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable

Duration of treatment / exposure:
29 d, 28 applications

Frequency of treatment:
Once a day for 28 d
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 62.5, 250, 1000
Basis:
other: Nominal in vehicle
No. of animals per sex per dose:
5/sex/dose in main groups
5/sex/dose in recovery groups



Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the acute oral study results (LD50 >2000 mg/kg bw), dose levels of 0, 62.5, 250.0 and 1000.0 mg/kg bw/d were selected for the present study
- Rationale for animal assignment (if not random): Randomization using computer-generated algorithm
- Rationale for selecting satellite groups: To check the reversibility of the effects, if any
- Post-exposure recovery period in satellite groups: Yes

Positive control:
Not used in the study

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily in all groups

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before start of the study and once a week during the study

BODY WEIGHT: Yes
- Time schedule for examinations: before the start of the study and then twice weekly throughout the study.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, twice a week

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE : No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the termination of the study and after the recovery period
- Anaesthetic used for blood collection: Yes (intraperitoneal injection of 67 + 6.7 mg/kg bw Ketamine HCl + Xylazine)
- Animals fasted: Yes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the termination of the study and after the recovery period
- Anaesthetic used for blood collection: Yes, killed by section of the vena cava cranialis in deep narcosis (intraperitoneal injection of 67 + 6.7 mg/kg bw Ketamine HCl + Xylazine) and exsanguinated

URINALYSIS: Yes
- Time schedule for collection of urine: Few days before termination of the study as well as before the end of the recovery period (overnight from Day 25 to Day 26 and from Day 39 to Day 40)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Once before start of the study and once a week during the study
- Dose groups that were examined: All groups
- Battery of functions tested: sensory reactivity, grip strength and motor activity

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals were necropsied and checked for macroscopically visible abnormalities. The autopsy included macroscopic examination of the skin, orifices, eyes, teeth, oral mucosa and internal organs.

HISTOPATHOLOGY: Yes, Following tissues/organs were preserved in a suitable fixative and processed for histopathological investigations: adrenal gland, bone marrow (sternum), brain, heart, colon, jejunum, kidneys, liver, lungs, lymph nodes (mandibular and iliac), ovaries, uterus, thyroid and parathyroid glands, prostate gland, spleen, stomach, testis, epididymides, thymus, trachea, urinary bladder, N. ischiadicus and spinal cord (cervical).
Other examinations:
Following organs were weighed and the organ to body weight ratios calculated:
Heart, liver, kidneys, adrenal glands, spleen, testes, epididymides, ovaries, thymus and brain


Statistics:
t-Test for body weights and organ weights (obsolute).
Wilcoxon's Test for organ weights (relative to bodyweight), Clinical pathology data,

Results and discussion

Results of examinations

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):
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):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: No deaths occurred throughout the study. No significant treatment related clinical signs were observed. As an incidental finding one male animal of the control group had a scabby wound on the dorsal neck and another male animal of the same group had his head
inclined left, from Day 28 and 29, respectively, onwards.

BODY WEIGHT AND WEIGHT GAIN: Body weight gains were not affected by the administration of the test substance throughout the study in any groups.
FOOD CONSUMPTION AND COMPOUND INTAKE: Food consumption remained unaffected by the administration of the test substance throughout the study in all dose groups.

HAEMATOLOGY: Final and recovery hematology did not reveal any test substance related findings in any group

CLINICAL CHEMISTRY: Final and recovery clinical chemistry was considered not adversely influenced by administration of the test substance in any group

URINALYSIS: An increase in the volume of the urine in females of the intermediate and high dose group. The urine of most males of the 28-d treatment and the recovery high-dose group was discolored salmon-pink in different intensities. In female high-dose animals the urine was discolored very light to light salmon-pink in one animal of the final and three animals of the recovery group.

NEUROBEHAVIOUR: Neurotoxicological measurements including 'open field' observations, assessment, of sensory function, and forelimb and hindlimb grip strength were not influenced by the administration of the test substance in all groups.

ORGAN WEIGHTS: Mean absolute and relative organ weights were not affected by administration of the test substance in any group.

GROSS PATHOLOGY: Discoloured organs (kidneys, testes, adipose tissue, spleen, and/or gastrointestinal tract) in all high dose males and in three high dose female animals at the terminal necropsy. Additionally, discoloured testes were seen in high dose males after the recovery period. There was one mid dose female with red discoloured spleen.

HISTOPATHOLOGY: NON-NEOPLASTIC: There were no histopathological findings that could be related to administration of the test substance.

HISTORICAL CONTROL DATA (if applicable): Most changes were within the historical control data range

Effect levels

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant biological effects were observed at any dose levels

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the NOAEL of the test substance was determined to be 1000 mg/kg bw/day in SD rats

Executive summary:

A study was conducted to assess the sub acute repeated dose toxicity of the test substance in rats according EU Method B.7, OECD guideline 407, OPPTS 870.3050 and MITI Guidelines for screening toxicity testing of chemicals in compliance with GLP

 

Groups of male and female rats received test substance by oral gavage at dose levels of 0, 62.5, 250 or 1000 mg/kg bw/day for a period of 28 d. On Day 29, 5 males and five females from each group were killed and necropsied. Five males and five females from the control and high dose group were killed and necropsied after a recovery period of 14 d.

Behavior and state of health were observed daily in all groups, Body weights and food consumption were recorded twice weekly. Once before the first treatment and once a week thereafter detailed clinical observations were performed in all animals outside the home cage in a standard arena ('open field'). Additionally, the animals were examined for opacity of the refracting media of the eyes and damage to the oral mucosa.

Neurotoxicological measurements including assessment of sensory function, motor activity, forelimb and hind limb grip strength were conducted at the end of the treatment period. Hematological examinations, clinical chemistry and urine analysis were carried out at the end of the treatment period and after the recovery period.

During necropsy the animals were examined for macroscopically visible abnormalities, the main organs were weighed and the organ to body weight ratios calculated. Organs and tissues were processed for histopathological examination and checked for microscopically visible changes.

 

Body weights, hematological and clinical chemistry data, urine data (volume, specific weight), absolute and relative organ weights and neurotoxicological measurements (motor activity, forelimb and hind limb grip strength) were analysed with the aid of a statistical program.

 

No deaths occurred throughout the study. Body weight development, food consumption and general health status including Neurobehaviour were not affected by the administration of the test substance throughout the study in any groups.

Clinical pathology (hematology, clinical chemistry, and urinalysis) was not adversely affected by administration of the test substance in any group.

Organ weights were not affected by administration of the test substance in any group, and no compound-related changes were detected at necropsy or histopathology.

 

In conclusion, repeated administration of test substance did not cause any substance related changes at the doses administered. Hence, under the test conditions, NOAEL of the test substance was determined to be 1000 mg/kg bw/day in SD rats.