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Repeated dose toxicity: oral

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Administrative data

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:
guideline study
Remarks:
well performed GLP and OECD guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
1981
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Test material form:
solid: bulk

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HOECHST AG, company breeding colony
- Age at study initiation: ca. 6 weeks
- Weight at study initiation:
-- control male: 124 +/- 2 g
-- control female: 130 +/- 5 g
-- low dose male: 124 +/- 8 g
-- low dose female: 131 +/- 9 g
-- mid dose male: 128 +/- 7 g
-- mid dose female: 133 +/- 5 g
-- high dose male: 128 +/- 5 g
-- high dose female: 133 +/- 5 g
- Fasting period before study: none
- Housing: Makrolon(R) cages, groups of five animals of the same sex, air-conditioned
- Diet (e.g. ad libitum): rat diet Altromin 1324(R), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least five days

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: daily, immediately before application

VEHICLE
- Concentration in vehicle: 0.00 / 0.63 / 2.50 / 10.00 % (w/v)
- Amount of vehicle (if gavage): Applied Volume = 10 ml/kg bw
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
28 applications within 29 days, one application per day, 7 times a week
Frequency of treatment:
once a day
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
0.0 mg/kg bw
Basis:
actual ingested
Dose / conc.:
62.5 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
62.5 mg/kg bw
Basis:
actual ingested
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
250.0 mg/kg bw
Basis:
actual ingested
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
1000.0 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes (absolute and relative)

WATER CONSUMPTION): Yes

OPHTHALMOSCOPIC EXAMINATION: Yes (macroscopic examination and opacity)

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
ORGAN WEIGHT: Yes
Statistics:
Statistics applied for differences (p=0.05) betweeen control and dose groups for: Body weight, body weight gain, hematology parameters, clinical parameters, albumin, globulin, organ weight (absolute and relative), pH and specific weight of urine

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):
no effects observed
Ophthalmological findings:
no effects observed
Description (incidence and severity):
based on examination of macroscopic effects and opacity
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Female, 1000 mg/kg bw group: statistically increased Alpha1-Globulin, decreased Alpha3- and Beta1-Globulin but within the range of historical controls. Decreased inorganic phosphate.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Male and female, 1000 mg/kg bw group: decreased specific urine weight
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:
not examined

Effect levels

Key result
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 adverse effects observed at 1000 mg/kg bw, the highest dose tested.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the findings in this oral 28-day repeated dose toxicity study the NOAEL was determined to be >= 1000 mg/kg bw, which was the highest dose tested.
Executive summary:

The test item was tested for subacute oral toxicity according to OECD guideline 407. Following this protocol male and female Wistar rats were treated once daily by oral gavage with 0.00, 62.50, 250.00, or 1000.00 mg/kg bw (28 applications).

 

Behavior and health condition were observed twice daily and once a day at weekends and at public holidays. Body weight and food consumption were determined twice a week and water consumption once a week. At the end of the study hematology, clinical chemistry and urine parameters were collected. At necropsy macroscopic investigations were performed, organ weights were determined, and relative organ weights were calculated. Heart, lung, liver, kidney, spleen, stomach, jejunum, colon, thymus, testes, adrenal gland, and bone marrow were subject of histopathological examinations.

 

Behavior, health condition, food and water consumption, and body weight gain were not affected by the treatment. Hematological examinations revealed no signs of toxicity. From the clinical chemistry parameters phosphate was decreased, alpha1-globulin was increased and alpha3- and beta1-globulin were decreased in females of the high dose group. Except the specific urine weight which was decreased in males and females of the high dose group no other urine parameters were affected by the treatment.

 

Necropsy revealed no macroscopic or microscopic abnormalities that could be attributed to the treatment. Organ weights of the dose groups showed no treatment related differences as compared to the control groups.

 

In conclusion it can be stated that doses up to 250 mg/kg bw didn't cause any signs of toxicity. Although single urine and clinical parameters showed differences between the control and the 1000 mg/kg bw groups, the values were still within the range which is typical for rats of this strain. Moreover there are neither signs of morphological and functional impairments nor any other indications for adverse effects caused by the test item. Therefore the findings were considered to be accidental and/or of no toxicological relevance.