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Reference
Endpoint:
endocrine system modulation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline available
Principles of method if other than guideline:
uterotrophic asssay in juvenile rats
GLP compliance:
yes
Type of method:
in vivo
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature and protected from light
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River France (Saint Aubin-les-Elbeuf, France)
- Age at study initiation: 14 days
- Weight at study initiation: 46 g to 59 g
- Fasting period before study: no data
- Housing: barriered rodent unit in polycarbonate cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21± 2 °C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air.
- Photoperiod (hrs dark / hrs light):12h/12h (07:00 -19:00)
Route of administration:
oral: gavage
Vehicle:
other: methylcellulose at 0.5%
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility
- Concentration in vehicle: 20, 60 and 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg/day
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
five consecutive days
Frequency of treatment:
once per day
Post exposure period:
none
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
Juvenile (22 days old) female Sprague-Dawley rats received the test daily by oral gavage for five days.-vehicle (group No. 1), - EE at 0.001,0.01 or 0.1 mg/kg/day (groups No. 2 to 4), -tris(2,4-ditert-butylphenyl) phosphite at 100, 300 or 1000 mg/kg/day (groups No. 5 to 7). A clinical examination was performed daily. Body weight was recorded before the treatment period and on days 1, 3 and 5.On completion of the treatment period, animals were weighed and killed. The uterus was weighed wet, immediately after sacrifice, with and without the uterine fluid. A complete macroscopic post-mortem examination was performed in the abdominal cavity, focused on the reproductive tract. Uterus and vagina were preserved.
Examinations:
CLINICAL EXAMINATIONS (Morbidity and mortality, Clinical signs, Body weight)

PATHOLOGY (Organ weights)

SAMPLING FOR PLASMA LEVELS OF 17 beta-ESTRADIOL (possible measurements of 17 beta-estradiol)
Positive control:
17 alpha-ethynylestradiol (EE)
Details on results:
No unscheduled deaths occurred during the study.No clinical signs were observed in any control, reference or treated animals during the study. No notable differences were observed in mean body weight gain between the reference or treated groups and the control group. No statistically significant differences from control group in Uterus weights were observed in dosed animals. The mean absolute and relative uterus weights (with or without uterine fluid) of animals given EE at 0.01 mg/kg/day (respectively, full: +144% and +151%, empty: +137% and +143%, p<0.01) or 0.1 mg/kg/day (respectively, full: +110% and +121%, empty: +111% and +122%, p<0.05) were significantly higher than those of the control group animals. There were no macroscopic post-mortem findings in any group.
Conclusions:
The administration of the test substance by oral route to juvenile female rats for five days was well tolerated. The absence of differences in uterus weight observed in animals receiving the test item indicated the absence of estrogenic activity under these conditions.

Description of key information

No indication of an estrogenic effect was observed in juvenile rats (CIT 1999).

Additional information

The study was performed according to the principles of GLP, but prior to establishment of a standard procedure (CIT 1999). No specific attention was paid to phytoestrogen levels in the diet. Groups of 6 juvenile female rats received a single dose of up to 1000 mg/kg bw of the substance in 0.5% methylcellulose on five consecutive days. 24 hours after the last dose the animals were sacrificed and uteri were dissected weighed. No changes in body weight and no changes in the wet uterus weight were observed. From these results, there is no evidence of an uterotrophic response.