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Toxicological information

Endocrine disrupter mammalian screening – in vivo (level 3)

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Administrative data

Endpoint:
endocrine disrupter mammalian screening – in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1997-12-01 to 1998-03-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 440 (Uterotrophic Bioassay in Rodents: A Short-term Screening Test for Oestrogenic Properties)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4-(4-isopropoxyphenylsulfonyl)phenol
EC Number:
405-520-5
EC Name:
4-(4-isopropoxyphenylsulfonyl)phenol
Cas Number:
95235-30-6
Molecular formula:
C15H16SO4
IUPAC Name:
4-[4-(propan-2-yloxy)benzenesulfonyl]phenol
Details on test material:
- Name of test material (as cited in study report): D - 8
- Molecular formula: C15 H16 O4 S;
- Molecular weight: 292.4;
- Physical state: solid;
- Analytical purity: 99.94 %;
- Purity test date: not stated;
- Lot/batch No.: ME-685;
- Expiration date of the lot/batch: not stated;
- Stability under test conditions: stable at ambient temperature and conditions;
- Storage condition of test material: store in a cool dry place, protected from direct sunlight;

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
State:
ovariectomized female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: 4 - 5 weeks
- Weight at study initiation: 123 - 149 g
- Fasting period before study: No
- Housing: 5 animals per cage in polypropylene cages with grid floors
- Diet: standard certified laboratory rodent diet (RM1(ESQC) ad libitum
- Water: tap water ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21 +/- 3 °C
- Humidity: 50 +/- 15 % R.H.
- Air changes (per hr): not indicated
- Photoperiod : 12 hrs light /12 hrs dark from 07:00 a.m. to 07:00 p.m.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Test formulations were prepared on the days of dosing.
Test articles were formulated in 0.5 % (w/v) carboxymethylcellulose (CMC) at the highest concentration.
Lower concentrations were obtained by serial dilution of the highest concnetration using 0.5 % (w/v) CMC.
Test articles were administered as a single oral dose over a period of 4 days, using a constant dose volume of 10 mL/kg. Oestradiol benzoate was administered by a single subcutaneous injection under the loose skin at the back of the neck over a period of 4 days, using a constant dose volume of 5 mL/kg.

VEHICLE
- Concentration in vehicle: 100 mg/mL, 10 mg/mL
- Amount of vehicle: 10 mL/kg
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
4 days
Frequency of treatment:
Once per day
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Study with young adult females after ovariectomy: yes
- Age at ovariectomy and duration of acclimatization after ovariectomy: 5-6 weeks; 10 days
Positive control:
Oestradiol benzoate, 10 µg/kg, sc.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: Twenty-four hours after the final dose

SPECIFIC ENDPOINTS
- Wet uterine weight: Yes
- Time schedule: Twenty-four hours after the final dose the animals were sacrificed by CO2 asphyxiation followed by cervical dislocation and the uteri removed. The uterine contents were gently squeezed out and the uteri weighed.
Sacrifice and pathology:
GROSS PATHOLOGY: No
HISTOPATHOLOGY: No
Statistics:
A comparison of the uterine weights of the test article-treated and vehicle treated control animals was made using analysis of covariance using initial body weights as covariate. (Shirley, 1977, The analysis of organ weight data, Toxicology, 8, 13-22).
After conversion of the uterine weight data into percentage of total body weight, similar comparision were made using analysis of variance.

Results and discussion

Endocrine disrupting potential:
negative
Maximum tolerated dose level exceeded:
no

Results of examinations

Clinical signs:
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Water consumption and compound intake (if drinking water study):
not examined
Clinical biochemistry findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No marked or statistically significant increases in uterine weight was observed when compared with vehicle-treated control animals.
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Details on results:
Oral administration of the test item to rats in doses of 100 and 1000 mg/kg for 4 days produced no marked or statistically significant increases in uterine weight when compared with vehicle-treated control animals.
As expected, the reference standard oestradiol benzoate administered subcutaneously at 10 µg/kg/day for 4 days produced marked and statistically significant increases in uterine weight when compared with the relevant vehicle-treated control group.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights

Any other information on results incl. tables

Table 1: Assessment of the effects of the test item on oestrogenic activity in the rat on uterine weight

Group

Treatment

Route

Dose (mg/kg)

Group mean uterus weight (mg±sd)

% increase in the mean uterus weight from relevant vehicle group

1

Vehicle (0.5 % CMC)

po

-

45.4± 4.2

-

2

D-8

po

100

52.8 ± 42.6

16.3

3

D-8

po

1000

41.2 ± 5.3

-9.25

4

Vehicle (arachis oil)

sc

-

39.8 ± 25.0

-

5

Oestradiol benzoate

sc

10 µg/kg

158.2 ± 11.8 **

297.49

sd: Standard deviation

Statistical significance of difference compared to Group 4 using analysis of covariance: ** p< 0.01

 

Table 2: Assessment of the effects of the test item on oestrogenic activity in the rat on uterine weight as a % of bodyweight

Group

Treatment

Route

Dose (mg/kg)

Group mean uterus weight as a % of bodyweight (±sd)

% increase in the mean uterus weight from relevant vehicle group

1

Vehicle (0.5 % CMC)

po

-

0.028± 0.004

-

2

D-8

po

100

0.035 ± 0031

25.00

3

D-8

po

1000

0.026 ± 0.003

-7.14

4

Vehicle (arachis oil)

sc

-

0.025 ± 0.017

-

5

Oestradiol benzoate

sc

10 µg/kg

0.104 ± 0.006 **

316.00

sd: Standard deviation

Statistical significance of difference compared to Group 4 using analysis of variance: ** p< 0.01

Applicant's summary and conclusion

Conclusions:
The test item produced no notable estrogenic effects in this test as determined by increases in rat uterine weight.
Executive summary:

The test item was administered as an oral dose to female Wistar rats over a period of 4 days at a dose of 100 mg/kg or 1000 mg/kg bw in order to assess the possible oestrogenic effects as determined by increases in uterine weight. The test item administered orally to rats at 100 and 1000 mg/kg bw for 4 days produced no marked or statistically significant increases in uterine weight when compared with control animals dosed with vehicle (0.5% w/v carboxymethylcellulose, (CMC)). As expected, the reference standard oestradiol benzoate administered subcutaneously at 10 µg/kg/day for 4 days produced marked and statistically significant increases in uterine weight when compared with the relevant vehicle-treated control group.