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Diss Factsheets

Toxicological information

Specific investigations: other studies

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Administrative data

endocrine system modulation
Type of information:
experimental study
Adequacy of study:
other information
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: incomplete reporting (e.g. with respect to absolute bw and uterus weight data, statistical analysis)

Data source

Referenceopen allclose all

Reference Type:
Relationship between the results of in vitro receptor binding assay to human estrogen receptor a and in vivo uterotrophic assay: Comparative study with 65 selected chemicals.
Akahori Y. et al.
Bibliographic source:
Toxicology in Vitro 22, 225–231
Reference Type:
Comparative study of the uterotrophic potency of 14 chemicals in a uterotrophic assay and their receptor-binding affinity
Yamasaki K. et al.
Bibliographic source:
Toxicology Letters 146, 111–120

Materials and methods

Test guideline
equivalent or similar to guideline
other: Draft guideline OECD440 Uterotrophic Bioassay in Rodents: A short-term screening test for estrogenic properties
Principles of method if other than guideline:
Immature rat uterotrophic assay as estrogenic and anti-estrogenic system.

The test chemical was evaluated as estrogenic or anti-estrogenic if the uterine weights were significantly increased in the estrogenic assay or decreased in the antiestrogenic assay.
The log of the lowest effective doses (logLED, µmol/kg/day) were identified.
GLP compliance:
Type of method:
in vivo

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
4,4´-Sulfonyldiphenol, Supplier: TCI (Tokyo Kasei Kogyo Co.)
Purity > 99.4%

Test animals

Crj: CD(SD)
Details on test animals or test system and environmental conditions:
- Source: Charles River Japan Inc. (Shiga, Japan)
- Age at study initiation: rat pups (10-day old)
- Housing: individual, in polycarbonate pens until weaning, following 19 days weaning in stainless steel wire-mesh cages throughout
the study.
- Diet (e.g. ad libitum): commercial diet (CRF-1, Oriental Yeast Co., Tokyo, Japan)
- Water (e.g. ad libitum): yes

- Temperature (°C): 23 +/-2°C
- Humidity (%): 55 +/-5%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
olive oil
Details on exposure:
Female rat pups (10-day old) were weaned with their dams and individually housed until 19-days old.
These immature female rats were weighted and weight-ranked to assign to each of the treated and control groups (6 rats/group).
Three doses were used and the highest dose was set at the maximum tolerance dose based on the results of dose-range finding test.
Subcutaneous injections were applied into the back for three consecutive days (4 mL/kg/day).
At the day of first injection the animals were 20 days old.
Vehicle control group:olive oil (s.c.)
Frequency of treatment:
3x on 3 consecutive days
No. of animals per sex per dose:
6 females


Body weight and clinical signs were recorded daily.
The animals were sacrificed by bleeding from the abdominal vein under deep ether anesthesia 24 h after the final administration, and body weight and uterine weight of each animal were recorded.
Positive control:
Positive control group estrogenic activity:
0.6 µg/kg/day 17alpha-ethynylestradiol (s.c.) after administration of the chemicals at the same doses.
A vehicle control group was injected with olive oil alone.
A group injected with the estrogen-antagonist chemical tamoxifen in a dose of 1 mg/kg per day plus EE was also established to confirm the reliability of this study.

Results and discussion

Details on results:
Of 65 chemicals evaluated in this study 31 and 25 chemicals were identified as estrogenic and anti-estrogenic in immature rat uterotrophic assay, respectively. 29 exhibited both estrogenic and anti-estrogenic responses.
logLED estrogenic 4,4´-sulphonyldiphenol: 1.9 µmol/kg/day
logLED anti-estrogenic 4,4´-sulphonyldiphenol: 3.3 µmol/kg/day
logLED estrogenic 17beta-estradiol: <-2.43 µmol/kg/day (as determined in independent study from 23-days old rats, Padilla-Banks et al. 2001)
logLED anti-estrogenic 17beta-estradiol: N.A.
The lowest logLED was itentified with the positive control (17beta-estradiol: <-2.43 µmol/kg/day) highest with 4-tert-Butylcatechol (3.78).

Any other information on results incl. tables

 Table: body and uterine weights [mg]/[mg/100g]



Relative uterine wet

Relative uterine blotted

Vehicle control

58.3 +/-3.4

64 +/-9.3

63 +/-9.4


59.7 +/-3.8

81.6 +/-13.3*

80.7 +/-12.8*


57.6 +/-1.9

73.8 +/-8.5

72.6 +/-8.3


58 +/-2.8

107.5 +/-25**

105.6 +/-23.8**

Vehicle +EE

60.6 +/-2.3

245.3 +/-13.8

193.8 +/-13.2

20 +EE

58.9 +/-4

307.5 +/-38.8°°

218.4 +/-10.6°°

100 +EE

59 +/-2.8

257 +/-73.7

201.4 +/-21.2

500 +EE

58.2 +/-3.8

137.7 +/-20.8°°

135.4 +/-20.3°°


57.5 +/-3.6

158.5 +/-15.2°°

156.6 +/-15°°

*significantly different from vehicle control at p<0.05

**significantly different from vehicle control at p<0.01

°°significantly different from vehicle control plus EE at p<0.01


The uterine weight of the rats given EE was higher than that of the rats given vehicle alone, and the uterine weight of the rats given tamoxifen plus EE was lower than that of the rats given EE, confirming the reliability of this study.

Uterine weight was significantly higher in the 20 (p<0.05) and 500 mg/kg (p<0.01) groups.

Uterine weight was significantly lower in the 500 mg/kg plus EE group (p<0.01) and, by contrast, significantly higher in the 20 mg/kg plus EE group (p<0.01).

Applicant's summary and conclusion

The very low relative binding affinity observed with 4,4´-sulfonyldiphenol in an in vitro receptor binding assay (logRBA -2.26, Akaori et al. 2008) well correlated to the high dose required to observe a statistically significant effect in the uterotrophic assay (logLED 1.9), as compared to the internal positive control 17beta-estradiol, respectively.
This in vivo screening assay is included in the third of five levels of an OECD conceptual framework for testing and assessment of potential endocrine disrupting chemicals. This assay may provide data about a single endocrine mechanism, i.e. oestrogenicity.