O,O,O-tris(2(or 4)-C9-10-isoalkylphenyl) phosphorothioate

Specific investigations: other studies

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

endocrine system modulation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

01.08.2012 - 08.08.2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

recent study conducted according to reliable in-house protocol

Qualifier:

according to guideline

Guideline:

other: according to E. Routledge and J.P. Sumpter (1996)

Principles of method if other than guideline:

The aim of the study was to determine the estrogenic and antiestrogenic potential of (4nonylphenoxy) acetic acid. The yeast cells used in the yeast estrogen screening (YES) assay have been stably transformed with genes for the human estrogen receptor a and the ß-galactosidase reporter gene. Estrogenic as well as antiestrogenic potentials of the test substances mediated by receptor binding or blocking can be determined using this assay, respectively.

GLP compliance:

no

Type of method:

in vitro

Vehicle:

DMSO

Details on results:

ln this study, the test substance showed clear estrogenic activity at a concentration 10E-5 mol/L and higher in comparison to 17ß-estradiol. ln this study, the test substance showed no antiestrogenic activity in comparison to hydroxytamoxifen. No cytotoxicity was observed.

Reference 2

Endpoint:

endocrine system modulation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

01.08.2012 - 08.08.2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

recent study conducted according to reliable in-house protocol

Qualifier:

according to guideline

Guideline:

other: according to P. Sohoni and J.P. Sumpter (1998)

Principles of method if other than guideline:

The aim of the study was to determine the androgenic and antiandrogenic potential of the test article. The yeast cells used in the yeast androgen screening (YAS) assay have been stably transformed with genes for the human androgen receptor and the ß-galactosidase reporter gene. Androgenic as weil as antiandrogenic potentials of the test substances mediated by receptor binding or blocking can be determined using this assay, respectively.

GLP compliance:

no

Type of method:

in vitro

Vehicle:

DMSO

Details on results:

ln this study, the test substance showed no androgenic activity in comparison to dihydrotestosterone. ln this study, the test substance showed clear antiandrogenic activity from about 10-4 mol/L in comparison to hydroxyflutamide. No cytotoxicity was observed.

Description of key information

The positive findings in vitro are most likely not relevant in vivo due to lack of bioavailability.

Additional information

The test article was found to have antiandrogenic and estrogenic activity in vitro, as shown in the available YES and YAS assays. However, these tests are artificial test systems and cannot reflect the situation under in vivo conditions. In order to assess the test articles potential to bind estrogen receptors in vivo, the bioavailability of the compound needs to be considered. Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4. Thus, with a logPow greater than 19 and a molecular weight range at the edge of and greater than 500 (486.0 - 846.0 g/mol), the substance is expected to highly unlikely pass biological membranes. Furthermore, the substance is highly insoluble in water. In addition, the substance is expected to unlikely undergo hydrolysis. Taken together, the physico-chemical properties of the substance indicate that intestinal absorption is highly unlikely. Therefore, the test substance is expected to be not or only very poorly absorbed. This is confirmed by findings of toxicity studies with the test substance. In an acute oral as well as a 28 days repeated dose toxicity study no signs of toxicity were observed up to the highest doses tested of 2000 and 1000 mg/kg bodyweight per day, respectively, indicating that the substance was not absorbed even at very high dose levels. In the repeated dose study, possibly treatment related findings were observed for hematology and clinical biochemistry. However, these findings were all within the historical control values and may be incidental. They do not reflect adverse findings and are no proof of systemic availability. Similarly, the estrogen receptor binding profiler of the OECD toolbox also categorizes the test aticle as “non binder”, due to the large size of the molecule. It is therefore assumed that the test article is not bioavailable and the positive findings in the in vitro studies are not relevant. Furthermore, it cannot be excluded that the positive findings in the YES/YAS assays are triggered by impurities rather than the by the test item. For instance by 4-nonylphenol, which is present in the test substance in small amounts. 4-nonylphenol is classified for toxicity to reproduction and development. However, it is reasonable to assume that the very low levels of 4-nonylphenol will have no influence on the toxicity profile of the test article. It should be noted that the test article is used as an additive at low concentrations, therefore the potential emission of 4-nonylphenol is estimated to be very low. As a result, the amount of nonylphenol consumers and workers could potentially get in contact with is estimated to be far below the DNEL available for 4-nonylphenol (published on ECHA dissemination view). See also chapter 7.8.