Registration Dossier

Toxicological information

Specific investigations: other studies

Currently viewing:

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
endocrine system modulation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Remarks:
US EPS Endocrine Disruptor Screening Program - Estrogen Receptor Bioactivity. These data are still considered iterative and intended for review and comment purposes only. Data presented should not be taken as final decisions regarding potential bioactivity, exposure, hazard or risk of the chemical or substance, or that the EPA has or will make a determination that any use of the chemicals or substances necessarily will pose a risk. These data do not provide a scientific basis, by themselves, supporting a conclusion that chemicals or substances have potential for endocrine disruption. EPA will continue to update high throughput data and computational models for chemicals and substances in the Endocrine Disruptor Screening Program.
Principles of method if other than guideline:
A computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional activation, and ER-dependent cell proliferation. The network model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist, or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform (“assay interference”).
GLP compliance:
not specified
Remarks:
High quality QC methodology
Type of method:
other: High throughput screening
Endpoint addressed:
other: Estrogen receptor activity
Species:
other: In vitro high-throughput systems
Details on results:
The results of the ToxCast high-throughput screening matrix is expressed as an area under the curve (AUC) value for estrogen agonist and antagonist activity. The AUC value for both agonist and antagonist activity was below 0.1 and therefore isoeugenol is predicted not to be an estrogen endocrine disruptor.

The ToxCast results for the analogues of isoeugenol (eugenol and methyleugenol) are also presented in the attached table of results. In this case both substances are predicted not to be estrogen endocrine disruptors. Eugenol and methyleugenol had agonist and antagonists AUC values of zero, whilst isoeugenol had an agonist AUC value of 0.0124 and an antagonist AUC value of 0.00199. According to the USEPA ToxCast documentation, a value below 0.1 is considered to be inactive and a value between 0.1 and 0.2 to be weakly active. isoeugenol AUC values were significantly below the minimum threshold of 0.1.

Conclusions:
Isoeugenol is predicted negative for estrogen endocrine disruptor potential in a battery of 18 in vitro high-throughput assays. Two analogues of isoeugenol (eugenol and methyleugenol) are also predicted to have no estrogen endocrine disruptor potential.
Executive summary:

A computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional activation, and ER-dependent cell proliferation. The network model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist, or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform (“assay interference”).

Isoeugenol is predicted negative for estrogen endocrine disruptor potential in a battery of 18 in vitro high-throughput assays. Two analogues of isoeugenol (eugenol and methyleugenol) are also predicted to have no estrogen endocrine disruptor potential.

Description of key information

A computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional activation, and ER-dependent cell proliferation. The network model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist, or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform (“assay interference”). A two-generation reproductive toxicity study on isoeugenol showed no effects on any reproductive parameters throughout both generations. Sperm parameters and vaginal cytology were unchanged in the F0 and F1 generations.  

Additional information

A computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional activation, and ER-dependent cell proliferation. The network model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist, or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform (“assay interference”).

Eugenol is predicted negative for estrogen endocrine disruptor potential in a battery of 18 in vitro high-throughput assays. Two analogues of eugenol (isoeugenol and methyleugenol) are also predicted to have no estrogen endocrine disruptor potential.

The chemical structure of eugenol was investigated in the Derek Nexus (Q)SAR system for potential structural alerts for oestrogenicity and thyroid toxicity. In both cases the prediction was negative and it is concluded that eugenol does not have a potential for endocrine disruption.

A validated (standardized) estrogen receptor(ER) competitive-binding assay was used to determine the ER affinity for Eugenol. Uteri from ovariectomized Sprague-Dawley rats were the ER source for the competitive-binding assay. Eugenol was demonstrated to have no binding affinity for the estrogen receptor.

A two-generation reproductive toxicity study on a read-across substance (isoeugenol) showed no effects on any other reproductive parameters throughout both generations. Sperm parameters and vaginal cytology were unchanged in the F0 and F1 generations.

Based on good quality high-throughput data and on good quality in vivo data generated on the substance it is concluded that isoeugenol has no potential for endocrine disruptor activity.