21/10/2010 ethinyl estradiol EQS template
Ethinylestradiol
1 Chemical identity
Common name / EthinylestradiolChemical name (IUPAC) / (8R,9S,13S,14S,17R)-17-ethynyl-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3,17-diol
Synonym(s) / 17a-ethinyloestradiol
17a -ethinylestradiol,
17a -ethynyloestradiol,
17a -ethynylestradiol, EE2
Chemical class (when available/relevant) / Estrogen/Synthetic steroid
CAS number / 57-63-6
EU number / 200-342-2
Molecular formula / C19H24O2
Molecular structure /
Molecular weight (g.mol-1) / 296.41
2 Existing evaluations and Regulatory information
Annex III EQS Dir. (2008/105/EC) / Not IncludedExisting Substances Reg. (793/93/EC) / Not applicable
Pesticides(91/414/EEC) / Not included in Annex I
Biocides (98/8/EC) / Not included in Annex I
PBT substances / No
Substances of Very High Concern (1907/2006/EC) / No
POPs (Stockholm convention) / No
Other relevant chemical regulation (veterinary products, medicament, ...) / Directive 2004/27/EC (European Directive for approval of medicinal products)
Endocrine disrupter / Yes
The endocrine disrupting properties of 17α-ethinylestradiol are the key mechanism of action of the substance.
3 Proposed Quality Standards (QS)
3.1 Environmental Quality Standard (EQS)
QS for -- is the “critical QS” for derivation of an Environmental Quality Standard
Value / CommentsProposed AA-EQS for [matrix] [unit]
Corresponding AA-EQS in [water] [µg.L-1] / Critical QS is QS--.
See section 7
Proposed MAC-EQS for [freshwater] [µg.L-1]
Proposed MAC-EQS for [marine waters] [µg.L-1] / See section Error! Reference source not found.
3.2 Specific Quality Standard (QS)
Protection objective[1] / Unit / Value / CommentsPelagic community (freshwater) / [µg.l-1] / See section Error! Reference source not found.
Pelagic community (marine waters) / [µg.l-1]
Benthic community (freshwater) / [µg.kg-1 dw] / e.g. EqP,
see section Error! Reference source not found.
Benthic community (marine) / [µg.kg-1 dw]
Predators (secondary poisoning) / [µg.kg-1biota ww] / See section Error! Reference source not found.
[µg.l-1] / (freshwaters)
(marine waters)
Human health via consumption of fishery products / [µg.kg-1biota ww] / See section Error! Reference source not found.
[µg.l-1] / (freshwaters)
(marine waters)
Human health via consumption of water / [µg.l-1]
4 Major uses and Environmental Emissions
4.1 Uses and Quantities
Ethinylestradiol (EE2) is a synthetic steroid. The most frequent use is as the estrogen component of combined oral contraceptives with concentrations in the contraceptive pill varying from 20 to 50 mg. It is also used for the treatment of menopausal and post menopausal symptoms (especially the vasomotor effects), in the treatment of female hypogonadism, as a palliative treatment in malignant neoplasm of breast and prostate, in the treatment of some women with acne and in Turner`s syndrome (HSDB, 2010).
Worldwide, 61% of all women of reproductive age (aged 15–49 years) who are married or in a consensual union use contraception. In 2000, approximately 100 million women worldwide were current users of combined hormonal contraceptives (Blackburn et al., 2000 and United Nations, 2004 in IARC, 2007).
The total use of EE2 in Europe was 262 kg in 2009 (Source: IMS MIDAS, Database: ESTRO, Q4/2009) A Stakeholder associated to the dossier stated that “there was relatively little change over the last 3 years, which [they] evaluated, therefore, this figure can be assumed as representative for the use in Europe”.
A recent study (Hannah et al., 2009) gives a total sales estimate (kg/y) for 6 EU MS (BE, FR, DE, IT, NL and UK) and USA for a period from 2006-2007. Data are reported hereunder in the following table:
In Austria about 4.3 kg 17α-EE2 are used per year (ARCEM, 2003 in Ivashechkin, 2006).
4.2 Estimated Environmental Emissions
In the Netherlands, an estimated number of 1.4 million women use contraceptive pills on the basis of which a daily emission of 50g has been calculated (Health Council of the Netherlands, 1999 in Vethaak et al., 2002 in van Vlaardingen et al., 2007).
For Germany the German advisory Council on Environment (SRU, 2007) reported the use of 50 kg per day and a the percentage of dose that is excreted unaltered as 85% which comes up to 42.5 kg per year. Another source of information states that “overall 27.3 ± 4.8% of the dose is excreted in urine, i.e.7.1 µg.d-1. Of this amount 63% is present as the glucuronide conjugate, giving an excretion value of 4.5 µg.d-1 for EE2 in urine (17%). For feces, 30% of the EE2 dose is excreted of which 77% is in the form of the parent molecule giving 6 µg.d-1. The total EE2 excreted by those ingesting EE2 is therefore estimated to be 10.5 µg.d-1. Since 8.5% of the population are ingesting EE2 (17% of women), the average excretion per head of population is considered as 0.89 µg.d-1” (Johnson and Williams, 2004).
Fate of EE2 in Sewage Treatment Plants (STPs) (Hannah et al., 2009)
“The average removal efficiency of EE2 in primary STPs was estimated to be 10% using EpiSuite 3.02 (Syracuse Research Corporation). The removal efficiency in secondary STPs (e.g., activated sludge and trickling filters) was estimated to be 82%, an average of measured values” (for detailed original references, please see Hannah et al., 2009).
5 Environmental Behaviour
5.1 Environmental distribution
Master referenceWater solubility (mg.l-1) / 11.3 at 27°C / Yalkowsky and Dannenfelser, 1992
in HSDB, 2010
4.7 at 20°C
19 at 20°C / Norpoth et al., 1973
Schweinfurth et al., 1996
in Young et al., 2004
Volatilisation / According to vapour pressure and Henry constant values, the substance is not likely to volatilise from water phase.
Vapour pressure (Pa) / 1.5 10-7 at 25°C (calculated) / US-EPA, 2008
6 x 10-9 Pa at 25°C (GLP study) / Schering AG, 1993a
Henry's Law constant (Pa.m3.mol-1) / 8.04 10-7 (calculated) / US-EPA, 2008
Adsorption / The range 192 – 275423 is used for derivation of quality standards.
Organic carbon – water partition coefficient (KOC) / Log KOC = 2.92 – 4.68
KOC = 192 – 2955 / van Vlaardingen et al., 2007
Williams et al., 2001
log KOC = 3.21 – 5.44
KOC = 1622 – 275423 / Yu et al., 2004
KOC = 4590 (GLP study) / Schering AG, 1993a
Sediment – water partition coefficient(Ksusp-water) / 25 – 34429 / Calculated from KOC
Bioaccumulation / The BCF value 610 on fish is used for derivation of quality standards.
Octanol-water partition coefficient (Log Kow) / 3.67 / Hansch et al., 1995
4.2, 25°C, pH 7 (GLP study) / Schering AG, 1993a
BCF (measured) / 123
600 – 610 (Pimephales promelas) / US-EPA, 2008
Länge et al., 2001
5.2 Abiotic and Biotic degradations
Master referenceHydrolysis / DT50= 17 days
Half life surface water = 17 – 46 d / van Vlaardingen et al., 2007
Young et al., 2004
DT50 > 365d at 25°C (buffered distilled water) (GLP study) / Schering AG, 1999
Photolysis / DT50= 10 days (12 hours sunlight a day) / van Vlaardingen et al., 2007
Williams et al., 2001
Light adsorption maximum <290 nm, no adsorption at ≥300 nm / Schering AG, 1999
Biodegradation / Low biodegradability
DT50 (activated sludge) = 1.3 – 12h (aerobic)
DT50 (activated sludge) = 1.0 – 8.3 d (anaerobic)
DT50 (Tiver Thames) = 17d / SRU, 2007
van Vlaardingen et al., 2007
Williams et al., 2001
DT50 (freshwater)> 150 d (TGD default, based on lack of degradation in a ready biodegradability test) (GLP study) / Schering AG, 1999
Ethynil estradiol has a relatively long active period of effectiveness.
6 Aquatic environmental concentrations
An evaluation of measured and predicted concentrations of 17a-ethinylestradiol in surface waters of the United States and Europe was conducted in a recent study (Hannah et al., 2009) to develop expected long-term exposure concentrations for this compound. “Measured environmental concentrations (MECs) in surface waters were identified from the literature. Predicted environmental concentrations (PECs) were generated for European and U.S. watersheds using the GREAT-ER and PhATETM models, respectively. The majority of MECs are nondetect and generally consistent with model PECs and conservative mass balance calculations. However, the highest MECs are not consistent with concentrations derived from conservative (worst-case) mass balance estimates or model PECs. A review of analytical methods suggests that tandem or high-resolution mass spectrometry methods with extract cleanup result in lower detection limits and lower reported concentrations consistent with model predictions and bounding estimates. Based on model results using PhATE and GREAT-ER, the 90th-percentile low-flow PECs in surface water are approximately 0.2 and 0.3 ng/L for the United States and Europe, respectively. These levels represent conservative estimates of long-term exposure that can be used for risk assessment purposes. Our analysis also indicates that average concentrations are one to two orders of magnitude lower than these 90th-percentile estimates. Higher reported concentrations (e.g., greater than the 99th-percentile PEC of ,1 ng/L) could result from methodological problems or unusual environmental circumstances; however, such concentrations are not representative of levels generally found in the environment, warrant special scrutiny, and are not appropriate for use in risk assessments of long-term exposures.”
6.1 Estimated concentrations
Compartment / Predicted environmental concentration (PEC) / Master referenceFreshwater (µg.l-1) / 0.001 / SRU, 2007
No data available / Daginnus et al., 2009(1)
75 – 110 10-6 (2) / Bayer Schering Pharma AG, 2008
Marine waters (coastal and/or transitional) / No data available / Daginnus et al., 2009(1)
Sediment / No data available / Daginnus et al., 2009(1)
Biota (freshwater) / No data available / Daginnus et al., 2009(1)
Biota (marine) / No data available / Daginnus et al., 2009(1)
Biota (marine predators) / No data available / Daginnus et al., 2009(1)
(1) data originated from EU modelling-based prioritisation results
(2) based on daily dose of 20-30 µg, calculation according to EMEA CHMP/SWP/4447/00, London, 2006
6.2 Measured concentrations
The literature search undertaken by Hannah et al. (2009) uncovered 52 papers that report EE2 concentrations in surface water in 16 countries. “These papers span a range of analytical detection methods from immunoassay to MS to tandem MS methods. Individual MECs from these papers were compiled into a database along with details regarding sample location and analytical methods.
A cumulative probability distribution of all MECs (n = 1,652) is presented in the figure below.”
“Concentrations range from nondetect to 273 ng/L. The 90th-percentile concentration is 1.7 ng/L. Approximately 70% of the measurements are nondetect with limits of detection ranging from 0.01 to 30 ng/L. Note that 24 of 1,652 reported MECs (1.5%) in surface water are greater than the maximum expected STP effluent concentration of 13 ng/L (Figure 1 above).”
For the highest MECs reported in surface water (i.e., 73 and 273 ng/L) the authors Anderson et al., 2004 concluded that they are unlikely to result from human use.
“For samples analyzed by GC-MS/MS or LC-MS/MS with an additional cleanup step following the extraction (n = 360), 87% of measurements are nondetect, with limits of detection ranging from 0.1 to 1 ng/L; concentrations range from nondetect to 4.6 ng/L; and the 90th-percentile concentration is 0.43 ng/L (Figure 2 below). A similar range of concentrations (nondetect to 5.1 ng/L; n 5 35) was also found without the additional cleanup step when high-resolution MS methods were employed. None of the MECs analyzed using tandem MS methods (either with or without extract cleanup) or high resolution MS methods exceed the maximum STP effluent concentration of 13 ng/L derived from mass balance estimates.”
Compartment / Measured environmental concentration (MEC) / Master referenceFreshwater (µg.l-1) / 2.5 10-3 – 3 10-3
(median 1 10-4) / SRU, 2007
cf.table below / James et al., 2009(1)
0.073 (LOD= 0.005) (USA) / Santos et al., 2010
Marine waters (coastal and/or transitional) / cf.table below / James et al., 2009(1)
WWTP effluent (µg.l-1) / 4 10-3 – 22 10-3l
<1 10-3 – 5.2 10-3 / SRU, 2007
van Vlaardingen et al., 2007
<0.1-15 / Johnson and Harvey, 2002
DE / 16 STP / 1 (median)
15 (max) / Ternes et al., 1999
3 STP / 0.7 (median)
8.9 (max) / Kuch and Ballschmitter, 2001
IT / 6 STP / 0.45 (median)
1.7 (max) / Baronti et al., 2000
5 STP / nd (median)
2.2 (max) / Johnson et al., 2000
NL / 5 STP / nd (median)
7.5 (max) / Belfroid et al., 1999
SP / 4 STP / nd / Solé et al., 2000
SE / 1 STP / 4 / Larsson et al., 1999
UK / 7 STP / nd (median)
7 (max) / Desbrow et al., 1998
3 STP / nd (median)
1.85 (max) / Niven et al., 2001
2 STP / Nd / Kanda et al., 2001
Hospital effluent (Taiwan):
0.032 (LOD= 0.025) / Santos et al., 2010
Pharmaceutical production facility effluent : ND
Sediment (µg.kg-1dw) / Sed 2 mm / No data (0) / James et al., 2009(1)
Sed 20 µm / No data (0)
Sed 63µm / No data (0)
Biota / Invertebrates (µg.kg-1ww) / No data (0) / James et al., 2009(1)
Fish (µg.kg-1ww) / No data (0)
Marine predators / No data available
(1) data originated from EU monitoring data collection.
Hannah et al., 2009 reviewed the available literature on analytical measurements of ethinylestradiol in waters. In this review, measured concentrations including non-detects were plotted and compared this to model calculations using GREAT-ER for European surfacewater compartments. 90th-percentile PEC at low flow was calculated with 0.3ng.l-1, at mean flow rates it was 0.15ng.l-1. This compared to estimated concentrations of ≤0.5ng.l-1 (90% of MECs).
The authors concluded that EE2 concentration in surface waters is unlikely to exceed 1ng.l-1. Higher concentrations could result from methodological problems or unusual environmental circumstances. (see footnote page 2).
EFPIA note that data on the concentrations of 17a-ethinylestradiol in European surface waters indicates that although levels in the region of 1ng.l-1 are reported, most values (90% of those published) are below the limit of detection which is typically between 0.1 and 0.3ng.l-1 (WRC 2002)
In German effluents maximum EE2 levels of 0.022 µg.l-1 were measured. EE2 has been detected in one study in the outfalls of several sewage treatment plants but not in surface waters, probably because determination limit of 1 ng.l-1 was very high compared to the anticipated substance concentration (BLAC, 2003). By contrast, in another study (Adler et al., 2001), the median concentration of unconjugated EE2 and total EE2 in raw sewage were 7 and 9.5 ng.l-1 respectively while in treated effluents, the concentration of EE2 was much lower than in the raw sewage, i.e. 0.3 ng.l-1, conjugates still contributed significantly (60 %) to the EE2 concentrations (median: 0.5 ng.l-1). In surface waters, the median concentrations of the unconjugated analytes were generally below the limit of quantification (0.05 ng.l-1).