Detaljerad miljöinformation

Estradiol valerate, estradiol hemihydrate, polyestradiol phosphate

Estradiol valerate is an ester of estradiol. Estradiol hemihydrate is estradiol containing one molecule of water per molecule estradiol. Polyestradiol phosphate is a polymer prodrug of estradiol, which is metabolized to estradiol. The biological active moiety of these compounds is 17ß-estradiol. Therefore, the classification is based on estradiol.

Detailed background information

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.5*10^-6*A(100-R)

In order to normalize the different estradiol esters on estradiol units, all sales volumes are adjusted to estradiol based on molecular weight. For polyestradiol phosphate the molecular weight of one unit estradiol phosphate is used.

Molecular weight, normalization factor estradiol

PEC = 0.0036 μg/L

Where:

A = [18.5520847 kg * 0.76 =] 14.099584 kg (estradiol valerate) + [19.45314398 kg * 0.48 = ] 9.337509 kg (estradiol hemihydrate) + [0.46376 kg * 0.74 = ] 0.3431824 kg (polyestradiol phosphate) = 23.780275 kg normalized on estradiol (total sold amount API in Sweden year 2016, data from QuintilesIMS).

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. 

P = number of inhabitants in Sweden = 9 *10⁶ 

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (1) 

D = factor for dilution of wastewater by surface waterflow = 10 (ECHA default) (1)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies
(All studies were performed with estradiol as active moiety in estradiol-esters such as valerate or hemihydrate).

Algae (Desmodesmus subspicatus):

EC50 /72 h (growth inhibition, growth rate) = >3100 μg/L (as estradiol) (guideline OECD 201) (2)

Crustacean (waterflea Daphnia magna):

Chronic toxicity

NOEC /21 days (reproduction) = ≥ 139 μg/L (NOEC, reproduction, mortality (guideline FDA TAD 4.09) (3)

Fish:

Acute toxicity (Rainbow trout Oncorhynchus mykiss)

LC50 /96 h (mortality) = >500 μg/L (guideline FDA TAD 4.11) (4)

Chronic toxicity (fathead minnow Pimephales promelas) (extended development test: hatching, survival, growth, secondary sexual characteristics, histology) (EPA FIFRA Subdev. E,72-5, with modifications)
NOEC growth, 52 days = 0.008 μg/L (5)

Chronic toxicity (medaka Oryzias latipes) (2 generation test: fertility/fecundity (F0), hatching, survival, growth, sexual development (F1))
NOEC fertility (F0), 59d = 0.0029 µg/L (6)

PNEC = 0.00029 μg/L (Lowest chronic NOEC fish = 0.0029 µg/L; AF 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0.0036/0.00029 = 12.4, i.e. PEC/PNEC >10 which justifies the phrase "Use of estradiol (including esters) has been considered to result in high environmental risk".

Degradation

Biotic degradation

Ready degradability: not readily biodegradable, but significant mineralization.

Estradiol was studied for aerobic biodegradability in water in three different CO₂ evolution tests. In one test, biodegradation was studied according to OECD method 301B (7). Estradiol was introduced into the test system at concentrations of 10 mg/L. In two other tests, the degradation was studied according to FDA TAD method 3.11(8)(9). In the latter, two concentrations (1 and 10 mg/L) were tested. In all assays, estradiol was degraded to more than 60 % after 28 days. However, degradation proceeded too slowly to formally classify the compound as being readily biodegradable.

Abiotic degradation

Hydrolysis:

Estradiol is hydrolytically stable (10).

Due to the high mineralization rate in the ready biodegradability test, the phrase estradiol (as valerate or hemihydrate) is slowly degrading in the environment.

Bioaccumulation

Partitioning coefficient:

Log P_OW 4.0 (HPLC method, FDA TAD 3.02) (11).

A bioaccumulation study was performed with ¹⁴C labeled estradiol (12). Twenty fish were exposed to ¹⁴C labeled estradiol and additionally 40 to the dilution water (tap water) for a period of 22 days. Additionally, the fish was depurated over a period of 8 days.

The test substance solution was delivered continuously to the tanks. The nominal concentration of estradiol in the water was 276 ng/L. The concentration of the test substance in the fish and in the water was determined through both phases of the test. The ¹⁴C concentration in the fish was analyzed by liquid scintillation after oxidative degradation of the fish in samples taken on day 4, 6, 10, 14, 21, 24, 26, and 30. The ¹⁴C concentration in the water was analyzed by liquid scintillation in samples taken at the same time points.
The bioconcentration factor in fish (BCFss) was calculated as the ratio of the mean values of the ¹⁴C concentration in fish and in water.

The BCFss was 108.8 (normalized to 6 % lipid: 85.9). The uptake rate constant (k1) was 1.1, the depuration rate constant (k2) was -2.2. The DT₅₀ for depuration was determined with 3.2 days, indicating a rapid turnover of estradiol. This was expected, since estradiol is an endogenous hormone metabolized rapidly during normal physiological processes.

Justification of chosen bioaccumulation phrase:

Since log P_OW was 4.0  but the BCF was 109 (86 normalized on 6 % fat), the trigger of a BCF of 500 was not exceeded. Therefore, the substance was considered to have a low potential for bioaccumulation.

Excretion (metabolism)

Estradiol valerate is readily cleaved into estradiol and valeric acid. Estradiol undergoes the same metabolic pathways as endogenous estrogen, i.e. it is further metabolized into the major metabolites estrone, estriol, estrone sulfate and estrone glucuronide (13), (14), (15).

PBT/vPvB assessment

Estradiol is not PBT/vPvB, because the threshold of a BCF of 2000 was not exceeded.

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

   http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

2. Growth inhibition test with estradiol (ZK 5018) on the green algae Desmodesmus subspicatus. Experimental Toxicology, Schering AG, study no. TXST20020260, report no. A30506 (2006)

3. Reproduction and chronic immobilization study of estradiol in Daphnia magna. Experimental Toxicology, Schering AG, study no. TX96156, report no. AQ94 (2001)

4. Acute toxicity of 1717β-estradiol with the rainbow trout. Experimental

   Toxicology, Schering AG, study no TX95070, report no A05662 (2001).

5. 17β estradiol - Extended early life-stage toxicity test with fathead minnow (Pimephales promelas). Experimental Toxicology, Schering AG, report no. B945 (1999)

6. Seki M, Yokota H, Maeda M, Kobayashi K. Fish full lifecycle testing for 17β-estradiol on medaka (Oryzias latipes). Environmental Toxicology and Chemistry 24, 1259-1266 (2005)

7. Study of aerobic biodegradablity of estradiol. Experimental Toxicology, Schering AG, study no TX95270, report no A05658 (2001)

8. Study on the biodegradability of estradiol in the CO₂-evolution test (Modified Sturm-Test). Experimental Toxicology, Schering AG, study no TXST19970041, report no A05659 (2001)

9. Study of aerobic biodegradability of estradiol. Experimental Toxicology, Schering AG, study no TX96181, report no A05814 (2001)

10. Estradiol/ZK 5018/Report on physicochemical properties/Rate of hydrolysis. General Physical Chemistry, Schering AG, study no 0353, report no N408 (2001)

11. Estradiol/ZK5018/Report on physicochemical properties/Water solubility/N-octanol/water partition coefficient. General Physical Chemistry, Schering AG, study no 2966, report no A02014 (2000)

12. Bioconcentration flow-through fish test with estradiol [BAY 86-5435 (14-C)].

    Non-clinical Drug Safety, Bayer Schering Pharma AG, study no TOXT7082197, report no A52549 (2011)

13. Hobkirk, R, Mellor JD, Nilsen M: In vitro metabolism of 17β-estradiol by human liver tissue. Can J Biochem. 53, 903-906 (1975). (1.6.1.3.1 Hobkirk et al. 1975)

14. Lievertz, R.W.: Pharmacology and pharmacokinetics of estrogens. Am. J. Obstet. Gynecol. 156, 1289-1293 (1987). (1.6.1.3.1 Lievertz 1987)

15. Slaunwhite, R.W, Kirdani, R.Y., Sandberg A.A.: Metabolic aspects of estrogens in man. In: Greep, R. O., Astwood, E. B. (Eds.): Handbook of Physiology, Section 7: Endocrinology, Vol. 2, Female Reproductive Sytem, part 1, Chapter 21, American Physiology Society, Washington DC, 1973, pp. 485-523. (1.6.1.3.1 Slaunwhite et al. 1973)