Detaljerad miljöinformation

Estradiol valerate, estradiol hemihydrate

Estradiol valerate is an ester of estradiol. Estradiol hemihydrate is estradiol containing one molecule of water per molecule estradiol. The biological active moiety of these compounds is 17ß-estradiol. Therefore, this classification is based on estradiol.

Detailed background information

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

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

Estradiol	272.4 g/Mol	--
Estradiol valerate	356.5 g/Mol	0.75
Estradiol hemihydrate	562.8 g/Mol	0.48

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10^9*(100-R)) / (365*P*V*D*100) = 1.5*10^-6*A*(100-R)

Where:

A = 24.08 kg estradiol equivalents as the total of 19.02 kg estradiol valerat and 19.72 kg estradiol hemihydrate (total sales data in Sweden in 2019 from IQVIA database).

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*10^6

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

D = factor for dilution of wastewater by surface water flow = 10 (1)

Based on this formula and data the PEC was calculated as 0.0036 μg/L = 3.6 ng/L.

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) (OECD TG 201).

(2)(1)

Crustacean (waterflea Daphnia magna):

Chronic toxicity NOEC 21 days (reproduction) = ≥

139 μg/L (reproduction, mortality) (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):

EC10 56 d (weight) = 0.008 μg/L (EPA FIFRA Subdev. E, 72-5). (5)

The lowest chronic NOEC or EC10 was determined with fish (Pimephales promelas) and used to calculate the PNEC applying an assessment factor of 10: 0.008 μg/L / 10 = 0.0008 μg/L = 0.8 ng/L.

Environmental risk classification (PEC/PNEC ratio)

The PEC/PNEC ratio calculates as 3.6 ng/L / 0.8 ng/L = 4.5, i.e. the ratio is > 10, which justifies the phrase "Use of estradiol has been considered to result in moderate environmental risk."

Degradation

Biotic degradation

Ready degradability: not readily biodegradable, but significant mineralization

Estradiol was studied for aerobic biodegradability in a study according to OECD 301 B and in two studies according to FDA TAD 3.11. In all studies, estradiol was determined to degraded to more than 60 % after 28 days, however, failing the criterion for ready biodegradation.(6)(7)(8)

Abiotic degradation

Hydrolysis: Estradiol is hydrolytically stable (9).

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

Bioaccumulation

Partitioning coefficient: Log KOW 4.03 (FDA TAD 3.02) (10).

In addition, a bioaccumulation study according to OECD TG 305 was conducted (11). 20 fish (Lepomis macrochirus) were exposed to14C labeled estradiol as well as 40 fish in the tap water control and exposed for an uptake period of 22 days, followed by 8 days depuration.There were 2 replicates per treatment and 1 for the control.

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 in the uptake and depuration phase 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 finding could be expected, since estradiol is an endogenous hormone metabolized rapidly during normal physiological processes.

Justification of chosen bioaccumulation phrase:

The log KOW of 4.03 fulfills the screening criterion, while the BCF of 108.8 is clearly below the threshold of 500. Therefore, the phrase “The substance has a low potential for bioaccumulation” applies.

Excretion (metabolism)

Estradiol valerate are 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 (12), (13), (14).

PBT/vPvB assessment

As the BCF of estradiol is 108.8 and clearly below the threshold of 2000 the substance is not PBT or vPvB.

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 17β-estradiol with the rainbow trout. Experimental Toxicology, Schering AG, study no. TX95070, report no. A05662 (2001)

(5) Evaluation of the reports entitled: [14C]Ethinylestradiol – Early life-stage toxicity test with fathead minnow (Pimephales promelas); [14C]Ethinylestradiol – Extended early life-stage toxicity test with fathead minnow (Pimephales promelas); [14C]Ethinylestradiol – Partial life-cycle toxicity test with adult fathead minnow (Pimephales promelas); 17β estradiol – Early life-stage toxicity test with fathead minnow (Pimephales promelas); 17β estradiol – Extended early life-stage toxicity test with fathead minnow (Pimephales promelas); 17β estradiol – Early life-stage toxicity test with fathead minnow (Pimephales promelas). Experimental Toxicology, Schering AG, study no. TXST19960143, report no. No. B945 (1999)

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

(7) 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)

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

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

(10) Estradiol/ZK 5018/Report on physicochemical properties/Water solubility/Noctanol/ water partition coefficient. General Physical Chemistry, Schering AG, study no. 2966, report no. A02014 (2000)

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

Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TOXT7082197, report no. A52549 (2011)

(12) Hobkirk, R., Mellor, J. D., 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)

(13) Lievertz, R.W.: Pharmacology and pharmacokinetics of estrogens. Am. J. Obstet.

Gynecol. 156, 1289-1293 (1987). (1.6.1.3.1 Lievertz 1987)

(14) 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)