Detaljerad miljöinformation

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) = 1.37*10^-6*A*(100-R) = 0.014 μg/L

Where:

A = 105 kg (total sold amount API in Sweden year 2021, data from IQVIA / LIF)

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 = 10 *10⁶

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

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies*

Algae (green algae, Desmodesmus subspicatus):

E_rC₅₀ 72 hours (growth rate) > 7600 μg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Acute toxicity

EC₅₀ 48 hours (immobilization) > 8000 μg/L. Guideline OECD 202. (Reference III)

Chronic toxicity

NOEC 21 days (reproduction) = 556 μg/L. Guideline OECD 211. (Reference IV)

Fish (zebrafish, Danio rerio):

Acute toxicity

LC₅₀ 96 hours (survival) = 7000 μg/L. Guideline OECD 203. (Reference V)

Chronic toxicity

NOEC 216 days (fecundity, sex ratio, histopathological changes of gonads) = 0.23 μg/L. non-standard test method – fish full life-cycle test. (Reference VI)

Microorganisms (activated sludge):

EC₅₀ 30 min (respiration inhibition) > 100 mg/L. Guideline OECD 209. (Reference VII)

The PNEC was calculated by division of the lowest effect level (NOEC) of the most sensitive taxonomic group considering an appropriate assessment factor (AF). The most sensitive taxonomic group were fish and the lowest effect level was reported as NOEC = 0.23 µg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish).

PNEC = 0.23 µg/L / 10 = 0.023 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.014 µg/L / 0.023 µg/L = 0.63.

Justification of chosen environmental risk phrase:

A risk quotient between 0.1 and 1 qualifies for the phrase “Use of Drospirenone has been considered to result in low environmental risk.”.

Degradation

Biotic degradation

Ready degradability:

Drospirenone was studied for aerobic biodegradability in water in a manometric respiration test with municipal sewage sludge. The study reported less than 3 % biodegradation of Drospirenone in 28 days. Guideline OECD 301. (Reference VIII)

Simulation studies:

The transformation of [¹⁴C] drospirenone in sediments and natural water was assessed in two different aerobic and anaerobic sediment/water systems at a temperature of 20 ± 2 °C continuously in the dark according to guideline OECD 308. Water and sediment were extracted for radio-HPLC separation, by using various extraction solvents such as acetonitrile, acetonitrile/water mixture and acetonitrile/HCl mixture. For mass balance determination, aquatic samples were measured by liquid scintillation counting, sediment samples combusted.

Only slight ultimate biodegradation was observed in the test systems. The accumulative amount of evolved ^[14]CO₂ for the aerobic test systems was 1.4 and 3.8 % of the applied radioactivity.

Primary degradation was observed for drospirenone to a low degree in the water/sediment test samples. Two fractions with degradation products were observed in the HPLC analysis. Since the main metabolite appeared from day 3 onwards (although not continuously in the water phase), it is likely, that this metabolite is the isomer ZK 35096 (10). Because the second metabolite occurred only at day 37 (one replicate) and day 59 in one sediment type, it is of minor importance.

Dissipation was determined with DT₅₀, DT₇₅ and DT₉₀values in the water layer of the aerobic transformation with 2.1, 4.1and 6.8 days for high organic carbon sediment system and 2.2, 4.5 and 7.5 days for low organic carbon system. The degradation DT₅₀, DT₇₅ and DT₉₀ values in the total system were 9.9, 20 and 33 days for high organic carbon sediment system and 36, 72 and 119 days for low organic carbon system. The calculated systems half-lives, however, are very hypothetical, since there was no clear trend of decreasing concentrations of the extracted [14C] drospirenone between day 0 and day 100.

Therefore, the half-life of drospirenone in the environment is considered to exceed the threshold of 120 days. Guideline OECD 308. (Reference IX)

Abiotic degradation

Hydrolysis:

This study reported a half-life of > 12.8 days to a non-active isomer at pH 7. Guideline EC C7 (HPLC method). (Reference X)

Justification of chosen degradation phrase:

Drospirenone established a DT₅₀ > 120 d for the total system which qualifies for the phrase “Drospirenone is potentially persistent.”.

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported with 3.1 at pH 7. Guideline OECD 117. (Reference XI)

Bioconcentration factor (BCF):

The study with drospirenone was conducted in the bluegill sunfish Lepomis macrochirus. Concentrations were 0.1 and 1.0 µg/L [14C]drospirenone. The fish were exposed over 35 days with a subsequent depuration phase of 29 days.

The steady state bioconcentration factors for total radioactive residue were 97 and 99 for the 0.1 and 1.0 μg/L treatment level, respectively, based on lipid content of 4.83 %. Normalised to 5% fat tissue, the BCFss for whole fish are 100 and 102 for the 0.1 and 1.0 μg/L treatment levels, respectively. Guideline OECD 305. (Reference XII)

Justification of chosen bioaccumulation phrase:

As the log D_ow was < 4 and/or BCF < 500 Drospirenone is not considered bioaccumulative which qualifies for the phrase “Drospirenone has low potential for bioaccumulation.”.

Excretion (metabolism)

Drospirenone is only to a small extent excreted unchanged. Conjugates such as glucuronides and sulphates as well as hydroxylated compounds were identified. (Reference XIII, XIV)

References

1. Guidance on information requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment. V3.0, Feb. 2016.

2. Growth inhibition test of drospirenone on the green algae Scenedesmus subspicatus. Experimental Toxicology, Schering AG, study no. TX1997085, report no. AU49 (1997)

3. Acute immobilization of drospirenone with Daphnia magna. Experimental Toxicology, Schering AG, study no. TX97141, report no. AT51 (1997)

4. Reproduction study of drospirenone (ZK 30595) in Daphnia magna. Nonclinical Drug Safety, Bayer HealthCare AG, study no. TOXT6082178, report no. A52014 (2011)

5. Acute toxicity of drospirenone to the zebrafish (Danio rerio). Experimental Toxicology, Schering AG, study no TX97042, report no. AU44 (1997)

6. Full-life-cycle-tests with drospirenone (BAY 86-4888) on the fathead minnow (Pimephales promelas). Nonclinical Drug Safety, Bayer HealthCare AG, study no TOXT6082898, report no. A62532 (2011)

7. Respiration inhibition gest of drospirenone (ZK 30595) on activated sludge micro organisms. Nonclinical Drug Safety, Bayer Schering Pharma AG, study no TXST20070211, report no. A40777 (2008)

8. Study on the biodegradability of drospirenone in the CO2- evolution test (modified Sturm-test). Experimental Toxicology, Schering AG, study no. TX97155, report no. AT51 (1997)

9. [14C] Drospirenone: Aerobic and anaerobic transformation in aquatic sediment systems). Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TXEX20070018, report no. A48365 (2008)

10. The rate of hydrolysis of drospirenone (ZK 30595). General Physical Chemistry, Schering AG, study no. 1274, report no. LY67 (1997)

11. The determination of the n-octanol-water partition coefficient of ZK 30595. General Physical Chemistry, Schering AG, study no. 1290, report no. LY66 (1997)

12. [14C] Drospirenone: Bioconcentration study with bluegill sunfish (Lepomis macrochirus) under flow-through conditions. Nonclinical Drug Safety, Bayer Schering Pharma AG. Study no. TXEX20070017, report no. A48324

13. Absolute and relative bioavailability of ZK 30595 after oral administration of SH T 470 C and SH T 470 D, respectively to 8 young women. Schering AG, Pharmacokinetics/Biometrics/Human Pharmacology, study no. KI87053, report no. 8235 (1990)

14. Absolute bioavailability, excretory balance, and qualitative investigation of the biotransformation of 14C-ZK 30595 following i.v. and p.o. administration in healthy, elderly female volunteers. Schering AG, Pharmacokinetics, study no. KI93037, report no. A166 (1995)

Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

Currently, estradiol is marketed in Sweden as estradiol hemihydrate and estradiol valerate. Estradiol is the active pharmaceutical ingredient (API) and marketed volumes need to be adjusted to this moiety for PEC calculation.

Estradiol varieties	Molecular weight	Conversion factor	Sale volume (2022)	API amount (2022)
Estradiol	272.4 g/Mol	1.00	---	---
Estradiol hemihydrate*	562.8 g/Mol	0.97	28.56	27.70
Estradiol valerate	356.5 g/Mol	0.76	16.87	12.82
Total sale volume API (kg/year)				40.52
* contains two moieties of estradiol

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6*A*(100-R) = 0.00102 μg/L

Where:

A = 40.52 kg (total sold amount API in Sweden year 2022, data from IQVIA / LIF

R = 81.69 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10 *10⁶

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

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies*

Algae (green algae, Desmodesmus subspicatus):

NOEC 72 hours (growth rate) ≥ 3100 μg/L, E_rC₅₀ 72 hours (growth rate) > 3100 μg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) ≥ 139 μg/L. Guideline FDA TAD 4.09. (Reference III)

Fish (rainbow trout, Oncorhynchus mykiss):

Acute toxicity

LC₅₀ 96 hours (survival) ≥ 500 μg/L. Guideline FDA TAD 4.11. (Reference IV)

Fish (fathead minnow, Pimephales promelas):

Chronic toxicity

EC₁₀ 56 days (weight) = 0.008 μg/L. Guideline EPA FIFRA Subdev. E, 72-5. (Reference V)

Fish (Japanese rice fish, Oryzias latipes):

Chronic toxicity

Besides the OECD studies complying with GLP documentation requirements, there is a published fish full life-cycle study, that was conducted with the Japanese rice fish (Oryzias latipes). The test setup is exploratory but the publication was considered sufficiently reliable for derivation of the environmental quality standard (EQS) and therefore is included here. The study started with fish embryos 12 hours after fertilization and continued for up to 101 days including filial fish generation (spawned at day 98, 99, and 100) and assessed various endpoints. Fish were exposed continuously (flow-through system) at 0.939, 2.86, 8.66, 27.9, and 92.4 ng/L. Most endpoints showed no concentration-response related effects of estradiol. However, sex differentiation, induced vitellogenin (VTG; yolk protein), and reproductive impairment were observed with concentration-response relationship in the parent fish generation, coming up with a NOEC of 2.86 ng/L. There were no effects in the filial fish generation at concentrations below 8.66 ng/L.

NOEC 101 days (fertility) = 2.86 ng/L = 0.00286 μg/L. Fish full life-cycle exploratory study. (Reference VI)

The PNEC was calculated by division of the lowest effect level (NOEC) of the most sensitive taxonomic group considering an appropriate assessment factor (AF). The most sensitive taxonomic group were fish and the lowest effect level was reported as NOEC = 0.00286 µg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish).

PNEC = 0.00286 µg/L / 10 = 0.000286 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated as 0.00102 µg/L / 0.000286 µg/L = 3.57.

Justification of chosen environmental risk phrase:

A risk quotient above 10 qualifies for the phrase “Use of estradiol has been considered to result in moderate environmental risk.”.

Degradation

Biotic degradation

Ready degradability:

Ready biodegradation of estradiol was determined in three studies, one in accordance with OECD 310B and two according to FDA TAD 3.11. The studies reported more than 60 % biodegradation of estradiol in 28 days. Guideline OECD 301. (Reference VII, VIII, IX)

Abiotic degradation

Hydrolysis:

This study reported that estradiol is stable. Guideline FDA TAD 3.09. (Reference X)

SimpleTreat modelling – elimination in sewage treatment plants

The SimpleTreat model (v4.1) was used to estimate the fraction of estradiol that is retained in sewage treatment plant and does not enter the surface water compartment. The calculation is based on experimental physico-chemical data of estradiol. Molecular weight: 272.4 g/mol, octanol-water partition coefficient (K_OW): 4.03, vapour pressure: 0.00000003 Pa at 25 °C, water solubility: 1.7 mg/L at 20 °C, organic carbon partition coefficient (K_OC): 2511 and biodegradation: readily biodegradable, failing 10-day window. (Reference VIII, XI, XII, XIII)

SimpleTreat calculated the release to surface water after sewage treatment as 18.31 %, i.e., 81.69 % are eliminated by ready biodegradation or binding to sludge. The PEC calculation was refined taking account of this elimination.

Justification of chosen degradation phrase:

The high ready biodegradation and elimination in sewage treatment plants qualifies for the phrase “Estradiol is slowly degraded in the environment.”.

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported as 4.03. Guideline FDA TAD 3.02. (Reference XI)

Bioconcentration factor (BCF):

In addition, a bioaccumulation study according to OECD TG 305 was conducted. 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 5 % lipid: 71.58). 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.

The study reported a BCF of 71.58. Guideline OECD 305. (Reference XIV)

Justification of chosen bioaccumulation phrase:

As the BCF was < 500 estradiol is not considered bioaccumulative which qualifies for the phrase “Estradiol has low potential for bioaccumulation.”.

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.

Despite the high metabolization this was not considered for refinement of the PEC calculation, as the primary metabolites are estrogenic as well, although to a lesser extent (Reference XV, XVI, XVII)

References

1. Guidance on information requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment. V3.0, Feb. 2016.

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). Experimental Toxicology, Schering AG, study no. TXST19960143, report no. 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 biodegradability 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, Berlin, report no. A02014.

12. Estradiol/ZK 5018/Report on physicochemical properties/ Vapour pressure. General Physical Chemistry, Schering AG, Berlin, study no. 0121, report no. M963EY10.

13. Estradiolhemihydrat/ ZK 5018/Report on physico-chemical properties/ Estimation of the adsorption coefficient (KOC) on soil and sewage sludge (HPLC method). Analytical Development Physical Chemistry, Schering AG, Berlin, study no. 07100160, report no. A39007.

14. 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)

15. 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)

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

17. 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)