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Miljöpåverkan (Läs mer om miljöpåverkan)

Drospirenon

Miljörisk: Användning av drospirenon har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning: Drospirenon är potentiellt persistent.
Bioackumulering: Drospirenon har låg potential att bioackumuleras.


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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) = 1.5*10-6*A(100-R)

PEC = 0.0098 μg/L

Where:

A = 65.184 kg (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 waste water by surface water flow = 10 (ECHA default (1))


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus):

EC50 /72 h (growth inhibition, growth rate) > 7600 µg/L (guideline OECD 201) (2)

Crustacean (waterflea Daphnia magna):

Acute toxicity

EC50 /48 h (immobilization) > 8000 μg/L (saturated solution) (guideline OECD 202) (3)

Chronic toxicity

NOEC /21 days (reproduction, mortality) 556 μg/L, LOEC 1169 µg/L (guideline OECD 211) (4)

Fish:

Acute toxicity Zebrafish (Danio rerio)

LC50/96h 7000 µg/L (guideline 203) (5)

Chronic toxicity

NOEC 216 days (fecundity, sex ratio, histopathological changes of gonads) = 0.23 μg/L , LOEC 0.39 µg/L (full life-cycle test, non-standard) (6)


In this study, fish were exposed from eggs to adults over 216 days including a spawning phase of matured fish. Prominent endpoints investigated were hatching success, survival, juvenile development including sex ratio, egg-laying of adults. A histopathological examination was also performed to determine any morphological abnormalities specifically in gonads to evaluate histological impacts on sexual development and sex organs. The most sensitive endpoint was adult reproduction and histopathological changes in gonads most likely due to the endocrine activity of drospirenone.


Microorganisms (activated sludge, respiration inhibition):

EC50 /30 min > 100 mg/L (nominal loading, saturated solution) (guideline OECD 209) (7)

PNEC = 0.023 μg/L (Lowest chronic NOEC fish = 0.23 µg/L; AF 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0.0098/0.023 = 0.42, i.e. 0.1 < PEC/PNEC ≤ 1 which justifies the phrase Use of drospirenone has been considered to result in low environmental risk.


Degradation

Biotic degradation

Ready degradability: not readily biodegradable


Drospirenone was studied for aerobic biodegradability in water in a manometric respiration test according to guideline OECD 301B (8). It was degraded to <3 % after 28 days. Hence, it is not readily biodegradable.


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 (9). 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 DT90 values 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 system 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.


The data indicated no decrease in any of the two locations, when the metabolite (isomere) was included in the calculation.


The overall disappearance half-life from the system exceeded the threshold of 120d described in the FASS guidance. Therefore, drospirenone can be classified as being potentially persistent.

Abiotic degradation

Hydrolysis:

Drospirenone hydrolyses to a non-active isomer ( > 12.8d, pH 7, 25 ºC) (HPLC- method; EC C7) (10)


Bioaccumulation

Partitioning coefficient:

Log POW 3.1 at pH 7 and 25°C (Shake flask method , OECD 117) (11)

Bioaccumulation study in fish (Lepomis macrochirus)


The study with drospirenone was conducted in the bluegill sunfish Lepomis macrochirus (12). 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.


Justification of chosen bioaccumulation phrase:

Since Log POW (at pH 7) < 4, and the BCFss is 100-102, the phrase drospirenone has a low potential for bioaccumulation is justified. 


Excretion (metabolism)

Drospirenone is only to a small extent excreted unchanged (13). Conjugates such as glucuronides and sulphates as well as hydroxylated compounds were identified (14).


References

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

(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) 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)

(13) 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)


Etinylestradiol

Miljörisk: Användning av etinylestradiol har bedömts medföra hög risk för miljöpåverkan.
Nedbrytning: Etinylestradiol bryts ned i miljön.
Bioackumulering: Etinylestradiol har hög potential att bioackumuleras.


Läs mer

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) = 1.5*10-6*A(100-R)

PEC = 0.00042 μg/L

Where:

A = 2.817153505 kg (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)(1))

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


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus):

EC50 /72 h (growth inhibition, growth rate) = 460 μg/L
NOEC/72 h = 120 µg/L (guideline OECD 201) (2)

Crustacean (waterflea Daphnia magna):

Acute toxicity

EC50 /48 h (immobilization) = 6400 μg/L (guideline OECD 202) (3)

Chronic toxicity

NOEC /21 days (reproduction) = ≥ 387 μg/L (guideline OECD 211) (4)

Fish:

Acute toxicity (rainbow trout Oncorhynchus mykiss)

LC50 /96 h (mortality) = 1600 μg/L (guideline OECD 203) (5)

Chronic toxicity (fathead minnow Pimephales promelas)

NOEC 300 days (life-cycle test; growth, sexual development) = 0.001 μg/L (guideline EPA FIFRA Subdev.E,72-5) (6)

Chronic toxicity (zebrafish Danio rerio)
NOEC 177d (2-generation test: growth, sexual development, reproduction (F0), hatching, growth, sexual development, reproduction (F1) = 0.0003 µg/L (7)

PNEC = 0.00003 μg/L (Lowest chronic NOEC fish = 0.0003 µg/L; AF 10)


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0.00042/0.00003 = 14, i.e. PEC/PNEC >10 which justifies the phrase "Use of ethinylestradiol has been considered to result in high environmental risk".


Degradation

Biotic degradation

Ready degradability: not readily biodegradable

Ethinylestradiol was studied for aerobic biodegradability in water in a CO2 evolution test according to guideline FDA TAD 3.11. (8). Ethinylestradiol was introduced into the test system at a concentration of 10 mg/L as carbon. It was only marginally degraded to 3 % after 28 days.


A study on transformation in aquatic/sediment systems according to test guideline OECD 308 was conducted (9). The transformation of [14C] ethinylestradiol in sediments and natural water was assessed in three different aerobic sediment/water systems. The disappearance half-lives of [14C] ethinylestradiol were in the overlying water of aerobic systems 4.0 and 5.9 days for the high and low organic carbon content, respectively. Since for one of the low organic carbon content sediment the total mass balance was not reached as recommended in the guideline OECD 308 (≥90%), this result was not further evaluated.

The extraction from sediments was performed by the following method, which was validated for spiked sediments prior to application to test samples: The sediment is extracted by using 50 mL acetonitrile: water, 80:20, v:v as extraction solvent. If more than 5% of the applied amount is found in the second extract the sediment is extracted a third time using acetonitrile:1 M HCl 80:20, v:v. A portion of the combined extracts was then reduced by rotary evaporation at 40°C and at least 60 mbar. The concentrated sample was then analyzed by HPLC for parent compound and extractable metabolites.

The parent compound was recovered to 0% from all water and sediment samples at day 99. Only slight ultimate biodegradation was observed in the test systems. The accumulative amount of evolved 14CO2 for the aerobic test systems was 2.5 and 5.1% of the applied radioactivity. Primary degradation was observed for ethinylestradiol to a low degree in the water/sediment test samples. One metabolite occurred only occasionally. Most of the introduced radioactivity was sediment-bound (50-62%).

In the total water/sediment systems the DT50 of [14C] ethinylestradiol was 24 and 28 days for the two systems. The DT50 values differed slightly and were below the FASS guidance level of 32 days for environmental degradation. Since the majority of the systems and the calculated mean of the three was below 32 days, ethinylestradiol can be classified as being degradable.


Due to the results of the water-sediment study with a total system half-life of <32d, the use of the phrase Ethinylestradiol is degraded in the environment is justified.


Abiotic degradation

Hydrolysis:

Ethinylestradiol is hydrolytically stable (pH 7, 25ºC) (FDA TAD 3.09) (10)


Bioaccumulation

Partitioning coefficient:

Log POW 4.2 (Shake flask method, FDA TAD 3.02) (11)

A bioaccumulation study with ethinylestradiol was conducted in the bluegill sunfish Lepomis macrochirus (11). The fish were exposed to concentrations of 1 and 10 ng/L [14C] ethinylestradiol over 35 days with a subsequent depuration phase of 29 days. The steady state bioconcentration factors (BCFs) for total radioactive residue were 371 and 634 for the 1.0 and 10 ng/L treatment level, respectively. The steady state bioconcentration factors for total radioactive residue (TRR) based on lipid content of 3.61 % were 10287 at the 1.0 ng/L treatment level and 17553 at the 10 ng/L treatment level. Normalised to 6 % fat tissue, the BCFss for total radioactive residues for whole fish are 617 and 1053 for the 1.0 and 10 ng/L treatment levels, respectively.

Justification of chosen bioaccumulation phrase:

Since log POW was 4,2 and BCF was 371-634 (617-1035 normalized on 6% fat), the trigger of a BCF of 500 was exceeded. Therefore, the substance was considered to have a "high potential for bioaccumulation".

Excretion (metabolism)

Ethinylestradiol is introduced mainly metabolized as glucoronides and oxidized products (12) (13).


PBT/vPvB assessment

Ethinylestradiol 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 of ethinylestradiol (ZK 4944) on the green algae Desmodesmus subspicatus. Experimental Toxicology, Schering AG, Study no. TXST20020060, Report no. A12518 (2004)

(3) Acute immobilization of ethinylestradiol with Daphnia magna. Experimental Toxicology, Schering AG, Study no. TXS94269, Report no. AG47 (1997)

(4) Chronic toxicity study of ethinylestradiol on Daphnia magna. Experimental Toxicology, Schering AG, Study no. TXS94268, Report no. AG95 (1999)

(5) Acute toxicity test of ethinylestradiol with rainbow trout. Experimental Toxicology, Schering AG, Study no. TX93145, Report no. A987 (1995)

(6) Ethinylestradiol: Determination of the chronic toxicity to fathead minnow Pimephales promelas full lifecycle. Experimental Toxicology, Schering AG, Zeneca study no. AA1099/B, Schering study no. TX95192 (1997)

(7) Schäfers C, Teigeler M, Wenzel A, Maack G, Fenske M, Segner H. Concentration and time dependent effects of the synthetic estrogen 17-alpha-ethinylestradiol on reproductive capabilities of the zebrafish Danio rerio. Journal of Toxicology and Environmental Health, Part A, 70, 768-779 (2007)

(8) Study on aerobic biodegradation of ethinylestradiol. Experimental Toxicology, Schering AG, Study no. TX93157, Report no. AA74 (1995)

(9) [14C] Ethinylestradiol: Aerobic and anaerobic transformation in aquatic sediment

systems. Bayer Schering Pharma AG, Nonclinical drug Safety, Springborn Smithers Laboratories,Horn, Switzerland study no. 1121.000.753 (2008)

(10) Physicochemical data for environmental risk assessment of ethinylestradiol (ZK 4944). General Physical Chemistry, Schering AG, report no. KO 41 (1993)

(11) [14C] Ethinylestradiol: Bioconcentration study with bluegill sunfish (Lepomis macrochirus) under flow-through conditions. Bayer Schering Pharma AG, Nonclinical drug Safety, Springborn Smithers Laboratories,Horn, Switzerland study no. 1121.000.135 (2008)

(12) Maggs, J.L., Grimmer, S.F., Orme, M.L., Breckenridge, A.M., Park, B.K. Gilmore, I.T.: The biliary and urinary metabolites of [3H]17 alpha-ethinylestradiol in woman. Xenobiotica, 13, 421-431 (1983)

(13) Orme, M.L., Back, D.J., Ball, S.: Interindividual variation in the metabolism of ethinylestradiol. Pharmacol Ther 43, 251-260 (1989)