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Diane®

MiljöinformationReceptstatusFörmånsstatus
Bayer

Tablett 2 mg/35 mikrogram
(beige, rund, 5 mm)

Antiandrogen och östrogen

ATC-kod: G03HB01
Läkemedel från Bayer omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Cyproteron

Miljörisk: Risk för miljöpåverkan av cyproteron kan inte uteslutas då det inte finns tillräckliga ekotoxikologiska data.
Nedbrytning: Cyproteron är potentiellt persistent.
Bioackumulering: Cyproteron 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 = 0.0026 μg/L


Where

A = 17.082 kg (total sold amount API in Sweden year 2016, data from IMS Health).

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

Crustacean (waterflea Daphnia magna):

Acute toxicity

EC50 /48 h (immobilization) = 2.4 mg/L (guideline OECD 202) (2)

Actvated sludge microorganisms inhibition

No inhibitory effect in toxicity control of biodegradation test (435 mg/L) (OECD 301B) (3)


Environmental risk classification (PEC/PNEC ratio)

A PNEC could not be calculated due to the lack of data which justifies the phrase “Risk of environmental impact of cyproterone acetate cannot be excluded, since there is not sufficient ecotoxicity data available".


Degradation

Biotic degradation

Ready degradability: not readily biodegradable.

CO2 evolution test, guideline OECD 301B (80).Test results 0% degradation in 28 days. (3)


Abiotic degradation

Hydrolysis:

Hydroxylation occurs (half-life for environmental conditions not given).


The lack of biotic and abiotic degradation justifies the phrase "cyproterone acetate is potentially persistent in the environment".


Bioaccumulation

Partitioning coefficient:

Log POW 3.36 (OECD 117) (4)

The substance has low potential for bioaccumulation.


Excretion (metabolism)

Cyproterone acetate is mainly metabolized (conjugated and hydroxylated) (5).


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. Acute immobilization test of cyproterone acetate with Daphnia magna. Experimental Toxicology, Schering AG, Study no. TXST19970152, Report no. X373 (1999)

  3. Study on the biodegradability of cyproterone acetate in the CO2-evolution test (modified Sturm-test). Experimental Toxicology, Schering AG, Study no. TXST19970028, Report no. X207 (1997)

  4. The determination of the n-octanol/water partition coefficient of ZK 9471 and estimation of its acid-base properties (pka value). General Physical Chemistry, Schering AG, study no. 1440, report no. ME47 (1997)

  5. Kolb KH, Roepke H. Pharmacokinetics of cyproterone acetate. A comparative study in humans and baboons. Int Z Klin Pharmakol Ther Toxikol. 1(3), 184-90, (1968)


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)