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MiljöinformationReceptstatusFörmånsstatus
MSD

Tablett
(Runda, vita, bikonvexa, 6 mm, märkta TR5 på ena sidan och ORGANON och en femuddig stjärna på den andra)

Hormonella antikonceptionella medel för systemisk användning, gestagener och estrogener.

ATC-kod: G03AA09
Utbytbarhet: Ej utbytbar
Företaget omfattas av Läkemedelsförsäkringen

Miljöpåverkan (Läs mer om miljöpåverkan)

Desogestrel

Miljörisk: Användning av desogestrel har bedömts medföra medelhög risk för miljöpåverkan.
Nedbrytning: Desogestrel bryts ned långsamt i miljön.
Bioackumulering: Desogestrel har låg 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 = 0.0005 ug/L


Where:

A = 3.6 kg (total sold amount API in Sweden year 2016, data from QuintilesIMS).

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 9 *106 

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

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. I)


Predicted No Effect Concentration (PNEC)

Desogestrel is a prodrug progestogen and is rapidly metabolized to 3-keto-desogestrel, also known as etonogestrel, which is the active drug substance (Ref. II). Therefore, all environmental data are based on the active drug substance, etonogestrel.


Ecotoxicological studies


Crustacean, water flea (Daphnia magna) (FDA TAD 4.08) (Ref. III):

Acute toxicity

EC50 48h (mortality) = 3900 µg/L


Fish, rainbow trout (Oncorhynchus mykiss) (FDA TAD 4.11) (Ref. IV):

Acute toxicity

LC50 96h (mortality) = 4000 µg/L


Fish, bluegill sunfish (Lepomis macrochirus) (OECD 203) (Ref. V):

Acute toxicity

LC50 96h (mortality) > 1300 µg/L


Green Algae (Selenastrum capricornutum) (FDA TAD 4.01) (Ref. VI):

EC50 8d (yield & growth rate) > 5400 µg/L

NOEC 8d (yield & growth rate) = 5400 µg/L


Green Algae (Selenastrum capricornutum) (FDA TAD 4.01) (Ref. VI):

EC50 8d (yield & growth rate) > 4500 µg/L

NOEC 8d (yield & growth rate) = 4500 µg/L


Crustacean, water flea (Daphnia magna) (FDA TAD 4.09) (Ref. VII):

Chronic toxicity

NOEC 21d (immobilization and growth) = 1200 µg/L

LOEC 21d (immobilization and growth) = 2400 µg/L


Fish, fathead minnow (Pimephales promelas) (OECD 210) (Ref. VIII):

Chronic toxicity

NOEC 32d (total length and dry weight) = 59 µg/L

LOEC 32d (total length and dry weight) = 120 µg/L


Fish, Japanese medaka (Oryzias latipes) (OECD 229 & Draft Fish Two-generation Test Guideline) (Ref. IX):

Chronic toxicity

NOEC 183d (genetic sex ratio of XX males to the total number of male fish) = 2.7 ng/L

LOEC 183d (genetic sex ratio of XX males to the total number of male fish) = 6.2 ng/L


PNEC = 0.00027 ug/L (2.7 ng/L / 10 based on the most sensitive chronic NOEC for the fish and an assessment factor (AF) of 10)


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0005/0.00027 = 2, i.e. 1 < PEC/PNEC < 10 which justifies the phrase for the prodrug (desogestrel) of "Use of desogestrel has been considered to result in moderate environmental risk." 


Biotic degradation

Biodegradation Simulation Screening (US FDA 3.11) (Ref. X):

Test results 3.6% degradation in 37 days in water, with a calculated half-life of 457 days


Biodegradation Simulation Screening (US FDA 3.12) (Ref. XI):

Half-life in sediment = 83 – 219 days. Degradation in sludge = 96% in 13 days


Biodegradation Simulation Screening (FDA TAD 3.12) (Ref. XII):

Half-life = 19 - 106 days in soil


Sediment Transformation (OECD 308) (Ref. XIII):

DT50 (total system) = 9.2 to 50 days


At each sampling interval, duplicate incubation vessels per sediment/water system were removed from incubation chamber and water layers were separated from sediment layers. The two layers were analyzed separately for [14C]etonogestrel and degradates. The sediment was extracted once with acetonitrile (80:20:0.1, v:v:v) for a total of three extractions. The water and sediment extracts were radioassayed by liquid scintillation counting (LSC) and then analyzed by high performance liquid chromatography with radiochemical detection (HPLC/RAM) to quantify [14C]etonogestrel and degradation products in the fractions. Radioactivity in the post-extracted solids (sediment-non-extractable residues (NER)) was quantified by combustion analysis and the liquid volatile organic traps were radioassayed by LSC.


Average material balance ranged from 94.9 to 107.0% AR over the course of the 99 day study.

Evidence of primary biodegradation was observed for [14C] etonogestrel in the aerobic water/sediment test samples. Two major peaks (≥ 10% AR) were observed in some of the chromatograms for the Taunton River and Weweantic River samples at retention times of 20.9 (Met-1) and 23.1 minutes (Met-2). Several minor peaks were observed in some of the chromatograms for the Taunton River and Weweantic River test samples. In all cases, these minor peaks represented less than 10% AR in the water and sediment extracts and were not considered further.

Ultimate biodegradation of [14C] etonogestrel was observed in the aerobic samples with evolution of 14CO2 reaching an average maximum of 1.2 and 5.3% AR for the Taunton River and Weweantic River aerobic test samples, respectively, at Day 99. Radioactivity was not detected in the volatile organic compound traps for the aerobic test systems accumulatively at Day 99.


Abiotic degradation

Photolysis (US FDA 3.10) (Ref. XIV):

Half-life = 61.7 hours


Hydrolysis (US FDA 3.09) (Ref. XV):

Hydrolytically stable, <10% degradation at pH 5, 7, 9


Justification of chosen degradation phrase:

Etonogestrel has a DT50 for the total system of ≤120 days. Thus, the phrase chosen for the prodrug (desogestrel) is “Desogestrel is slowly degraded in the environment.”


Bioaccumulation

Partitioning coefficient (FDA TAD 3.02) (Ref. VXI):

Log Kow = 3.5


Bioaccumulation (OECD 305) (Ref. VXII):

Flow through study with Bluegill sunfish (Lepomis macrochirus)

Lipid normalized kinetic BCF = 128


Justification of chosen bioaccumulation phrase:

Since log Kow < 4 and BCF < 500, the substance has low potential for bioaccumulation


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. Madden, S. et al., 1989. Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa. Br. J. Clin. Pharmac. 27: 295-299.

  3. Batelle, 1992. "A Study on the Daphnia Acute Toxicity of 3-keto-desogestrel According to USFDA Guideline 4.08," Study No. BE-EA-152-92-01-DAK-01, Batelle Europe, Frankfurt am Main, Germany, 3 Aug 1992.

  4. Batelle, 1992. "A Study of the Freshwater Fish Acute Toxicity for Oncorhynchus mykiss of 3-keto-desogestrel According to USFDA Guideline 4.11," Study No. BE-EA-152-92-01-F1A-01, Batelle Europe, Frankfurt am Main, Germany, 4 Aug 1992.

  5. Smithers Viscient, 2013. "ORG 3236: Acute Toxicity to Bluegill Sunfish (Lepomis macrochirus) Under Static Conditions," Study No., 359.6778, SV, Wareham, MA, USA, 28 August 2013.

  6. Batelle, 1992. "Effect of 3-keto-desogestrel on growth rate and standing crop on two algal species (Selenastrum capricornutum and Microcystic aeruginosa)," Study No. BE-EA-152-92-01-ALG-01, Batelle Europe, Frankfurt am Main, Germany, 16 June 1992.

  7. Batelle, 1992. "A Study on the Daphnia Chronic Toxicity of 3-keto-desogestrel According to USFDA Guideline 4.09," Study No. BE-EA-152-92-01-DCH-01, Batelle Europe, Frankfurt am Main, Germany, 4 Aug 1992.

  8. Smithers Viscient, 2012. "ORG 3236: Early Life-Stage Toxicity Test with Fathead Minnow, Pimephales promelas, Based on OECD Guideline 210," Study No., 1560.6266, SSL, Wareham, MA, USA, 15 May 2012.

  9. Smithers Viscient, 2015. "Etonogestrel - Multi-Generation Exposure with Japanese Medaka (Oryzias latipes)," Study No., 359.6747, SV, Wareham, MA, USA, 12 May 2015.

  10. Batelle, 1992. "Aerobic Biodegradation of 3-keto-desogestrel in Water," Study No. SC920045, Batelle, Columbus, Ohio, USA, 24 July 1992.

  11. Batelle, 1992. "Aerobic Biodegradation of 3-keto-desogestrel in Sediment and Sludge," Study No. SC920046, Batelle, Columbus, Ohio, USA, 31 July 1992.

  12. Batelle, 1992. "Aerobic Biodegradation of 3-keto-desogestrel in Soil," Study No. SC920043, Batelle, Columbus, Ohio, USA, 13 August 1992.

  13. Smithers Viscient, 2014. "[14C]Etonogestrel: Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308," Study No., 359.6697, SV, Wareham, MA, USA, 5 August 2014.

  14. Batelle, 1992. "Aquatic Photodegradation of 3-keto-desogestrel," Study No. SC920055, Batelle, Columbus, Ohio, USA, 24 July 1992.

  15. Batelle, 1992. "Hydrolysis of 3-keto-desogestrel in buffered aqueous solutions," Study No. SC920053, Batelle, Columbus, Ohio, USA, 16 June 1992

  16. Batelle, 1992. "Octanol/Water Partition Coefficient of 3-keto-desogestrel," Study No. SC920057, Batelle, Columbus, Ohio, USA, 06 July 1992.

  17. Smithers Viscient, 2014. "[14C]Etonogestrel: Flow-Through Bioconcentration and Metabolism Study with Bluegill Sunfish (Lepomis macrochirus)," Study No., 359.6699, SV, Wareham, MA, USA, 17 February 2014.







Etinylestradiol

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


Läs mer

Detaljerad miljöinformation


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)


PEC = 0.43 ng/L


Where:

A = 2.86 kg (total sold amount API in Sweden year 2015, data from IMS Health).

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 9 *106

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

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. I)


Predicted No Effect Concentration (PNEC)


Ecotoxicological studies


Algae (Pseudokirchneriella subcapitata) (OECD 201) (Ref. II):

EC50 72hr (cell number and growth) > 6700 μg/L

NOEC 72hr (cell number and growth) = 6700 μg/L


Crustacean, water flea (Daphnia magna) (OECD 211) (Ref. III):

NOEC 21d (survival) = 750 μg/L
LOEC 21d (survival) = 1600 μg/L


Fish, fathead minnow (Pimephales promelas)

(OECD 210) (Ref. IV):

NOEC 35d (total length and dry weight) = 0.010 μg/L

LOEC 35d (total length and dry weight) = 0.025 μg/L


(Non-guideline full life-cycle) (Ref. V):

NOEC 301d (increased vitellogenin and lack of sexual differentiation F1 males) = 1 ng/L


PNEC = 0.1 ng/L (1 ng/L/ 10 based on the most sensitive NOEC for the fathead minnow and an assessment factor (AF) of 10)


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.43/0.1 = 4.3, i.e. 1 < PEC/PNEC < 10 which justifies the phrase "Use of ethinylestradiol has been considered to result in moderate environmental risk."


Biotic degradation

Ready Biodegradation (OECD 301B) (Ref. VI):

Not readily biodegradable


Sediment Transformation (OECD 308) (Ref. VII):

DT50 (total system) = 46 to 75 days


At each sampling interval, duplicate incubation vessels per sediment/water system were removed from incubation chamber and water layers were separated from sediment layers. Two layers were analyzed separately for [14C]ethinyl estradiol and degradates. The sediment was then extracted once with acetonitrile, once with acetonitrile:purified reagent water (80:20, v:v) and once with acetonitrile:purified reagent water:trifluoroacetic acid (80:20:0.1, v:v:v) for a total of three extractions. The water and sediment extracts were radioassayed by LSC and then analyzed by high performance liquid chromatography with radiochemical detection (HPLC/RAM) to quantify [14C]ethinyl estradiol and degradation products in the fractions. Radioactivity in the post extracted solids (sediment bound) was quantified by

combustion analysis and the liquid volatile organic traps were radioassayed by LSC.


The transformation of ethinyl estradiol in sediments and natural water was assessed in two different aerobic water/sediment systems at a temperature of 20 ± 2 °C continuously in the dark for 100 days. Average material balance ranged from 87.9 to 94.9% AR over the course of the 100-day study. The DT50 (half-life) of ethinyl estradiol in the water phase was 15 and 5 days for the Taunton River and Weweantic River aerobic test systems, respectively. The DT50 (half-life) of [14C]ethinyl estradiol in the total water/sediment test systems ranged from 46 to 75 days for the aerobic test systems. Evidence of primary biodegradation was observed for [14C]ethinyl estradiol in the aerobic water/sediment test systems. Several minor peaks were observed in some of the chromatograms for the Taunton River and Weweantic River test samples, including a peak at a polar region and retention times of approximately 10, 14, 16 and 18 minutes. In all cases, these minor peaks represented less than 10% AR in the water and sediment extracts and were not considered further. Ultimate biodegradation of [14C]ethinyl estradiol was observed in the aerobic samples with evolution of 14CO2 reaching an average maximum of 1.5 and 4.1% AR for the Taunton River and Weweantic River aerobic test samples, respectively, at Day 100. Radioactivity was not detected in the volatile organic compound traps for the aerobic test systems accumulatively at Day 100.


Justification of chosen degradation phrase:

Ethinylestradiol has a DT50 for the total system of ≤120 days. Thus, the phrase “Ethinylestradiol is slowly degraded in the environment” is chosen.


Bioaccumulation

Partition Coefficient

Several studies conducted (unknown methods) showed the log Kow value for ethinylestradiol to range from 3.67 to 4.15. (Ref. VIII, Ref. IX, Ref. X)


Bioaccumulation Study (OECD 305) (Ref. XII):

Flow through study with Bluegill sunfish (Lepomis macrochirus)

Lipid normalized kinetic BCF = 248 to 264


Justification of chosen bioaccumulation phrase:

Since log Kow < 4 and BCF < 500, ethinylestradiol has low potential for bioaccumulation


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. Smithers Viscient, 2012. ORG 224: 72-Hour Growth Inhibition Test with a Freshwater Green Alga, Pseudokirchneriella subcapitata, Based on OECD Guideline 201.

  3. Smithers Viscient, 2012. ORG 224: Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static Renewal Conditions Based on OECD Guideline 211.

  4. Smithers Viscient, 2012. "ORG 224: Early Life-Stage Toxicity Test with Fathead Minnow, Pimephales promelas, Based on OECD Guideline 210.

  5. Länge, R. et al., 2001. Effects of the Synthetic Estrogen 17α-ethinylestradiol on the Life-Cycle of the Fathead Minnow (Pimephales promelas), Environ. Toxicol. Chem. 2001, 20: 1216-1227.

  6. Wildlife International, 2011. ORG 224: Determination of Ready Biodegradability by the Carbon Dioxide Evolution Test Method.

  7. Smithers Viscient, 2014. "[14C]Ethinyl Estradiol: Aerobic Transformation in Aquatic Sediment Systems following OECD Guideline 308," Study No. 359.6753, Smithers Viscient, Wareham, MA, USA, 27 May 2014.

  8. Lai, K.M. et al., 2000. Binding of Waterborne Steroid Estrogens to Solid Phases in River and Estuarine Systems, Environ. Sci. Technol. 2000, 34: 3890-3894.

  9. Keenan, H.E. et al., 2008. Environmental Fate and Partition Co-Efficient of Oestrogenic Compounds in Sewage Treatment Process, Environmental Research 2008, 106: 313-318.

  10. Yu, Z. et al., 2004. Sorption of Steroid Estrogens to Soils and Sediments, Environ. Toxicol. Chem. 2004, 23: 531-539

  11. Smithers Viscient, 2014. "{14C]-Ethinyl Estradiol: Flow-through Bioconcentration and Metabolism Study with Bluegill Sunfish, (Lepomis macrochirus)" Study No., 359.6751, SV, Wareham, MA, USA, 23 April 2014.

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