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Esmya


MiljöinformationReceptstatusFörmånsstatus
Gedeon Richter

Tablett 5 mg
(vit till benvit, rund och bikonvex tablett på 7 mm med ”ES5” tryckt på en sida)

Oralt aktiv, syntetisk och selektiv progesteronreceptormodulator

Aktiv substans:
ATC-kod: G03XB02
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Vad är viktig säkerhetsinformation?
2018-02-19: Viktig säkerhetsinformation
Begränsningar av användningen av ESMYA 5 mg tablett (ulipristalacetat) och viktiga varningar om allvarlig leverskada samt rekommendationer om leverprover

Miljöpåverkan (Läs mer om miljöpåverkan)

Ulipristal

Miljörisk: Användning av ulipristal har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Ulipristal bryts ned långsamt i miljön.
Bioackumulering: Ulipristal 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)


PEC (µg/L) = (3.99*109*(100-0))/(365*9*106*200*10*100)


PEC for Ulipristal Acetate =6.07 x 10-04 μg/L


Where:

A =3.99 kg (total sold ulipristal acetate in Sweden in 2016 (QuintilesIMS) (Ref. I).


R (%) = % removal during wastewater (sewage) treatment (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). For ulipristal acetate it is assumed that R = 0 as a worst case.


P = number of inhabitants in Sweden = 9 x 106


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


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


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (OECD 201) (Reference III)

EbC50 72 h (biomass) = 5.01 mg/L

EyC50 72 h (yield) = 4.48 mg/L

NOEC = 1.17 mg/L


Giant water flea (Daphnia magna) (OECD 211) (Reference IV)

Chronic toxicity

EC50 21-d (Juvenile production) = 1.61 mg/L

NOEC 21-d (Juvenile production) = 0.58 mg/L


Fathead minnow (Pimephales promelas) (OCSPP Guideline 850.1500) (Reference V)

Chronic toxicity

NOEC effects seen in the F1 and F2 generations = 0.0047 mg/L


Environmental risk classification (PEC/PNEC ratio)


PNEC

Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Based on an understanding of the mode of action, the PNEC is based on full life cycle test on Fathead minnow (Pimephales promelas), in accordance with OCSPP Guideline 850.1500, and an assessment factor of 10 is applied, in accordance with EMA guidance (Ref. VI).


PNEC = 4.7/10 μg/L = 0.47 μg/L

PEC/PNEC

PEC =6.07 x 10-4 μg/L

PNEC = 0.47 μg/L

PEC/PNEC =1.29 x 10-3 μg/L


PEC/PNEC ≤ 0.1 which justifies the phrase ‘Use of the substance has been considered to result in insignificant environmental risk’ in the www.fass.se scheme.


Degradation


Ready degradability:

Test results: 4% degradation in 28 days (OECD 301B) (Ref. VII)


Simulation studies:

Aerobic and anaerobic transformation in aquatic sediment (OECD 308) (Ref. VIII)


The degradation of [14C]-ulipristal acetate was studied in two natural water-sediment systems: Calwich Abbey (CA) and SwissLake (SL), both maintained under aerobic conditions at 20 ± 2°C in the dark over a period of 100 days.


[14C]-Ulipristal acetate was applied dropwise over the surface of the water in the units. Microbial biomass units were taken for analysis on the day of application and at the end of the incubation period using units treated with the application solvent.


Samples, along with the associated traps, were removed for analysis immediately after application of [14C]-ulipristal acetate and at3, 7, 15, 30, 61 and 100 DAT (days after treatment).


Surface water was separated from the sediment and following concentration by centrifugal or rotary evaporation of a subsample, the samples were reconstituted in acetonitrile prior to analysis by high performance liquid chromatography (HPLC).


Sediment samples were extracted with acetonitrile and each extract was combined. Following concentration (by rotary or centrifugal evaporation), samples were reconstituted with acetonitrile prior to analysis by HPLC.


The total mean recovery over all the sampling intervals was 96.0 – 101.2 %AR (CA) and 93.8 – 100.8 %AR (SL). Extracted radioactivity from the sediment increased to a maximum of 7 %AR at 7 days after treatment (7 DAT)in both systems before decreasing during the remainder of the incubation period.


Levels of unextracted radioactivity from the sediment increased to 42.7 %AR (CA) and 71.0 %AR (SL) by the end of the100 DAT.


The total level of radioactivity in the sediment (summation of extractable and non-extractable radioactivity) increased throughout the study in Calwich Abbey to reach a maximum of 97.4% AR by the end of the 100 day study period. In Swiss Lake, the maximum level was reached at 61 DAT (88.1% AR) and by 100 DAT, 85.9% AR was determined.


Radioactivity in the trapping solutions was < 3% AR, the nature of the radioactivity trapped in the sodium hydroxide traps was not investigated further. It was assumed to be carbon dioxide.


Bound residue fractionation of one of the replicates of the 100 DAT Calwich Abbey gave the following results: fulvic acid (5.6%AR); humic acid (15.4 %AR); and humin (25.5 %AR), and 61 DAT Swiss Lake sample gave the following results: fulvic acids (14.4 %AR); humic acids (37.2 %AR) and humin (30.1 %AR).


The dissipation rate of ulipristal acetate was determined in the water phase using a single phase first-order model (SFO). The rate of degradation in the total system was determined using both SFOand double first-order in parallel (DFOP).


DT50 in water = 1 – 1.2 days

DT50 in sediment = 92.2 – 95.9 days

DT50 in total system = 1.8 – 75.1 days (SFO), 1.6 – 58.5 days (DFOP)


Ulipristal acetate fails the ready degradation test and the DT50 for the total system ≤ 120 days. The phrase “ulipristal acetate is slowly degraded in the environment is thus chosen”.


Bioaccumulation


Bioconcentration factor (BCF):


Oncorhynchus mykiss were continuously exposed to Ulipristal acetate at two concentrations, nominally 36.4 μg/L (low dose) and 364 μg/L (high dose), for a period of 18 days under flow-through conditions. At the end of the 18 day uptake period, the remaining fish were transferred to untreated tanks containing dilution water only for a depuration period of 9 days under flow-through conditions. A control treatment consisted of a test vessel treated only with dilution water containing DMF.


The accumulation of Ulipristal acetate in fish tissues reached steady state following seven days of exposure. Following seven days of depuration >95% of Ulipristal acetate had been removed from fish tissues. Measured tissue concentrations indicated that Ulipristal acetate was considered to have limited bioaccumulation potential (bioconcentration factors <25).


Bioaccumulation in fish: aqueous and dietary exposure (OECD 305)


BCF = 24.4 (Ref. IX)


Partition coefficient:

Partition coefficient (n octanol/water): Shake flask method (OECD 107)


For ulipristal acetate, the log Kow is 4.21 (Ref. X)


Since BCF < 500, ulipristal acetate has low potential for bioaccumulation.


Excretion (metabolism)


While Ulipristal acetate is metabolized in humans (Ref. XI), little is known about the ecotoxicity of the metabolites. Hence, as a worst case scenario it is assumed, for the purpose of this calculation, that 100% of excreted metabolites have the same ecotoxicity as the parent ulipristal acetate.


PBT/vPvB assessment


Ulipristal acetate does not fulfil the criteria for PBT or vPvB.


References


  1. Data from QuintilesIMS: Consumption assessment of ulipristal in Sweden 2013 - 2017.

  2. 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

  3. Burke, J., (2011b). Ulipristal acetate: Inhibition of Growth to the Alga Pseudokirchneriella subcapitata. Study Report Number 8243524, Covance Laboratories Ltd.

  4. Burke, J., (2011a). Chronic Effects of Ulipristal acetate to Daphnia magna. Study Report Number 8243525, Covance Laboratories Ltd.

  5. Sayers, L.E., (2015). Chronic Effects of Ulipristal acetate in Fishes: Full Life-Cycle Toxicity Test with Fathead Minnow (Pimephales promelas). Study Report Number 14045.6100, Smithers Viscient.

  6. European Medicines Agency (2006). Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. European Medicines Agency/Committee for Medicinal Products for Human Use. 01 June 2006. Doc ref. EMEA/CHMP/SWP/4447/00 corr 21*.

  7. Graham, R. (2011a). Ulipristal acetate: Assessment of Ready Biodegradability by Measurement of CO2 Evolution. Study Report Number 8243538, Covance Laboratories Ltd.

  8. Hurst, L., (2012b). [14C]-Ulipristal acetate: Degradation in Water-Sediment Systems under Aerobic Conditions. Study Report Number 8243540, Covance Laboratories Ltd.

  9. Last, G., (2012). Ulipristal acetate: Fish Bioconcentration Study. Study Report Number 8243528, Covance Laboratories Ltd.

  10. Anon (2008). Determination of the Partition Coefficient (log P) in Octanol/Water of Ulipristal acetate, Crystal pharma.

  11. Andrea Kim; and Mary Barna Bridgeman (2011). Ulipristal Acetate (ella) A Selective Progesterone Receptor Modulator For Emergency Contraception. Pharmacy and Therapeutics 36(6): 325-331.




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