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Miljöpåverkan (Läs mer om miljöpåverkan)

Ezetimib

Miljörisk: Användning av ezetimib har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Ezetimib bryts ned långsamt i miljön.
Bioackumulering: Ezetimib 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 = 0.01 μg/L


Where:

A = 92 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

Green Algae (Selenastrum capricornutum) (OECD 201) (Ref. II)

EC50 72 h (density) = >0.3 mg/L

EC50 72 h (growth rate) = >0.3 mg/L

NOEC 72 h (growth rate) = 0.3 mg/L

Non-toxic up to highest concentration tested


Crustacean, water flea (Daphnia magna):

Acute toxicity

LC50 48 h (mortality) > 4 mg/L (OECD 202) (Ref. III)

Non-toxic up to highest concentration tested


Chronic toxicity

NOEC 21 day (mortality; reproduction) = 0.3 mg/L (OECD 211) (Ref. IV)

Non-toxic up to highest concentration tested


Fish, fathead minnow (Pimephales promelas):

Acute toxicity

LC50 96 h (mortality) > 0.13 mg/L (OECD 203) (Ref.V)

Non-toxic up to highest concentration tested


Chronic toxicity

NOEC 33 days (growth, total length) = 0.05 mg/L (OECD 210) (Ref. VI)


PNEC = 0.005 mg/L = 5 µg/L (0.05 mg/L / 10) based on the most sensitive chronic NOEC for the fathead minnow and an assessment factor (AF) of 10)


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = .01/5 = 0.002, i.e. PEC/PNEC ≤ .1 which justifies the phrase “Use of ezetimibe has been considered to result in insignificant environmental risk.”


Degradation

Biotic degradation


Biodegradation Simulation Screening (OECD 301B) (Ref. VII)

Test results 7% biodegradation to CO2 by Day 28.


Biodegradation in Sludge (OECD 314) (Ref. VIII)

Test results 4% biodegradation to CO2 by Day 28

83% biodegradation to metabolites


Sediment Transformation (OECD 308) (Ref. IX)

DT50 (total system) = 11 - 23 days


Two sediments and their associated waters were utilized in the study. Test systems

were dosed with 14C-labeled Ezetimibe at a nominal concentration of 0.55 mg/L in the water layer. Test systems were incubated in the dark at approximately 20 ºC for up to 103 days, and maintained under aerobic conditions by gently bubbling air into the water layers. Effluent gasses were passed through charcoal sorbent tubes to trap organic volatiles, followed by alkali solutions to trap evolved carbon dioxide. Duplicate test chambers of each sediment-water type were sacrificed on days 0, 5, 14, 28, 56 and 103. Water layers, sediment extracts and sediment solids were analyzed separately for total radioactivity by liquid scintillation counting (LSC). In addition, water layer samples were collected on days 1 and 2.


Ezetimibe demonstrated some transformation in aerobic Brandywine Creek and Choptank River test systems. The disappearance times of 50 percent of parent (DT50) from the water layers were 4.3 and 4.1 days, respectively. The DT90 values were 19.0 and 17.6 days, respectively. The amounts of Ezetimibe in the sediment layers increased to a maximum of 43% on day 14 in Brandywine Creek samples and 20% on day 28 in Choptank River samples. The amounts of Ezetimibe in the total test systems (i.e. water layers plus sediment extracts) at the end of the test were 19% and 8%, respectively. The DT50 values for parent in the total test systems were 23.1 and 11.0 days, and the DT90 values were >103 and 47.0 days, respectively. Through all test intervals, the maximum percentages of dosed radioactivity recovered as transformation products were 58% and 73%, respectively. The fractions of radiolabeled residues that could not be extracted from the sediment layers at the end of the test were 27% and 32%. The maximum amounts of mineralization or ultimate biodegradation observed were <6% for both test systems. Total mean recoveries expressed as percentages of dosed radioactivity ranged from 91% to 103% throughout the study.


Abiotic degradation


Hydrolysis (OECD 111) (Ref. X)

Half-life of 4.5 days at pH 7


Justification of chosen degradation phrase:

Ezetimibe is inherently degradable in biological systems and via hydrolysis. The DT50 for the total system is < 32 days with > 15% parent compound remaining at the end of the study therefore the phrase, “Ezetimibe is slowly degraded in the environment” is thus chosen.


Bioaccumulation

Bioconcentration Factor (BCF) (OECD 305). (Ref.XI)

Measured BCF values were 69 (low concentration) and 137 (high concentration) in a 97 day study with bluegill sunfish


Justification of chosen bioaccumulation phrase:

Since 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. Wildlife International, 2009. "Ezetimibe: A 96-hr toxicity test with the freshwater alga (Pseudokirchneriella subcapitata)", OECD 201, Project No. 105A-174, Wildlife International, 2 February 2009.


  3. Toxikon Corp., 2001. "JV-AT-A: Acute Toxicity to the water flea, Daphnia magna, under static test conditions" OECD 202 (Part 1), Project ID 01J0006c. Toxicon Corp., 17 October, 2001.


  4. Wildlife International, 2009. "Ezetimibe: A flow-through life-cycle toxicity test with the cladoceran (Daphnia magna)", OECD 211, Project No. 105A-175, Wildlife International, 26 February 2009.


  5. Toxikon Corp., 2001. "JV-AT-A: Acute Toxicity to fathead minnow, Pimephales promelas, under static test conditions" OECD 203, Project ID 01J0006e. Toxicon Corp., 17 October, 2001.


  6. Wildlife International, Ltd., Ezetimibe: an early life-stage toxicity test with the fathead minnow (pimephales promelas), WIL Project Number 105A-176, Easton MD, 17 March 2009.


  7. Toxicon, 2002. "JV-AT-A: Ready Biodegradability: CO2 Evolution (Modified Sturm Test)", Toxicon Report 01J0001, Jupiter Fl, 10 April 2002.


  8. Wildlife International, 2009. "Ezetimibe dieaway in activated sludge", WIL Project Number 105E-129, Easton MD, 2 Nov 2009.Wildlife International, 2009.


  9. Wildlife International, 2010. "EZETIMIBE: AEROBIC TRANSFORMATION IN AQUATIC SEDIMENT SYSTEMS", WIL Project Number 105E-152, Easton MD, 1 October 2010.


  10. "Ezetimibe: An evaluation of hydrolysis as a function of pH" OECD 111, Project number 105C-121. Wildlife International, 4 May 2009.


  11. Wildlife International, 2011. "Ezetimibe: A Bioconcentration Test with the Bluegill (Lepomis macrochirus)," Project No. 105A-197, WIL, Easton, MD, USA, 16 March 2011.