Detaljerad miljöinformation

Detailed background information

Studies of ezetimibe indicate it is poorly soluble in water (0.5 mg/L). Adsorption/desorption studies indicate ezetimibe is likely to bind to soils and sludge to some degree (log Koc range 3.6 to 4.4) The high octanol/water partition coefficient (log Kow > 4) suggested the potential to bioaccumulate in aquatic organisms, however measured bioconcentration factors in bluegill sunfish ranged from 69 to 173, indicating a low potential for bioaccumulation [Ref X].

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) = 1.37*10^-6*A(100-R)

PEC = 0.053 μg/L

Where:

A = 386.55 kg (total sold amount API in Sweden year 2022, data from IQVIA). Reduction of A may be justified based on metabolism data.

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. (If R not equal to 0 this should be justified under the degradation section) 

P = number of inhabitants in Sweden = 10 *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 = 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)

Midge (Chironomus riparius)

Chronic toxicity

NOEC 28 days (growth) = 877mg/kg

While significant shifting of this compound to the sediment is likely to occur, chronic toxicity

tests with the midge (Chironomus riparius) indicate the compound is non-toxic to sediment dwelling organisms (21-day EC50 > 877 mg/kg, which is the highest concentration tested).(Ref XI)

PNEC (μg/L) = 50/10 = 5 μg/L where 10 is the assessment factor used for three long-term ecotoxicity data endpoints. NOEC for fathead minnow has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC =   0.053/5 = 0.011, i.e. PEC/PNEC ratio < 1 which justifies the phrase ‘Use of Ezetimibe has been considered to result in insignificant long-term risk to the environment.

Degradation*

Biotic degradation

Biodegradation Simulation Screening

Test results 7% biodegradation to CO2 by Day 28. (OECD 301B) (Ref. VII)

Test results 4% biodegradation to CO2 by Day 28; 83% biodegradation to metabolites (OECD 314) (Ref. VIII)

Abiotic degradation

Hydrolysis:

Half-life of 4.5 days at pH 7, 25^oC (OECD 111) (Ref. IX)

Justification of chosen degradation phrase:

Ezetimibe is inherently degradable in biological systems and via hydrolysis. However, as no data are available on the toxicity of the metabolites, the phrase “Ezetimibe is potentially persistent in the environment” is thus chosen.

Bioaccumulation

Bioconcentration Factor (BCF):

Measured BCF values were 69 (low concentration) and 137 (high concentration) in a 97 day study with bluegill sunfish (OECD 305). (Ref. X)

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.

2. Wildlife International, 2009. "Ezetimibe: A 96-hr toxicity test with the freshwater alga (Pseudokirchneriella subcapitata)", OECD 211, 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. August 2013

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

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

11. Wildlife International, 2011. “[14C] Ezetimbe: A Prolonged Sediment Toxicity Test with Chironomus riparius usind Spiked Sediment, OECD 218, Project No, 105A-198, 15 April 2011.