Detaljerad miljöinformation

Simvastatin) is a cholesterol-lowering agent intended for use in humans. Simvastatin is a pro-drug of the active pharmaceutical ingredient, simvastatin hydroxy acid, the molecule that inhibits 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) reductase. This enzyme is the rate-limiting step in the biosynthetic pathway responsible for the de novo synthesis of cholesterol in the liver. Patients taking simvastatin (and thereby simvastatin hydroxy acid) are found to significantly reduce the levels of cholesterol in the body. Because simvastatin hydroxy acid (salt form is simvastatin ammonium salt) is the active pharmaceutical ingredient, this assessment focuses on the fate and effects of this molecule. No chronic toxicity studies were conducted, as simvastatin is expected to hydrolyze to simvastatin hydroxy acid within a short time frame. Chronic toxicity was apparent with D. magna the most sensitive species base on neonate survival (reproduction endpoint). Although at concentrations unlikely to be seen in the environment, simvastatin ammonium salt was toxic to sediment dwellings midges at 4.4 mg/kg.

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 = 0.3108 μg/L

Where:

A = 2 268.6076 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.

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 wastewater by surface water flow = 10 (ECHA default) (Ref. I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies*

Green Algae (Pseudokirchneriella subcapitata) (guideline eg OECD 201) (Reference VI):

EC₅₀ 72 h (growth) = 27.4 (yield) 120 (growth rate) mg/L

EC₁₀ or NOEC = 2.45 mg/L

Water flea (Daphnia magna):

Acute toxicity

EC₅₀ 48 h (mortality) = 3.5 mg/L (guideline eg OECD 202) (Reference IV)

Chronic toxicity

NOEC 21 days (growth, reproduction) = 0.002 mg/L (guideline eg OECD 211) (Reference VIII)

Flathead Minnow (Pimephales promelas):

Acute toxicity

LC₅₀ 96 h (mortality) = 2.91 mg/L (guideline eg OECD 203) (Reference V)

Chronic toxicity

NOEC 31 days (growth) =   0.008 mg/L (guideline eg OECD 210) (Reference VI)

Midge (Chironomus riparious)

Chronic toxicity

NOEC 28 days (growth)  = 4.39 mg/kg  (Reference IX)

Other ecotoxicity data: PNEC = 0.2 μg/L (justification of chosen assessment factor (AF))

PNEC (μg/L) = 0.002 mg/L /10, where 10 is the assessment factor used for three long-term ecotoxicity data endpoints.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.3108/0.2 = 1.55

A complete set of environmental fate and effects data of the active pharmaceutical, simvastatin hydroxy acid, was collected. Simvastatin and its metabolites have a low risk to the environment from normal patient use.

Degradation*

Biotic degradation

The potential for persistence of simvastatin cannot be excluded, due to lack of data.

Bioaccumulation

Simvastatin hydroxy acid is expected to bioaccumulate due to its measured log octanol water partition coefficient based on OECD 107 [II]

Partitioning coefficient: Log Kow = pH 5 > 4.11

              pH 7 > 4.07

              pH 9 > 4.07

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, 2011. "Simvastatin - Determining the Partition Coefficient (n-Octanol/Water) by the Flask-Shaking Method Following OECD Guideline 107,"Study No., 359.6338, SSL, Wareham, MA, USA, 05 January 2011

3. Smithers Viscient, 2011. "Simvastatin - Determination of the Abiotic Degradation of the Test Substance by Hydrolysis at Three Different pH Values Following OECDGuideline 111," Study No., 359.6337, SSL, Wareham, MA, USA, 17 February 2011.

4. Smithers Viscient, 2010. "Simvastatin – Acute Toxicity to Water Fleas, (Daphniamagna) Under Static Conditions, Following OECD Guideline #202," Study No.,359.6336, SV, Wareham, MA, USA 3 December 2010.

5. Merck, 1997. Memo K. Kumke to E. Venkat "Preliminary Environmental QualityCriteria Guidance for Simvastatin", 21 March 1997.

6. Huntingdon Life Sciences, 2011. "Simvastatin Ammonium Salt Algal GrowthInhibition Assay," Study No. PPM0005, HLS, UK, 19 April 2011

7. Huntingdon Life Sciences, 2011. "Simvastatin Ammonium Salt Fish Early Life StageToxicity Test for Fathead Minnow," Study No. PPM0007, HLS, UK, 23 Dec 2011

8. Huntingdon Life Sciences, 2010. "Simvastatin ammonium salt Daphnia magna reproduction toxicity test" HLS report PPM0006, Huntingdon, Cambridgeshire, England. 12 May 2011.

9. Huntingdon Life Sciences, 2011. "Simvastatin Ammonium Salt; Toxicity to theSediment-Dwelling Phase of the Midge Chironomus riparius" Study No. PPM0009,HLS, UK, 23 March 2012