Detaljerad miljöinformation

Detailed background information

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) = 1.37 * 10^-6 * 0.126 * 100

PEC = 0.000017 μg/L = 0.0173 ng/L

Where:

A = 0.1266 kg (total sold amount of inclisiran in Sweden year 2023, data from IQVIA)

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) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Algae (Raphidocelis subcapitata) (OECD201) (Smithers Study No. 14199.6105):

NOEC 72 h = 110 mg/L

Crustacean (Daphnia magna, waterflea):

Chronic toxicity

NOEC 21 days (reproduction) = 12 mg/L (OECD 211) (Smithers Study No. 14199.6107)

Fish:

Chronic toxicity (Pimephales promelas, fathead minnow)

NOEC 28 days (larval survival) = 2.5 mg/L (OECD 210) (Smithers Study No. 14199.6106)

Other ecotoxicity data:

Bacterial respiration inhibition

NOEC 3 h = 1000 mg/L (activated sludge respiration inhibition) (OECD209) (Smithers Study No. 14199.6104)

Sediment-dwelling organisms (Chironomus riparius, non-biting midge)

NOEC 28 days (emergence) = 6.0 mg/kg dry sediment (OECD 218) (Smithers Study No. 14199.6110)

PNEC derivation:

PNEC = 250 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used if three chronic toxicity studies from three trophic levels are available. The NOEC for the fish species Pimephales promelas in a fish early-life stage study has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000017 μg/L / 250 μg/L = 0.00000007, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of inclisiran has been considered to result in insignificant environmental risk".

Degradation

Biotic degradation

Ready degradability:

Not readily biodegradable (OECD 301B). (Eurofins Study Number 846E-102)

Simulation studies:

DT₅₀ (total system) = 5.35 – >10’000 days (OECD 308) (Smithers Study No. 14199.6110)

Ultimate biodegradation of [¹⁴C]inclisiran was observed in significant proportions in the aerobic samples with evolution of radio-carbon dioxide (¹⁴CO₂) reaching an average maximum of 77.3 and 23.8% AR for the river systems (loamy with 4% organic carbon and sandy with 0.76% organic carbon, respectively). One major transformation product (≥ 10% AR) was observed in some of the water layer chromatograms, which has been identified as 2'-O-methyluridine. 

Sediment samples were extracted once with purified reagent water and up to three times with 1 M potassium carbonate in purified reagent water. Due to the low recovery in the purified reagent water extracts, HPLC-RAM analysis was not performed. With respect to the potassium carbonate extracts, barium chloride precipitation suggests that all radioactivity in these extracts was due to the presence of volatile carbon dioxide which was trapped in the sediments. NER generally increased over the course of the incubation period.  At the end of the study (day 60), the NER in the test systems represented 9.92 and 29.0% AR for the two river systems.

Following a highly conservative approach, the DT calculations considered that all radioactivity in the sediment extracts was inclisiran. The calculated DT₅₀ values for [¹⁴C]inclisiran were 5.35 and > 10,000 days in the total water/sediment test systems, and 4.19 and 3.00 days in the water phase.

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, inclisiran can be classified as “Inclisiran is slowly degraded in the environment” (DT50 for total system <120 days and > 120 days in river systems with high and low organic carbon content, respectively).

Bioaccumulation

Partitioning coefficient:

log P_ow at pH 5 < -1.4

log P_ow at pH 7 < -1.4

log P_ow at pH 9 < -1.4 (OECD 107) (Alcami, RPT87764.00)

Justification of chosen bioaccumulation phrase:

Since log P < 4, inclisiran has low potential for bioaccumulation.

Excretion (metabolism)

It is estimated that approximately 82.5% elimination of inclisiran from plasma is due to hepatic uptake. Besides hepatic uptake, renal clearance was identified a main route of elimination of unchanged inclisiran from plasma in human. 15.9% of unchanged inclisiran was excreted in urine over 48 hours following a single oral SC dose of 300 mg inclisiran sodium. Although rapidly cleared from plasma, inclisiran exhibits a slow elimination half-life from liver based on non-clinical studies and does not appear to undergo extensive metabolism (Leqvio EPAR, 2020).

References

• EMA 2006. Guideline on the environmental risk assessment of medicinal products for human use. EMEA/CHMP/SWP/4447/00 corr 21.

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• Smithers Study No. 14199.6105. Inclisiran – 72-hour toxicity to the freshwater green alga, Raphidocelis subcapitata, Following OECD Guideline 201. 5 January 2021.

• Smithers Study No. 14199.6107. Inclisiran – Full life-cycle toxicity to water flea (Daphnia magna) under static-renewal conditions, following OECD Guideline 211. Final report: 6 January 2021.

• Smithers Study No. 14199.6106. Inclisiran – Early life-stage toxicity test with Fathead Minnow (Pimephales promelas), following OECD Guideline 210. Final report: 21 May 2021.

• Smithers Study No. 14199.6104. Inclisiran – Activated sludge respiration inhibition test following OECD Guideline 209. Final report: 7 August 2020.

• Smithers Study No. 14199.6110. [¹⁴C]Inclisiran – Toxicity test with sediment-dwelling midges (Chironomus riparius) under static conditions, following OECD Guideline 218. Final report: 16 March 2021.

• Alcami report RPT87764.00. Partition Coefficient Determination for Inclisiran for Injection (200 mg/mL). Final report: 26 August 2019.

• Eurofins Study number 846E-102. Inclisiran: ready biodegradability by the carbon dioxide evolution test method. Final report: 30 March 2020.

• Smithers Study No. 14199.6103. [¹⁴C]Inclisiran – Aerobic transformation in aquatic sediment systems following OECD Guideline 308. Final report: 5 November 2021.

• Leqvio EPAR. EMA/696912/2020. Assessment report Leqvio. Procedure No. EMEA/H/C/005333/0000