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

PEC = 0.0000000256 μg/L = 2.56x10^-8 µg/L

Where:

A = 0.0496 kg (total sold amount API in Sweden in 2022; forecast sales data)

R = 99.62 (considering excretion of 79.4 % pharmacologically inactive metabolites and 98.17 % removal in sewage treatment plants), i.e., only 0.377 % of the sold amount enters the surface water

P = number of inhabitants in Sweden = 10*10⁶

V = volume of wastewater per capita and day = 200 L/day (ECHA default) (Reference I)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus) (guideline OECD 201) (Reference II):

ErC₁₀ 72 h (growth rate) = 11.29 mg/L

NOEC 72 h (growth rate) = 3.46 mg/L

Crustacean (Daphnia magna):

Chronic toxicity

EC₁₀ 21 days (reproduction) = 0.005 mg/L (guideline OECD 211) (Reference III)

Fish (Pimephales promelas):

Chronic toxicity

NOEC 28 d (survival, development) = 0.00001 mg/L (guideline OECD 210) (Reference IV)

The PNEC of 0.000001 mg/L = 0.001 µg/L was calculated with the lowest NOEC divided by 10, where 10 is the standard assessment factor (AF) used for three long-term ecotoxicity data endpoints. EC₁₀ for Pimephales promelas fish 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 = 0.0000000256 μg/L / 0.001 = 0.0000256, i.e., PEC/PNEC ≤ 0.1 which justifies the phrase ‘Use of finerenone has been considered to result in insignificant environmental risk.’

Degradation*

Biotic degradation

Simulation studies:

In an aerobic transformation study in aquatic sediment with two sediments of varying in organic carbon content and coarse grain size. Sediments were exposed over 100 days using radio-labelled test item. The dissipation from water resulted in a DT50 of 78.9-147.9 days and that of the total water-sediment system was 80.5-191.7 days. While degradation products were observed pointing to some primary biodegradation (not quantified) the rate of ultimate biodegradation was low with 0.3-0.7 % (guideline OECD 308). (Reference V)

Abiotic degradation

Hydrolysis:

Finerenone was determined to be stable under test conditions, i.e., DT50 > 1 year (guideline OECD 111). (Reference VI)

SimpleTreat modelling – elimination in sewage treatment plants

The SimpleTreat model (v4.0.9) was used to estimate the fraction of finerenone that is retained in sewage treatment plant and does not enter the surface water compartment. The calculation is based on experimental physico-chemical data of finerenone. Molecular weight: 378.43 g/mol, octanol-water partition coefficient (K_OW): 407.38, vapour pressure: 0.000000001 = 10^-9 at 20 °C, water solubility: 17.3 mg/L at 20 °C, organic carbon partition coefficient (K_OC): 125,892,514 and biodegradation: not readily biodegradable (worst case assumption, as no study on ready biodegradability available). (Reference VII, VIII, IX, X)

The vapour pressure is the lowest possible value in the tool, while the actual experimentally determine vapour pressure of finerenone is less < 0.0000000001 = 10^-10. The experimentally determined K_OC is > 5.52 and estimated to be 125,892,514 in the study.

SimpleTreat calculated the release to surface water after sewage treatment as 1.83 %, i.e., 98.17 % are eliminated by binding to sludge while there is no emission to air. The PEC calculation was be refined taking account of this elimination.

Justification of chosen degradation phrase:

Substance finerenone shows DT50 up to 191.7 days and is resistant to hydrolysis. The phrase “Finerenone is potentially persistent” was chosen.

Bioaccumulation

Partitioning coefficient:

Log Kow = 2.61 at pH 7 (guideline OECD 107). (Reference VII)

Justification of chosen bioaccumulation phrase:

Since log Kow < 4 at pH 7 the phrase “finerenone has low potential for bioaccumulation” was chosen.

Excretion (metabolism)

After oral administration to humans, finerenone is extensively metabolized to a major extent by oxidative biotransformation. The total recovery of the administered radioactivity was 101 % in humans. In total, 79.6 % of the radioactive dose given to healthy volunteers was excreted renally (via urine) and 21.2 % via feces. The finerenone associated radioactivity was recovered in the excreta, mainly in the form of metabolites, while excretion of unchanged finerenone with 1 % is negligible. Primary metabolic transformation involved aromatization of the dihydronaphthyridine moiety of metabolite M1 as a major clearance pathway with a second oxidative pathway leading to M4. These were both prone to further oxidative biotransformation reactions. Naphthyridine metabolites M-1 (48.9 %), M-2 (21.5 %) and M-3 (9 %) were the dominant metabolites identified in human plasma, with no on-target pharmacological activity.

Concluding, 1 % of finerenone is excreted unchanged, for 19.6 % of the metabolites on-target pharmacological activity is unknown and should and is considered to be similarly pharmacologically active as the parent substance (reasonable worst-case assumption). Metabolites M1-M3 summing up to 79.4 % are not pharmacologically active on-target. The PEC calculation was be refined taking account of the metabolism data. (Reference XI)

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. BAY 94-8862: Growth inhibition test with Finerenone on green algae (Desmodesmus subspicatus). Bayer AG, Toxicology. Report no. PH-40828, study no. T103240-0.

3. BAY 94-8862: Reproduction study with Finerenone (BAY 94-8862) in Daphnia magna. Bayer AG, Toxicology. Report no. PH-41492, study no. T104243-4.

4. BAY 94-8862: Early-life-stage-test with Finerenone (BAY 94-8862) on the fathead minnow (Pimephales promelas). Bayer AG, Toxicology. Report no. PH-41594, study no. T103937-3.

5. BAY 94-8862C14: Aerobic transformation in an aquatic sediment system with BAY 94-8862C14 [Finerenone]. Bayer AG, Toxicology. Report no. PH-40964, study no. T102785-3.

6. BAY 94-8862: Hydrolysis as a Function of pH [OECD 111]. Bayer AG, Toxicology. Report no. R12006, study no. T102723-5.

7. BAY 94-8862: Determination of the Partition Coefficient (n-Octanol/Water) by the Shake Flask Method. Bayer AG, toxicology. Report no. R-12545, study no. T102726-8.

8. BAY 94-8862: Determination of the Vapour Pressure by Isothermal Thermogravimetry. Bayer AG, Toxicology. Report no. R-11831, study no. T102724‑6.

9. BAY 94-8862: Determination of the Water Solubility (First Amendment). Bayer AG, Toxicology. Report no. R-12240, study no. T102725-7.

10. BAY94-8862: Estimation of the Adsorption Coefficient (Koc) by HPLC method [OECD 121]. Bayer AG, Toxicology. Report no. R-12959, study no. T104139-8.

11. Gerisch M, Heinig R, Engelen A, Lang D, Kolkhof P, Radtke M, Platzek J, Lovis K, Rohde G, Schwarz T. 2018. Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro. Drug Metab. Dispos. 46, 1546-1555.