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) = 0.0015 μg/L

Where:

A = 11.088 kg (total sold amount API in Sweden year 2021, data from IQVIA / LIF)

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) (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 (green algae, Desmodesmus subspicatus):

NOEC 72 hours (growth rate) ≥ 8037 µg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) ≥ 1137 μg/L. Guideline OECD 211. (Reference III)

Fish (fathead minnow, Pimephales promelas):

Chronic toxicity

NOEC 8 month (multigeneration study, reproduction) = 28 μg/L. Guideline OECD 240. (Reference IV)

The PNEC was calculated by division of the lowest effect level (NOEC) of the most sensitive taxonomic group considering an appropriate assessment factor (AF). The most sensitive taxonomic group were fish, and the lowest effect level was reported as NOEC = 28 µg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish).

PNEC = 28 µg/L / 10 = 2.8 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.0015 µg/L / 2.8 µg/L = 0.00054.

Justification of chosen environmental risk phrase:

A risk quotient of ≤ 0.1 qualifies for the phrase “Use of darolutamide has been considered to result in insignificant environmental risk.”.

Degradation

Biotic degradation

Ready degradability:

In a study on ready biodegradability activated sludge from a municipal sewage treatment plant was exposed to 200 mg ThOD for 28 days. The test item and the control were tested as triplicates. The positive control consisting of darolutamide and sodium acetate both at 200 mg ThOD as well as a control on viability and activity were tested in one replicate. All validity requirements were fulfilled. The study reported 0 % biodegradation of darolutamide in 28 days. Guideline OECD 301F. (Reference V)

Simulation studies:

A study on aerobic transformation in an aqueous water-sediment system was conducted. Two sediment types were used, one with higher organic carbon content and fine particle size (sediment 1, Teltowkanal km 21.7 / M11 Feldsoll, Müncheberg) and the other with a lower content of organic carbon and coarse grain size (sediment 2, Teltowkanal km 25.0). 50 g of intact sediment and approximately 150 g water were filled in each flask with 200 μgL (equivalent to 0.1 MBq) of stock solution (total radioactivity: 5 MBq / 10 mL ethanol). 18 test vessels were prepared per test system. Vessels were mounted by a glass tube containing sodium hydroxide pellets for the trapping of evolved CO₂. The study lasted 100 days at a temperature of 22-24 °C.

Radioactivity of darolutamide in sediment was quantified by combustion analysis and radio-assay. The water fraction was radio-assayed by liquid scintillation counting (LSC). Hydrochloric acid was added to the soda lime fraction and evolving ¹⁴CO₂ was absorbed in a scintillation cocktail and radio assayed by LSC. Samples for analyses were taken at the beginning, and at day 2, 15, 29, 43, 65, and 100. Three vessels were used for each analysis and discarded afterwards.

There were no deviations, and all validity criteria were fulfilled.

While darolutamide was transformed into several degradation products, there was one distinct transformation product which was measured with > 10 %. This could be identified as the metabolite M-1, a ketone of darolutamide (BAY 1896953), which was already known from metabolism studies with the test item. M-1 is reported to have increased of the course of the study while darolutamide decreased slowly with all of it degraded by end of the 100 experimental days of the study.

Non-extractable residues were 31.5 % and 47.3 % in sediment 1 and 2, respectively.

Half-lives were re-calculated for 12 °C. Darolutamide dissipated rapidly from the water phase and the DT₅₀ was determined by empirical extrapolation as < 1 day. This DT₅₀ for water was not re-calculated for the reference temperature of 12 °C as it is not a specific number. DT₅₀ for darolutamide in sediment 1 and 2 was calculated as 129.55 and 542.37 days, respectively. Half-lives of the metabolite M-1 in sediment 1 and 2 were calculated as 289.76 and 2139.74 days, respectively. Both half-lives exceed the threshold for fresh water and persistent as well as very persistent substances, respectively, and hence are considered very persistent. Guideline OECD 308. (Reference VI)

Abiotic degradation

Hydrolysis:

Darolutamide was reported to be hydrolytically stable at pH 4, 7, and 9 and 25ºC. Guideline OECD 111. (Reference VII)

Justification of chosen degradation phrase:

Darolutamide established a DT₅₀ > 120 d for the total system and is resistant to hydrolysis, which qualifies for the phrase “Darolutamide is potentially persistent.”

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported with 2.41 at pH 6-6.3. Guideline OECD 107. (Reference VIII)

Justification of chosen bioaccumulation phrase:

As the log D_ow was < 4 and/or BCF < 500 darolutamide is not considered bioaccumulative which qualifies for the phrase “Darolutamide has low potential for bioaccumulation.”

Excretion (metabolism)

In total 37 % of the administered dose is excreted as parent drug, another approx. 31 % of dose is excreted as drug glucuronides, and 17.4 % of dose is attributable to oxidative cleavage of the drug molecule. In addition, 1.6 % of dose is excreted as metabolite M-1. Only 8.4 % of the administered total dose could not be recovered or attributed to distinct structurally identified metabolites. Assuming that the observed glucuronides are quickly cleaved into the parent compound in the environment after excretion, approx. 77 % of the total administered dose is considered to be excreted as pharmacologically active drug related material (37 % parent compound +31 % glucuronides +1.6 % M1 are approx. 70 % of the administered dose, which is 53.9 % of the bioavailable fraction additionally the 23 % directly excreted fraction). (Reference IX)

References

1. Guidance on information requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment. V3.0, Feb. 2016.

2. Growth inhibition test with ODM-201 (BAY 1841788) on green algae (Desmodesmus subspicatus).  Bayer AG, Nonclinical Drug Safety, report no. PH-40085, study no. T102746-0.

3. BAY 1841788: Reproduction study of ODM-201 (BAY 1841788) in Daphnia magna. Bayer AG, Nonclinical Drug Safety, report no. PH-40103, study no. T103203-9.

4. Fish Full Life-Cycle Test. Bayer AG, Nonclinical Drug Safety, report no. R-12768, study no. T102861-8.

5. Study on the biodegradability of BAY 1841788 (ODM-201) in the manometric respiration test. Bayer AG, Nonclinical Drug Safety, report no. PH-38885, study no. T1021240.

6. Aerobic Transformation in an Aquatic Sediment System with BAY 1841788 [C-14] (Darolutamide). Bayer AG, Nonclinical Drug Safety, report no. PH-40570, study no. T103472-7.

7. BAY 1841788: Hydrolysis as a Function of pH [OECD 111]). Bayer AG, Nonclinical Drug Safety, report no. R-11242, study no. T102058-6.

8. BAY 1841788: Determination of the Partition Coefficient (n-Octanol/Water) by the Shake Flask Method). Bayer AG, Berlin, Nonclinical Drug Safety, report no. R-11239, study no. T102061-0, (2018)

9. Länge R. Nubeqa®, Environmental Risk Assessment. Bayer AG, Berlin, Toxicology, January 2019