Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

Darolutamide is a new active ingredient in the cancer treatment medicine Nubeqa^®.

The PEC is calculated based on the sales predictions for 2021/2022, since actual sales data are not available:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.5*10^-6*A(100-R)

PEC = 0,01 μg/L

Where:

A = 67.5 kg (no. of patients expected to be treated [154] * daily dose [1200 mg] * 365d, Sweden, year 2021).
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 = 9 *10⁶ 

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default (1))

D = factor for dilution of waste water by surface water flow = 10 (ECHA default (1))

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus):

NOEC/72 h ≥8037, LOEC>8037 µg/L (guideline OECD 201) (2)

Crustacean (waterflea Daphnia magna):

Chronic toxicity

NOEC /21 days (reproduction) = ≥ 1137 μg/L, LOEC >1137 µg/L (guideline OECD 211) (3)

Fish:

Chronic toxicity (fathead minnow Pimephales promelas)

NOEC / 8 months (fish multigen. test; most sensitive endpoint: hatching success) = 28 μg/L, LOEC 89 µg/L (OECD 240) (4) 

PNEC = 2.8 μg/L (Lowest chronic NOEC fish = 28 µg/L; AF 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0,01/2.8= 0.004, i.e. PEC/PNEC <0.01 which justifies the phrase "Use of *darolutamide* has been considered to result in insignificant environmental risk".

Degradation

Biotic degradation

Ready degradability: not ready biodegradable

Darolutamide was studied for aerobic biodegradability in water in a manometric respiration test according to guideline OECD 301F (5). Darolutamide was introduced into the test system at a concentration of 200 mg/L as theoretically oxidizable carbon. It was not degraded after 28 days. Hence, it is not readily biodegradable.

A study on transformation in aquatic/sediment systems according to test guideline OECD 308 was conducted (6). The transformation of [¹⁴C] darolutamide in sediments and natural water was assessed in two different aerobic sediment/water systems. Darolutamide was incubated in glass vessels containing sediment and overlaying water over 100 days. Sediment samples (0.9-2.4 g) were subsequently extracted with 3 mL methanol, 3 mL of a mixture of acetonitrile/methanol (1/1, v/v), 3 mL of a mixture of acetonitrile/1 % formic acid (2/8, v/v) and with 3 mL of a mixture of acetonitrile/0.1 % trifluoroacetic acid (111, v/v) at room temperature using an ultrasonic bath. Darolutamide partitioned into sediment compartment very quickly, the DT50 was estimated with less than a day. Ultimate biodegradation was accounted for 1.1 and 1.2 % of the radioactivity in location 1.and 2, respectively. The extraction of water and sediment showed that Darolutamide was transformed to several transformation products, and one prominent metabolite was identified. This metabolite is M-1, a ketone of Darolutamide (BAY 1896953), which is as pharmacologically active as both diastereoisomers. Non-extractable radioactivity was found in sediments up to 31.5% in sediment 1 and 47.3% in sediment 2

The DT50s for sediment degradation represent the total system degradation due to the rapid disappearance from the water phase, as described in REACH Guidance R11. It was 134.9 d and 35.8 d for sediment system km 21.7 and km 25, respectively, adjusted to temperature 12°C.

The overall disappearance half-life from the system exceeded slightly the threshold of 120d for persistence in one of the two sediment systems while at the other system, the half-life was close to the threshold of 32d for fast degradation. Overall, it is justified therefore to classify the compound as slowly degrading in the environment.

Abiotic degradation

Hydrolysis:

Darolutamide is hydrolytically stable (pH 4, 7, and 9, 25ºC) (OECD 111) (7)

Bioaccumulation

Partitioning coefficient:

Log P_OW 2.41 (Shake flask method, OECD 107) (8)

Justification of chosen bioaccumulation phrase:

According to the log Pow 2.41, 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)(9).

PBT/vPvB assessment

Darolutamide is not PBT/vPvB, because the log Pow was 2.41.

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) 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 (2018)

(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 (2018)

(4) Fish Full Life-Cycle Test. Bayer AG, Nonclinical Drug Safety, report no. R-12768, study no. T102861-8 (2019)

(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 (2018)

(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 (2018)

(7) BAY 1841788: Hydrolysis as a Function of pH [OECD 111]). Bayer AG, Nonclinical Drug Safety, report no. R-11242, study no. T102058-6 (2018)

(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