Detaljerad miljöinformation

Identification and characterisation

Chemical name: Entrectinib

CAS number: 1108743-60-7 [1]

Molecular weight: 560,6456 [1]

Remark: -

Brand name: Rozlytrek [1]

Physico-chemical properties

Aqueous solubility	0.964–2.94 mg/l (pH 7.3–8.7, 20 °C) (OECD 105) [1]
Dissociation constant, pKa	2.54±0.09 (pK1) (25 °C, potentiometric determination) [1]
	7.54±0.01 (pK2) (25 °C, potentiometric determination) [1]
Vapour pressure	7.23 × E-17 Pa (25 °C) QSAR (EPISuite)
KH	5.47 × 10-21 Pa m3 mol-1 QSAR (EPISuite)

Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (µg/l) = (A x 1'000'000'000 x (100 - R)) / (365 x P x V x D x 100) = 1.37 x 10^-6 x A x (100 - R) = 0.0004 µg

Where:

A Sold quantity = 2.643 kg/y sales data from IQVIA / LIF - kg consumption 2022

R Removal rate = 0% Default [2]

P Population of Sweden =10 000 000

V Volume of wastewater = 200 l/day [2]

D Factor for dilution = 10 Default [2]

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Desmodesmus subspicatus): [3]

72 h ErC50 (growth rate) >100 mg/l nominal concentration (OECD 201)

72 h EyC50 (yield) >100 mg/l nominal concentration (OECD 201)

72 h NOEC = 100 mg/l nominal concentration (OECD 201)

72 h NOEC = 0.197 mg/l geometric mean concentration (OECD 201)

Water-flea (Daphnia magna): [4]

48 h EC50 (immobilisation) >100 mg/l nominal concentration (OECD 202)

48 h NOEC = 100 mg/l nominal concentration (OECD 202)

48 h NOEC = 0.278 mg/l geometric mean concentration (OECD 202)

Water-flea (Daphnia magna): [5]

21 d EC10 (reproduction) = 64.5 μg/l (OECD 211)

Zebrafish (Danio rerio): [6]

30 d LC10 (survival of juvenile fish) = 3.11 μg/l (OECD 210)

Micro-organisms (activated sludge): [7]

3 h NOEC = 1000 mg/l (OECD 209)

PNEC Derivation

The PNEC is based on the following data:

PNEC (μg/l) = lowest chronic NOEC/EC10/LC10, where 10 is the assessment factor used. A LC10 of 3.11 μg/l for fish has been used for this calculation.

PNEC = 3.11 μg/l / 10 = 0.3 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.0004 μg/l

PNEC Predicted No Effect Concentration = 0.3 μg/l

Ratio PEC/PNEC = 0.001

PEC/PNEC = 0.0004/0.3 = 0.001 for Entrectinib which justifies the phrase 'Use of Entrectinib has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability: [8]

6–10% after 28 d of incubation BOD/ThOD (OECD 301 F)

not readily biodegradable

Fate in sediment/water systems [9]

DT50 (water) = 0.8 d (Lake System 1) (OECD 308)

DT50 (water) = 1.1 d (Lake System 2) (OECD 308)

DT50 (sediment) = 12.6 d (Lake System 1) (OECD 308)

DT50 (sediment) = 24.5 d (Lake System 2) (OECD 308)

DT50 (total system) 5.1 d (Lake System 1) (OECD 308)

DT50 (total system) = 4.9 d (Lake System 2) (OECD 308)

In a sediment/water study over 100 days, 87–95% of the applied radioactivity was observed in the sediment, of which 53–61% accounted for non-extractable residues (NER). Taking into account the high adsorptive properties of Entrectinib (K_oc >>10 000 l/kg [13]), and the high non‑extractable residues (NER) formation, it has to be assumed that the respective DT50 values for sediment and total system are >120 days and that Entrectinib has eventually to be classified as persistent (P) or even very persistent (vP).

Aerobic transformation in soil [10]

DT50 (LUFA 2.1 soil system) = 0.2 d (OECD 307)

DT50 (LUFA 2.2 soil system) = 9.6 d (OECD 307, first-order multiple compartments (FOMC) model)

DT50 (LUFA 2.2 soil system) >10000 d (OECD 307, double first-order in parallel (DFOP) model)

DT50 (LUFA 2.4 soil system) = 2.6 d (OECD 307)

DT50 (LUFA 65 soil system) = 0.8 d (OECD 307)

Taking into account the high adsorptive properties of Entrectinib (K_OC >>10000 l/kg, [13]) and the high non‑extractable residues (NER) formation observed in the LUFA 2.2 soil system, it has to be assumed that the respective DT50 values for all soils are >120 days and that Entrectinib has eventually to be classified as persistent (P) or even very persistent (vP). This could be confirmed for the LUFA 2.2 soil system using the DFOP model.

Abiotic Degradation

Photodegradation: ND

Hydrolysis: ND

Entrectinib is not readily biodegradable; it is also persistent or very persistent in water/sediment systems and soils. This justifies the phrase 'Entrectinib is potentially persistent.'

Bioaccumulation/Adsorption

logD_OW = 2.7 (pH 5, 20 °C) (OECD 107) [11]

logD_OW = 4.3 (pH 7, 20 °C) (OECD 107) [11]

logD_OW = 5.1 (pH 9, 20 °C) ( OECD 107) [11]

logD_OW = 4.43 (pH 7, 25 °C) (OECD 123) [12]

K_OC >>10000 l/kg (OECD 121) [13]

(Pre-experiments for an OECD 106 study indicated that the test item was precipitating in the aqueous phase under the conditions which are recommended by the OECD guideline (0.1% organic solvent). The OECD 106 adsorption/desorption study was not performed since valid and reliable results could not be obtained. Instead, an estimation of the K_OC using the HPLC method OECD 121 was performed.) [13]

BCF_KL 72.4 l/kg (OECD 305) [14]

BCF_SSL 116 l/kg (OECD 305) [14]

Entrectinib has low potential for bioaccumulation since the Bioconcentration Factor (BCF) is <500.

Excretion/metabolism

In addition to Entrectinib, eight other radioactive peaks were detected in samples of human excreta (M1, M2, M3, M4, M5, M7, M8, and M11). The N-desmethyl metabolite M5 accounted for approximately 22% of the dose. M1 and M2 were the only other identified metabolites present in significant amounts, accounting for approximately 15% and 10% of the administered dose, respectively. Other metabolites (M3, M4, M7, M8, and M11) each represented ≤2% of the administered dose. [1]

References

1. F. Hoffmann-La Roche Ltd (2021): Environmental Risk Assessment Summary for Entrectinib. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm

2. European Medicines Agency (EMA) (2020): CHMP assessment report for Rozlytrek, https://www.ema.europa.eu/en/documents/assessment-report/rozlytrek-epar-public-assessment-report_en.pdf

3. Arcadis Schweiz LTD, on behalf of F. Hoffmann-La Roche Ltd (2018): Entrectinib: Fresh water algal growth inhibition test with Desmodesmus subspicatus. ACH study no. A18-00991

4. Arcadis Schweiz LTD, on behalf of F. Hoffmann-La Roche Ltd (2018): Entrectinib: 48-Hour acute toxicity to Daphnia magna. ACH study no. A18-00992

5. ibacon GmbH, on behalf of F. Hoffmann-La Roche Ltd (2019): Entrectinib: Influence to Daphnia magna in a semi-static reproduction test. ibacon study no. 135981221

6. ibacon GmbH, on behalf of F. Hoffmann-La Roche Ltd (2019): Entrectinib: Toxicity to zebrafish (Danio rerio) in an early-life stage test. ibacon study no. 135981232

7. ibacon GmbH, on behalf of F. Hoffmann-La Roche Ltd (2019): Entrectinib: Toxicity to activated sludge in a respiration inhibition test. ibacon study no. 135981171

8. Arcadis Schweiz LTD, on behalf of F. Hoffmann-La Roche Ltd (2018): Entrectinib: Ready biodegradability – Evaluation of the aerobic biodegradability in an aqueous medium: Manometric Respirometry Test. ACH study no. A18-00993

9. ibacon GmbH, on behalf of F. Hoffmann-La Roche Ltd (2019): Entrectinib: Aerobic transformation in aquatic sediment systems [OECD 308]. ibacon study no. 135981172

10. ibacon GmbH, on behalf of F. Hoffmann-La Roche Ltd (2019): Entrectinib: Aerobic transformation in soil [OECD 307]. ibacon study no. 135981173

11. Charles River Laboratories Den Bosch BV, on behalf of Ignyta, Inc., San Diego, CA (2018): Determination of physico-chemical properties of Entrectinib. CRL study no. 20137509

12. Arcadis Schweiz LTD, on behalf of F. Hoffmann-La Roche Ltd (2018): Entrectinib: Determination of the partition coefficient between 1-octanol and water (logPOW): Slow-Stirring Method. ACH study no. A18-00990

13. ibacon GmbH, on behalf of F. Hoffmann-La Roche Ltd (2019): Entrectinib: Estimation of the adsorption coefficient (KOC) by HPLC method [OECD 121]. ibacon study no. 135981195

14. ibacon GmbH, on behalf of F. Hoffmann-La Roche Ltd (2020): Entrectinib: Bioaccumulation in zebrafish (Danio rerio) – aqueous exposure [OECD 305]. ibacon study no. 135981233