Detaljerad miljöinformation

Identification and characterisation

Chemical name: Alectinib hydrochloride

CAS number: 1256589-74-8 [1]

Molecular weight: 519.086 [1]

Brand name: Alecensa [1]

Physico-chemical properties

Aqueous solubility: 46 mg/l (37 °C, pH 5) (method not specified) [1]

Dissociation constant, pK_a: pK_a = 6.7–7.54 QSAR [1], pK_a = 11.2–13.7 QSAR [1], pK_a = 4.4 QSAR [1]

Melting point: ca. 302 °C (with decomposition) [1]

Vapour pressure: 3.89*E–13 Pa (25 °C) QSAR

K_H: 4.634*E–8 Pa*m3/mol QSAR

QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris)

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) = 0.009 μg/l

Where:

A Sold quantity = 65.301 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 Default [2]

D Factor for Dilution = 10 Default [2]

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Raphidocelis subcapitata): [3]

72 h ErC50 (growth rate) >11.7 mg/l (OECD 201)

72 h EyC50 (yield) >11.7 mg/l (OECD 201)

72 h NOEC (overall NOEC) = 11.7 mg/l (OECD 201)

Water-flea (Daphnia magna): [4]

21 d NOEC (overall NOEC) = 0.133 mg/l (OECD 211)

Zebrafish (Danio rerio): [5]

36 d NOEC (overall NOEC) = 10 mg/l nominal concentration (OECD 210)

36 d NOEC (overall NOEC) = 0.001 mg/l mean measured concentration (OECD 210)

Micro-organisms (activated sludge): [6]

3 h EC50 (respiration inhibition) >1000 mg/l (OECD 209)

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

PNEC Derivation

The PNEC is based on the following data:

PNEC (mg/l) = lowest chronic NOEC/10, where 10 is the assessment factor used. A NOEC of 0.001 mg/l (1 μg/l) for fish has been used for this calculation. [1]

PNEC = 1 μg/l / 10 = 0.1 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.009 μg/l

PNEC Predicted No Effect Concentration = 0.1μg/l

Ratio PEC/PNEC = 0.09

PEC/PNEC = 0.009/0.1 = 0.09 for Alectinib hydrochloride which justifies the phrase 'Use of Alectinib hydrochloride has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability: [7]

0% after 28 days of incubation BOD/ThOD (OECD 301 F)

Inherent biodegradability: ND

Other degradation information: [8]

DT50 (water) = 1.5–2.3 d (OECD 308)

DT50 (total system) = 75–273 d (OECD 308)

Abiotic Degradation

Photodegradation: ND

Hydrolysis: ND

Alectinib hydrochloride is not readily biodegradable; a DT50 (total system) of 75–273 d in water/sediment systems justifies the phrase 'Alectinib hydrochloride is potentially persistent.'

Bioaccumulation/Adsorption

logD_OW = 3.09 (pH 5) (OECD 117) [9]

logD_OW = 3.86 (pH 7) (OECD 117) [9]

logP_OW = 3.85 (pH 9, non-dissociated state) (OECD 117) [9]

K_OC (soils) = 14921–32878 l/kg (OECD 106) [10]

K_OC (sludges) = 5707–16634 l/kg (OECD 106) [10]

BCF = 146.8–147.7 l/kg (OECD 305) [11]

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

Excretion/metabolism

Alectinib hydrochloride is eliminated from human plasma in with a median apparent terminal t½ ranging from 18.2 to 25.3 hours. In massbalance studies, Alectinib hydrochloride was excreted predominantly by faecal pathway. [12]

References

1. F. Hoffmann-La Roche Ltd (2023): Environmental Risk Assessment Summary for Alectinib. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm

2. European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2.

3. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2015). CH5424802-002: A Study on the Toxicity to Algae (Pseudokirchneriella subcapitata) according to OECD Guideline No. 201, 2006 "Freshwater Alga and Cyanobacteria, Growth Inhibition Test". ECT study no. 14AZ3AO.

4. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2015). CH5424802-002: A Study on the Chronic Toxicity to Daphnia magna according to the OECD Guideline 211 "Daphnia magna, Reproduction Test" adopted 2nd October, 2012. ECT study no. 15AZ7DB .

5. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2015). CH5424802-002: A Study on the Toxicity to Early-Life Stages of Zebrafish according to OECD Guideline No. 210 "Fish, Early-life Stage Toxicity Test". ECT study no. 14AZ8FV.

6. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2015). CH5424802-002: A Study on the Respiration Inhibition of Activated Sludge according to OECD Guideline for Testing of Chemicals No. 209. ECT study no. 14AZ6XA.

7. Hydrotox GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2014). AF802, Biodegradability in the Manometric Respirometry Test according to OECD 301 F (July 1992). Hydrotox study no. 888.

8. Battelle UK Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2015). [14C]-RO5424802: Aerobic Aquatic Transformation in Aquatic Sediment Systems. Battelle UK study no. JC/13/014.

9. Battelle UK Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2014). RO5424802: Determination of Octanol/Water Partition Coefficient. Battelle UK study no. JC/13/006.

10. Battelle UK Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2015). [14C]-RO5424802: Adsorption to and Desorption from Three Soils and Two Sludges. Battelle UK study no. JC/13/013.

11. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2016). [14C]-CH5424802-002: A study on the bioconcentration in zebrafish according to OECD Guideline for Testing of Chemical No. 305. ECT study no. 14AZ3FX.

12. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). Assessment report for Alecensa. EMA/10821/2017, 15 December 2016.