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Zelboraf

Roche

Filmdragerad tablett 240 mg
(Ljusrosa till ljusorange, ovala, bikonvexa filmdragerade tabletter, cirka 19 mm, med ‘VEM’ ingraverat på ena sidan.)

Antineoplastiskt medel, proteinkinashämmare

Aktiv substans:
ATC-kod: L01XE15
Läkemedel från Roche omfattas av Läkemedelsförsäkringen.
Läkemedlet distribueras också av företag som inte omfattas av Läkemedelsförsäkringen, se Förpackningar.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Vemurafenib

Miljörisk: Användning av vemurafenib har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Vemurafenib är potentiellt persistent.
Bioackumulering: Vemurafenib har låg potential att bioackumuleras.


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Detaljerad miljöinformation

Identification and characterisation

Chemical name Vemurafenib

CAS number 918504-65-1 [1]

Molecular weight 489.93 [1]

Remark -

Brand name Zelboraf [1]


Physico-chemical properties

Aqueous solubility: 0.00271 mg/l (20 °C, pH 8) (OECD 105) [1]

Dissociation constant, pKa: 7.9 (pK1) (25 °C, titrimetric determination) [1], 11.1 (pK2) (25 °C, titrimetric determination) [1]

Melting point: 272 °C (OECD 102) [1]

Vapour pressure: 1.1*E–12 Pa (25 °C) QSAR

Boiling point: 643 °C QSAR

KH: 1.65*E–13 atm*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) = 1.5 x 10-6 x A x (100 - R) = 0.00027 μg/L


Where:

A Sold quantity = 1.82784 kg/y (total sold amount API in Sweden year 2017, data from sales data from IQVIA)

R Removal rate = 0 % Default [2]

P Population of Sweden = 9000000

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) = 2832 μg/l (OECD 201)

72 h EyC50 (growth rate) = 997 μg/l (OECD 201)

72 h NOEC = 156 μg/l (OECD 201)


Water-flea (Daphnia magna): [4]

21 d NOEC (intrinsic rate of population increase) = 17.1 μg/l (OECD 211)


Zebra fish (Danio rerio ): [5]

35 d NOEC (overall NOEC) = 1630 μg/l (OECD 210)


Micro-organisms (activated sludge):

3 h NOEC = 301 mg/l (OECD 209) [6]

28 d NOEC (toxicity control) = 30 mg/l (OECD 302 C) [7]


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 17.1 μg/l for daphnids has been used for this calculation.

PNEC = 17.1 / 10 = 1.71 μg/l


Environmental Risk Classification (PEC/PNEC Ratio)


PEC Predicted Environmental Concentration = 0.00027 μg/L

PNEC Predicted No Effect Concentration = 1.71 μg/L

Ratio PEC/PNEC = 0.00016


PEC/PNEC =0.00027/1.71 = 0.00016 for Vemurafenib which justifies the phrase 'Use of Vemurafenib has been considered to result in insignificant environmental risk.'


Degradation


Biotic Degradation

Ready biodegradability: ND


Inherent biodegradability: [7]

1.7% after 28 days of incubation BOD/ThOD (OECD 302 C)


Other degradation information: [8]

DT50 (water) = <2 d (OECD 308)

DT50 (total system) >1000 d (Lake System 1) (OECD 308)

DT50 (total system) = 417 d (Lake System 2) (OECD 308)


Abiotic Degradation

Photodegradation: ND

Hydrolysis: ND


Vemurafenib is not inherently biodegradable; it is also not degradable in water/sediment systems. This justifies the phrase 'Vemurafenib is potentially persistent.'


Bioaccumulation/Adsorption

logPOW = 4.74 (pH 5, non-dissociated state) (OECD 117) [9]

logDOW = 3.80 (pH 7) (OECD 117) [9]

logDOW = 3.26 (pH 9) (OECD 117) [9]

KOC (soils) = 37000–55454 l/kg (OECD 106) [10]

KOC (sludges) = 3739–53630 l/kg (OECD 106) [10]

BCF <150 l/kg (OECD 305) [11]


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


Excretion/metabolism

Vemurafenib is mainly excreted as the parent, with only two minor metabolites adding up to maximally 11% of the administered total. No data are available regarding the activity of the minor metabolites. [12]


References

1. F. Hoffmann-La Roche Ltd. 2018. Safety Data Sheet for Vemurafenib, 28.12.2018; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheetsrow. htm.

2. 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.

3. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). SAC-RO5185426-006 Milled: 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. 11AZ1AO.

4. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). SAC-RO5185426-006 Milled: A Study on the Chronic Toxicity to Daphnia magna according to the OECD Guideline 211 "Daphnia magna, Reproduction Test" adopted 3rd October, 2008. ECT study no. 10AZ3DB.

5. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). SAC-RO5185426-006 Milled: 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. 10AZ3FV.

6. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2010). SAC–RO5185426–006 Milled: A study on the respiration of activated sludge. ECT study no. 10AZ2XA.

7. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2010). Active substance RO5185426–000: Inherent biodegradability – evaluation of the aerobic biodegradability in an aqueous medium: Modified MITI Test (II). BMG study no. A09–01674.

8. Battelle UK Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). [14C]- RO5185426: Degradation and retention in two water/ sediment systems. Battelle UK study no. JC/10/018.

9. Battelle UK Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). RO5185426: Determination of Octanol/Water Partition Coefficient. Battelle UK study no. JC/10/014.

10. Battelle UK Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). [14C]-RO5185426: Adsorption to and desorption from three soils and two sludges. Battelle UK study no. JC/10/17.

11. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2011). [14C]-RO5185426–011–003: A study on the bioconcentration in zebrafish according to OECD Guideline 305. ECT study no. 10AZ2FX.

12. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). Assessment report for Zelboraf. EMA/200986/2012, 15 December 2011.