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Cotellic

Roche

Filmdragerad tablett 20 mg
(Vita, runda, filmdragerade tabletter, cirka 6,6 mm i diameter med ”COB” ingraverat på ena sidan.)

L01XE38

Aktiv substans:
ATC-kod: L01XE38
Utbytbarhet: Ej utbytbar
Läkemedel från Roche omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Kobimetinib

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


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Detaljerad miljöinformation

Identification and characterisation

Chemical name: Cobimetinib hemifumarate

CAS number: 1369665-02-0 [1]

Molecular weight: 589.36 [1]


Chemical name: Cobimetinib (free base)

CAS number: 934660-93-2 [2]

Molecular weight: 531.32 [2]


Brand name: Cotellic [1, 2]


Physico-chemical properties

Aqueous solubility 0.879 mg/l (20 °C) (OECD 105) Cobimetinib hemifumarate [1]

Aqueous solubility 100 mg/l (20 °C, pH 7.4) (OECD 105) Cobimetinib (free base) [2, 13] Dissociation constant, pKa 1.98 (base) [1]

Melting point 240 °C (OECD 102) [1]

Vapour pressure 1.77*E–12 PA QSAR

Boiling point ND

KH 5.29*E–14 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) = 0.0000009 μg/L


Where: Cobimetinib hemifumarate 0.006993 kg/y (total sold amount API in Sweden year 2017, data from IQVIA)


A Sold quantity = 0.00630 kg/y as: Cobimetinib (free base)

R Removal rate = 0 % Default [3]

P Population of Sweden = 9000000

V Volume of Wastewater = 200 l/day Default [3]

D Factor for Dilution = 10 Default [3]


Predicted No Effect Concentration (PNEC)


Ecotoxicological Studies

Green alga (Desmodesmus subspicatus): [4]

72 h ErC50 (growth rate) = 11.8 mg/l GMC (OECD 201)

72 h EyC50 (yield) = 2.25 mg/l GMC (OECD 201)

72 h ErC10 (growth rate) = 0.989 mg/l GMC (OECD 201)

72 h EyC10 (yield) = 0.265 mg/l GMC (OECD 201)

72 h NOErC (growth rate) < 0.615 mg/l GMC (OECD 201)

72 h NOEyC (yield) < 0.615 mg/l GMC (OECD 201)

Growth rate inhibition at the lowest 2 concentrations tested were 9.6 and 6.7% at 0.615 and 2.29 mg/l geometric mean concentration (GMC), respectively.


Water-flea (Daphnia magna): [5]

21 d NOEC (reproduction) = 0.0898 mg/l (OECD 211)


Zebra fish (Danio rerio): [6]

35 d NOEC (overall NOEC) = 0.109 mg/l (OECD 210)


Micro-organisms (activated sludge): [7]

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

3 h EC20 = 102.7 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 89.8 μg/l for Daphnia has been used for this calculation. For Alga only an ErC10 of 989 μg/l is available. The NOErC is estimated to be 615 μg/l. Alga test data suggest that Daphnia reproduction is the most sensitive endpoint. Moreover, the EC10 is preferred over the NOEC for PNEC derivation. Therefore, an assessment factor of 10 applies.

PNEC = 89.8 / 10 = 9.0 μg/l


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.0000009 μg/L

PNEC Predicted No Effect Concentration = 9.0 μg/L

Ratio PEC/PNEC = 0.0000001


PEC/PNEC = 0.0000009/9.0 = 0.0000001 for Cobimetinib which justifies the phrase 'Use of Cobimetinib has been considered to result in insignificant environmental risk.'


Degradation


Biotic Degradation

Ready biodegradability: [8]

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

29% after 28 days of incubation DOC/TOC (OECD 301 F)


Inherent biodegradability: ND


Other degradation information: [9]

DT50 (water) = 3.4–4.8 d (OECD 308)

DT50 (total system) = 211 – >1000 d (OECD 308)


Abiotic Degradation

Photodegradation: ND

Hydrolysis: ND


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


Bioaccumulation/Adsorption


logDOW = 1.19 (pH 5) (OECD 117) [10]

logDOW = 1.19 (pH 7) (OECD 117) [10]

logDOW = 2.33 (pH 9) (OECD 117) [10]

KOC (soils) = 2877–3799 l/kg (OECD 106) [11]

KOC (sludges) = 2356–5224 l/kg (OECD 106) [11]

BCF = 200 l/kg QSAR


Cobimetinib has low potential for bioaccumulation since the log DOW (at pH 7) is <4.


Excretion/metabolism


The metabolism of cobimetinib is extensive with less than 10% of the dose excreted as unchanged cobimetinib in urine, feces, or bile. Biliary excretion of cobimetinib-related metabolites into feces was the major pathway for cobimetinib elimination. [12]


References


1. F. Hoffmann-La Roche Ltd. 2018. Safety Data Sheet for Cobimetinib, 26.01.2018; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheetsrow. htm.

2. F. Hoffmann-La Roche Ltd. 2018. Safety Data Sheet for Cobimetinib (free base), 14.06.2018; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheetsrow. htm.

3. 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.

4. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2013). PAM-RO5514041 Free Base: Fresh water algal growth inhibition test with Desmodesmus subspicatus (OECD 201). BMG study no. A13-00313.

5. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2014). RO5514041 Free Base: A study on the chronic toxicity to Daphnia magna according to the OECD Guideline 21, "Daphnia magna, Reproduction Test", adopted 2nd October, 2012. ECT study no. 14AZ6DB.

6. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2014). RO5514041 Free Base: A Study on the Toxicity to Early-Life Stages of Zebrafish according to OECD Guideline No. 210 "Fish, Early-life Stage Toxicity Test", adopted on July 17, 1992. ECT study no. 13AZ7FV.

7. ECT Oekotoxikologie GmbH, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2014). RO5514041 Free Base: A study on the respiration of activated sludge. ECT study no. 13AZ5XA.

8. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2013). PAM-RO5514041 Free Base: Ready Biodegradability - Evaluation of the Aerobic Biodegradability in an Aqueous Medium, Manometric Respirometry Test, OECD301 F. BMG study no. A13-00316.

9. Battelle UK Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2013). [14C]-RO5514041: Degradation and retention in two water/ sediment systems. Battelle UK study no. JC/13/004.

10. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2013). PAM-RO5514041 Free Base: Determination of the partition coefficient between octanol and water (logPow) by high performance liquid chromatography (HPLC), OECD 117. BMG study no. A13-00312.

11. Battelle UK Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2013). [14C]-RO5514041: Adsorption to and Desorption from Three Soils and Two Sludges. Battelle UK study no. JC/13/005.

12. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). Assessment report for Cotellic. EMA/685908/2015, 24 September 2015.

13. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2013). PAM-RO5514041 Free Base: Determination of the water solubility by the flask method, OECD 105. BMG study no. A13-00311.