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Tamiflu®

Roche

Kapsel, hård 30 mg
(Ljust gul ogenomskinlig underdel präglad med ROCHE och en ljust gul ogenomskinlig överdel präglad med 30 mg, blå tryckfärg.)

Virushämmande medel för systemiskt bruk, neuraminidashämmare

Aktiv substans:
ATC-kod: J05AH02
Läkemedel från Roche omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Oseltamivir

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


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Detaljerad miljöinformation

Note . Tamiflu is oseltamivir ethylester phosphate (OEP; CAS no. 204255-11-8), formulated as a salt for oral administration. Oseltamivir ethylester (OE; CAS no. 196618-13-0) is a prodrug of the actual active substance, oseltamivir acid (OA; CAS no. 187227-45-8). [3]


Identification and characterisation

Brand name: Tamiflu [1]

API: Oseltamivir ethylester phosphate (OEP) [1]

CAS number: 204255-11-8 [1]

Molecular weight: 410.401 [1]


API: Oseltamivir ethylester (OE)

CAS number: 196618-13-0

Molecular weight: 312.407


API: Oseltamivir acid (OA)

CAS number: 187227-45-8

Molecular weight: 284.354


Physico-chemical properties

Aqueous solubility >200 mg/L (pH 5.14, 22 °C) OEP [2]

Dissociation constant pKa = 3.6 QSAR OA [3], pKb = 8.9 QSAR OA [3]

Melting point 192–196 °C OEP [2]

Boiling point 445.2 °C QSAR OE

Vapour pressure 1.74E-06 Pa (25 °C) QSAR OE

KH 2.96E-11 Pa*m3/mol QSAR OE

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) = 0.0013 μg/L


Where:

Sold quantity (OEP) = 11.1567 kg/y sales data for OEP (total sold amount API in Sweden year 2017, data from IQVIA)

A = Sold quantity (calculated) = 8.4928 kg/y calculated sales data for OE

R = Removal rate = 0 % Default value [4]

P = Population of Sweden = 9000000

V = Volume of Wastewater = 200 L/day Default value [4]

D = Factor for Dilution = 10 Default value [4]


Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Raphidocelis subcapitata): [5]

ErC50 96 h (growth rate) = 463 mg/l nominal (OECD 201) OEP

NOErC 96 h (growth rate) = 46 mg/L nominal (OECD 201) OEP

EbC50 96 h (biomass) = 59 mg/l nominal (OECD 201) OEP

NOEbC 96 h (biomass) = 10 mg/L nominal (OECD 201) OEP


Green alga (Raphidocelis subcapitata): [6]

ErC50 72 h (growth rate) >100 mg/l nominal (OECD 201) OE+OA 1:4

EyC50 72 h (yield) = 60.3 mg/l nominal (OECD 201) OE+OA 1:4

NOEC 72 h = 10 mg/L nominal (OECD 201) OE+OA 1:4


Water-flea (Daphnia magna): [7]

NOEC (overall) 21 d (endpoint) = 1 mg/L nominal (OECD 211) OE+OA 1:4


Zebra fish (Danio rerio ), Early Life-Stage Toxicity Test: [8]

NOEC (overall) 32 d (endpoint) = 1 mg/L nominal (OECD 210) OE+OA 1:4


Micro-organisms: [3]

NOEC 4 h (inhibition of nitrification) = 256 mg/L nominal (ISO 9509) OA


PNEC Derivation


The PNEC is based on the following data:

PNEC (mg/L) = lowest NOEC/10, where 10 is the assessment factor used. A NOEC of 1000 μg/L for Daphnia and fish has been used for this calculation. [3]

PNEC = 1000 / 10 = 100 μg/L


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.0013 μg/L

PNEC Predicted No Effect Concentration = 100 μg/L

Ratio PEC/PNEC = 0.000013


PEC/PNEC = 0.0013/100 = 0.000013 for Oseltamivir ethylester phosphate (OEP) which justifies the phrase 'Use of Oseltamivir ethylester phosphate (OEP) has been considered to result in insignificant environmental risk.'


Degradation

Biotic Degradation

Ready biodegradability: [9]

3% after 28 days of incubation CO2/ThCO2 (OECD 301 B) OEP

not readily biodegradable


Inherent biodegradability:

4% after 28 days of incubation BOD/ThOD (OECD 302 C) OEP [10]

≤5% after 50 days of incubation (porous pot) Parent (OECD 303 A) OE+OA 4:1 [11]

≤5% after 50 days of incubation (porous pot) Parent (OECD 303 A) OE+OA 1:4 [11]

not inherently biodegradable


Other degradation information:

not biodegradable (OECD 308) OE+OA 1:4 [12]

0% after 62 days (OECD 311) OEP [13]

anaerobically not biodegradable


Abiotic Degradation

Hydrolysis: [10]

2% after 5 days (incubation in the dark) (no guideline)


Photodegradation: [10]

13% after 5 days (incubation as in Algae testing) (no guideline)


Oseltamivir ethylester phosphate (OEP) is not readily degradable. This justifies the phrase 'Oseltamivir ethylester phosphate (OEP) is potentially persistent.'


Bioaccumulation/Adsorption

log KOW = 0.36 (pH 7.4, 25 °C) OEP [2]

log KOW = 0.95 (KOWWIN v1.68 estimate) QSAR OE


Oseltamivir ethylester phosphate (OEP) has low potential for bioaccumulation (log KOW <4).


Excretion/metabolism

Oseltamivir is formulated as oseltamivir ester phosphate, which is metabolised at approximately 80% to the active oseltamivir carboxylic acid metabolite. [7]


References

1. F. Hoffmann-La Roche Ltd (2016): Safety Data Sheet for Tamiflu, 29.12.2016;

https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheets-row.htm

2. F. Hoffmann-La Roche Ltd (2016): Safety Data Sheet for Oseltamivir ethylester phosphate, 09.05.2016; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheets-row.htm

3. Straub JO (2009): An environmental risk assessment for oseltamivir (Tamiflu®) for sewage works and surface waters under seasonal influenza and pandemic use conditions. Ecotoxicol Environ Saf 72(6): 1625–1634.

4. 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

5. Study Report: NOTOX Project 228713. Fresh water algal growth inhibition test with RO 64-0796/002, July 1998.

6. Study Report: Springborn Smithers study no. 1114.000.430: Oseltamivir (Ester + Carboxylate) Mixture 20:80 (w/w): Alga, growth inhibition test with Pseudokirchneriella subcapitata (syn. Selenastrum capricornutum) under static conditions, February 2008.

7. Study Report: Springborn Smithers study no. 1114.000.230: Oseltamivir (Ester + Carboxylate) Mixture 20:80 (w/w): Chronic reproduction test with daphnids (Daphnia magna) under semi static conditions, January 2008.

8. Study Report: Springborn Smithers study no. 1114.000.122: Oseltamivir (Ester + Carboxylate) Mixture 20:80 (w/w): Early Life-Stage Toxicity Test with Zebra Fish (Danio rerio syn. Brachydanio rerio ) under flow-through conditions, May 2008.

9. Study Report: NOTOX Project 228724. Determination of 'Ready' Biodegradability: Carbon dioxide (CO2) Evolution Test (Modified Sturm Test) with RO 64-0796/002, May 1998.

10. Study Report: BMG study no. 1405/b-05. OSELTAMIVIR PHOSPHATE SK: Inherent Biodegradability - Evaluation of the Aerobic Biodegradability in an Aqueous Medium: Modified MITI Test (II), June 2006.

11. Study Report: Springborn Smithers study no. 1698.6104: Determination of the Inherent Biodegradability of Oseltamivir by the Porous Pot Test, Basewd on OECD 303 A Guideline and the OPPTS Method 835.3220, January 2008.

12. Study Report: Springborn Smithers Study no. 1114.000.750. Oseltamivir (Ester + Carboxylate) Mixture 20:80 (w/w): Aerobic Transformation in Aqiatic Sediment Systems, April 2008.

13. Study Report: BMG study no. 1405/a-05. OSELTAMIVIR PHOSPHATE SK: Ultimate Biodegradability - Evaluation of the Anaerobic Biodegradability in an Aqueous Medium: ISO 11734: 1995, June 2006.