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). [2]
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 [1]
Dissociation constant pKa = 3.6 QSAR OA [2], pKb = 8.9 QSAR OA [2]
Melting point 192–196 °C OEP [1]
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) = 1.37 x 10-6 x A x (100 - R) = 0.0004 μg/l
Where:
Sold quantity (OEP) = 3.8239 kg/y sales data from IQVIA / LIF - kg consumption 2021
A = Sold quantity (calculated) = 2.9108 kg/y calculated sales data for OE
R = Removal rate = 0 % Default value [3]
P = Population of Sweden = 10 000 000
V = Volume of Wastewater = 200 L/day Default value [3]
D = Factor for Dilution = 10 Default value [3]
Predicted No Effect Concentration (PNEC)
Ecotoxicological Studies
Green alga (Raphidocelis subcapitata): [4]
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): [5]
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): [6]
NOEC 21 d (overall; i.e. for the endpoints survival of parental daphnids, length of parental daphnids, weight of parental daphnids and number of offspring per female) = 1 mg/L nominal (OECD 211) OE+OA 1:4
Zebra fish (Danio rerio ), Early Life-Stage Toxicity Test: [7]
NOEC 32 d (overall; i.e. for the endpoints hatching success, post-hatch mortality, total length, dry weight) = 1 mg/L nominal (OECD 210) OE+OA 1:4
Micro-organisms: [2]
NOEC 4 h (inhibition of nitrification) = 256 mg/L nominal (ISO 9509) OA
PNEC Derivation
The PNEC is based on the following data:
PNEC (μg/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. [2]
PNEC = 1000 μg/l / 10 = 100 μg/l
Environmental Risk Classification (PEC/PNEC Ratio)
PEC Predicted Environmental Concentration = 0.0004 μg/l
PNEC Predicted No Effect Concentration = 100 μg/L
Ratio PEC/PNEC = 0.000004
PEC/PNEC = 0.0004/100 = 0.000004 for Oseltamivir ethylester (OE) which justifies the phrase 'Use of Oseltamivir has been considered to result in insignificant environmental risk.'
Degradation
Biotic Degradation
Ready biodegradability: [8]
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 [9]
≤5% after 50 days of incubation (porous pot) Parent (OECD 303 A) OE+OA 4:1 [10]
≤5% after 50 days of incubation (porous pot) Parent (OECD 303 A) OE+OA 1:4 [10]
not inherently biodegradable
Other degradation information:
not biodegradable (OECD 308) OE+OA 1:4 [11]
0% after 62 days (OECD 311) OEP [12]
anaerobically not biodegradable
Abiotic Degradation
Hydrolysis: [9]
2% after 5 days (incubation in the dark) (no guideline)
Photodegradation: [9]
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 [1]
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. [2]
References
1. F. Hoffmann-La Roche Ltd (2021): Environmental Risk Assessment Summary for Oseltamivir. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm
2. 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.
3. 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
4. Study Report: NOTOX Project 228713. Fresh water algal growth inhibition test with RO 64-0796/002, July 1998.
5. 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.
6. 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.
7. 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.
8. Study Report: NOTOX Project 228724. Determination of 'Ready' Biodegradability: Carbon dioxide (CO2) Evolution Test (Modified Sturm Test) with RO 64-0796/002, May 1998.
9. 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.
10. 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.
11. 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.
12. 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.