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

K_H 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) = 0.0005 μg/l

Where:

Sold quantity (OEP) = 4.8104 kg/y sales data from IQVIA / LIF - kg consumption 2020

A = Sold quantity (calculated) = 3.6618 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 = 0.0005 μg/l

PNEC Predicted No Effect Concentration = 100 μg/L

Ratio PEC/PNEC = 0.000005

PEC/PNEC = 0.0005/100 = 0.000005 for Oseltamivir ethylester phosphate (OEP) 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 K_OW = 0.36 (pH 7.4, 25 °C) OEP [1]

log K_OW = 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.