Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R)/(365*P*V*D*100) = 1.5*10^-6*A(100-R)

PEC = 0.0000375 μg/L

Where:

A = 0.25 kg (total sold amount API in Sweden year 2019, data from IQVIA). Total volume of Fosamprenavir calcium = 0.27 = 0.25 Kg of Fosamprenavir free base. Reduction of A may be justified based on metabolism data.

R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 9 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Reference 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Reference 1)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Selenastrum caprocornutum):

IC50 72h (growth) > 100,000 μg/L (OECD 201) (Reference 4)

NOEC = 100,000 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 109,000 μg/L (OECD 202) (Reference 7)

NOEC = 109,000 μg/L

Water flea (Ceriodaphnia dubia):

Chronic toxicity

LOEC 7 days (reproduction) > 100,000 μg/L (EPA 1002) (Reference 6)

NOEC = 100,000 μg/L

Rainbow Trout (Juvenilee Ocorhynchus mykiss):

Acute toxicity

LC50 96 h (lethality) > 100,000 μg/L (OECD 203) (Reference 3)

NOEC = 100,000 μg/L

Other ecotoxicity data:

Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 1,000,000 μg/L (OECD 209) (Reference 7)

PNEC = 100,000/50 = 2000 μg/L

PNEC (μg/L) = lowest NOEC/50, where 50 is the assessment factor applied for two long-term NOECs. NOEC for water flea (= 100,000 ug/L) has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0000375/2000 = 1.875 x 10^-8, i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of fosamprenavir has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

1.0% degradation in 28 days (TAD 3.11) (Reference 7)

Inherent degradability:

17% degradation in 28 days (OECD 302B) (Reference 5)

100% primary (loss of parent) degradation in 28 days

Abiotic degradation

Hydrolysis:

Half-life, pH 7 > 1 year (TAD 3.09) (Reference 5)

Photolysis:

No Data

Justification of chosen degradation phrase:

Fosamprenavir is not readily biodegradable nor inherently biodegradable. The phrase “Fosamprenavir is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log P < 1.00 (method unknown) (Reference 7)

Justification of chosen bioaccumulation phrase:

Since log Pow < 4, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium, following oral administration. Amprenavir is primarily metabolised by the liver with less than 1 % excreted unchanged in the urine. The primary route of metabolism is via the cytochrome P450 3A4 enzyme. Amprenavir metabolism is inhibited by ritonavir, via inhibition of CYP3A4, resulting in increased plasma concentrations of amprenavir. Amprenavir in addition is also an inhibitor of the CYP3A4 enzyme, although to a lesser extent than ritonavir.

Following administration of Telzir, the half-life of amprenavir is 7.7 hours. When Telzir is co-administered with ritonavir, the half-life of amprenavir is increased to 15 – 23 hours. The primary route of elimination of amprenavir is via hepatic metabolism with less than 1 % excreted unchanged in the urine and no detectable amprenavir in faeces. Metabolites account for approximately 14 % of the administered amprenavir dose in the urine, and approximately 75 % in the faeces (Reference 2).

PBT/vPvB assessment

Fosamprenavir does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Fosamprenavir does not fulfil the criteria for PBT and/or vBvP based on a log Dow < 4.

Please, also see Safety data sheets on http://www.msds-gsk.com/ExtMSDSlist.asp.

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

2. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Telzir (Fosamprenavir calcium) 700mg Film Coated Tablets. GlaxoSmithKline, March 2013.

3. Wetton PM and McKenzie J. Fosamprenavir calcium: Acute Toxicity to Rainbow Trout. Report No. 1127/296. Safepharm Laboratories Limited, May 2004.

4. Vryenhoef H and McKenzie J. Fosamprenavir calcium: Algal Inhibition Test. Report No. 1127/297. Safepharm Laboratories Limited, July 2004.

5. Clarke N and McKenzie J. Fosamprenavir calcium: Assessment of Inherent Biodegradability; Modified Zahn-Wellens/EMPA Test. Report No. 1127/298. Safepharm Laboratories Limited, July 2004.

6. Wetton PM. Fosamprenavir calcium: Daphnid, Ceriodaphnia dubia Survival and Reproduction Test. Report No. 1127/1209. Safepharm Laboratories Limited, Mar 2006.

7. MSDS ID 129351. Telzir (Fosamprenavir calcium) Oral Suspension. ViiV Healthcare UK Ltd., April 2011.