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) = 1.37*10^-6*A(100-R)

PEC = 1.16 x10^-5 μg/L 

Where:

A = 0.085 kg (total sold amount API in Sweden year 2022, data from IQVIA). 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 = 10 *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)

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of zanamivir is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 μg/L.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae:

No data

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 1,000,000 μg/L (OECD 202) (Reference 6)

NOEC > 1,000,000 μg/L

Water flea (Daphnia magna):

Chronic toxicity

EC50 21 days (reproduction) > 100,000 μg/L (OECD 211) (Reference 8)

NOEC = 100,000 μg/L

Fish:

Acute toxicity

No data

Other ecotoxicity data:

EC50 3 hours (Inhibition) =1,000,000 μg/L (OECD 209) (Reference 5)

PNEC cannot be calculated because data is not available for all three (algae, crustacean and fish) of the short-term toxicity endpoints.

Environmental risk classification (PEC/PNEC ratio)

Risk of environmental impact of zanamivir cannot be excluded, since there is not sufficient ecotoxicity data available.

Degradation

Biotic degradation

Ready degradability:

0.1% degradation in 28 days (OECD 301B) (Reference 7)

Inherent degradability:

No Data

50% primary (loss of parent) degradation in 3 days

Abiotic degradation

Hydrolysis:

Half-life, pH 7 > 1 year (OECD 111) (Reference 4)

Photolysis:

No data

Justification of chosen degradation phrase:

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

Bioaccumulation

Partitioning coefficient:

Log Dow < 1 at pH 7 (OECD 107) (Reference 3)

Log Dow at pH 5 < 1

Log Dow at pH 7 < 1

Log Dow at pH 9 < 1

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

Zanamivir has been shown to be renally excreted as unchanged drug, and does not undergo metabolism. In vitro studies demonstrated that zanamivir did not affect the activity of a range of probe substrates for cytochrome P450 isoenzymes (CYP1A/2, A6, 2C9, 2C18, 2D6, 2E1, 3A4) in human hepatic microsomes, nor did it induce cytochrome P450 expression in rats, suggesting that metabolic interactions between zanamivir and other drugs are unlikely in vivo.

The serum half-life of zanamivir following administration by oral inhalation ranges from 2.6 to 5.05 hours. It is entirely excreted unchanged in the urine. Total clearance ranges from 2.5 to 10.9 L/h as approximated by urinary clearance. Renal elimination is completed within 24 hours (Reference 2).

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 Relenza (Zanamivir) 5 mg dose Inhalation Powder. GlaxoSmithKline, May 2011.

3. Croudace CP, Stanley RD and Cornish SK. GG167: Determination of Octanol-Water Partition Coefficient. Report No. BL5269/B. Brixham Environmental Laboratory, January 1996.

4. Croudace CP, Stanley RD and Cornish SK. GG167: Hydrolysis as a Function of pH. Report No. BL5270/B. Brixham Environmental Laboratory, January 1996.

5. Croudace CP and Latham M. GG167: Determination of Activated Sludge respiration Inhibition. Report No. BL5272/B. Brixham Environmental Laboratory, January 1996.

6. Croudace CP, Banner AJ and Magor SE. GG167: Acute Toxicity to Daphnia magna. Report No. BL5271/B. Brixham Environmental Laboratory, January 1996.

7. Long KWJ and Demsey M. GG167: Aerobic Biodegradation in Water. Report No. BL5375/B. Brixham Environmental Laboratory, January 1996.

8. Goodband TJ. Zanamivir: Daphnid, Ceriodaphnia dubia Survival and Reproduction Test. Report No. 1127/1209. Safepharm Laboratories Limited, July 2006.