Detaljerad miljöinformation

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 = 1.27 10^-4 μg/L

Where:

A = 0,9265 kg (total sold amount API in Sweden year 2021, data from IQVIA.)

R = X % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. R=0

P = number of inhabitants in Sweden = 10*10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae:

No data

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 360,000 μg/L (OECD 202) (Reference 2)

Water flea:

Chronic toxicity

No data

Fish:

Acute toxicity

No data

Fish:

Chronic toxicity

No Data

Other ecotoxicity data:

Microorganisms in activated sludge:

EC50 3 h (inhibition) > 91,200 μg/L @ 3 hrs (OECD 209) (Reference 3)

A 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 remifentanil cannot be excluded, since there is not sufficient ecotoxicity data available.

Degradation

Biotic degradation

Ready degradability:

4% degradation in 28 days (TAD 3.11). (Reference 4)

Inherent degradability:

No data

Soil degradation

22.62% - 30.41% degradation in 64 days (TAD 3.12). (Reference 5)

Abiotic degradation

Hydrolysis:

Half-Life at pH 7, 9.5 Hours (FDA TAD 3.09) (Reference 6)

Half-Life at pH 5, 21.3 Days

Half-Life at pH 9, 3.5 Hours

Photolysis:

No data

Justification of chosen degradation phrase:

Remifentanil is not readily degradable or inherently degradable. This substance is hydrolytically unstable under environmental conditions but hydrolytic transformation products have not been identified. This substance will be moderately degraded in soil matrices. The phrase “Remifentanil is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = 1.36 at pH 7 (TAD 3.02). (Reference 7)

Log Dow at pH 5 = -0.9

Log Dow at pH 7 = 1.36

Log Dow at pH 9 = 1.61

Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Remifentanil is an esterase metabolised opioid that is susceptible to metabolism by non-specific blood and tissue esterases. The metabolism of remifentanil results in the formation of an essentially inactive carboxylic acid metabolite (1/4600th as potent as remifentanil). The half life of the metabolite in healthy adults is 2 hours. Approximately 95% of remifentanil is recovered in the urine as the carboxylic acid metabolite. Remifentanil is not a substrate for plasma cholinesterase (Reference 8).

PBT/vPvB assessment

Remifentanil 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). Remifentanil does not fulfil the criteria for PBT and/or vBvP based on log Pow < 4.

References

1. [ECHA] European Chemicals Agency. December 2022. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0)

2. Jenkins CA. Gl87084B: Acute Toxicity to Daphnia magna. Report No. 93/GLX109/0818. Pharmaco Life Science Research Laboratories, October 1994.

3. Jenkins WR. Gl87084B: Activated Sludge – Respiration Inhibition Test. Report No. 93/GLX120/0765. Pharmaco Life Science Research Laboratories, October 1994.

4. Jenkins WR. Gl87084B: Biotic Degradation with Acclimatised Composite Inoculum- Modified Sturm Test. Report No. 93/GLX114/0764. Pharmaco Life Science Research Laboratories, October 1994.

5. O’Connor J. Gl87084B: Aerobic Biodegradation in Soil. Report No. 93/GLX117/0721. Pharmaco Life Science Research Laboratories, October 1994.

6. Colwyn TC. Gl87084B: Determination of Hydrolysis as a Function of pH. Report No. 93/GLX108/0652. Pharmaco Life Science Research Laboratories, September 1994.

7. Colwyn TC. Gl87084B: Determination of Physico-Chemical Properties. Report No. 93/GLX107/0713. Pharmaco Life Science Research Laboratories, September 1994.

8. Pharmacokinetic properties: Meatbolism and Elimination. Summary of Product Characteristics Ultiva (Remifentanil hydrochoride) Injection. GlaxoSmithKline, January 2011.