Detaljerad miljöinformation

Detailed background information

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 = 0.0311979277 µg/L

Where:

A = total actual API sales in Sweden for the most recent year 227.7221 kg (total sold amount API in the most recent sales data for Sweden (2022) was distributed by IQVIA in 2023)

R = 0

P = number of inhabitants in Sweden = 10 *10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (guideline e.g. OECD 201) [Reference IV]:

E_bC₅₀ 72 h (biomass) > 43 mg/L

NOEC_b (biomass) = 43 mg/L

E_rC₅₀ 72 h (growth) > 43 mg/L

NOEC_r (growth) = 43 mg/L

Crustacean (Daphnia magna) (water-flea) (guideline e.g. OECD 202) [Reference II]:

Acute toxicity

EC₅₀ 48 h > 44 mg/L (immobilization)

NOEC = 2.6 mg/L (immobilization)

Following 48 hours of exposure, immobilization of 10% was observed among daphnids exposed to the highest treatment level tested (44 mg a.i./L). Several surviving daphnids exposed to this treatment level were observed to be either on the bottom of the test vessel or lethargic and on the bottom of the test vessel. Immobilization of 5% was observed among daphnids exposed to the 10 mg a.i./L treatment level. Several daphnids exposed to this treatment level were observed to be lethargic and on the bottom of the test vessel. No immobilization was observed among daphnids exposed to the 5.4 and 21 mg a.i./L treatment levels, but several daphnids were also observed to be lethargic and on the bottom of the test vessel. No immobilization or adverse effects were observed among daphnids exposed to the remaining treatment level tested (2.6 mg a.i./L) or the controls

Since no concentration tested resulted in ≥ 50% immobilization, the 48-hour EC50 value for Darunavir and Daphnia magna was empirically estimated to be > 44 mg a.i./L, the highest mean measured concentration tested.

The No-Observed-Effect Concentration (NOEC) was determined to be 2.6 mg a.i./L.

The highest concentration producing 0% immobilization was 21 mg a.i./L. The lowest concentration producing 100% immobilization was > 44 mg a.i./L. Additional testing at higher concentrations to further define the EC50 was not performed since the concentration of the test substance in the highest nominal test concentration approximated the water solubility limit of Darunavir under the maintained test conditions.

Chronic toxicity

Reproduction test with water-flea (Daphnia magna) (guideline e.g. OECD 211) [Reference V]:

NOEC 21 days = 19 mg/L

Fish:

Acute toxicity

Acute toxicity to rainbow trout (Oncorhynchuss mykiss) (guideline e.g. OECD 203) [Reference III]:

LC₅₀ 96 h > 38 mg/L

NOEC = 38 mg/L

Chronic toxicity

NOEC 28 days (Length and Dry Weight) Fish early life stage test with fathead minnow (Pimephales promelas) (guideline e.g. OECD 210) [Reference VI]:

NOEC 28 days = 9.4 mg/L

Other ecotoxicity data:

Activated sludge respiration inhibition test (guideline e.g. OECD 209) [Reference I]:

EC50 3 h > 1000 mg/L

NOEC 3h ≥ 1000 mg/L

PNEC (µg/L) = lowest NOEC from long-term ecotoxicity/10, where 10 is the assessment factor used. NOEC for fathead minnow (Pimephales promelas) (9.4 mg/L) has been used for this calculation since it is the most sensitive of the three tested species.

PNEC = 9.4 mg/L/10 = 940 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0311979277 / 940 = 0.0000331892 i.e. PEC/PNEC ≤ 0.1

The calculated PEC/PNEC ratio is ≤ 0.1.

Use of Darunavir has been considered to result in insignificant environmental risk.

Degradation

Biotic degradation

Ready degradability:

Darunavir was investigated for its ready biodegradation in a 28-day manometric respirometry test according to OECD 301B [Reference VII]:

Result: Not readily biodegradable.

Inherent degradability: -

Simulation studies:

Aerobic degradation in aquatic sediment systems

Darunavir was investigated for its aerobic degradation in a 106-day aquatic sediment test, according to OECD 308 [Reference IX]:

Overall, [¹⁴C]TMC114 ethanolate underwent gradual depletion from the Taunton (TR) and Weweantic (WR) sediment/water systems with a significant amount of the radioactivity accumulating as non-extractable bound residues in the sediments. Depletion rates (DT₅₀) from the TR and WR sediment/water systems were 38.9 and 37.1 days, respectively. Bound residues accounted for 67% and 43% of the applied dose at day 106 in the TR and WR, respectively. Very little formation of [¹⁴C]CO₂ (<3% of the applied dose) occurred over the 106-day study. Multiple small radioactive peaks, both more polar and less polar, were observed primarily in the TR sediments. However non accumulated to  more than 10% of the applied dose.

For extraction samples containing the test substance were extracted twice with methanol, concentrated by rotary evaporation and reconstituted in acetonitrile and acidified water. Samples were analyzed by liquid scintillation counter (LSC) and automated injection on a high performance liquid chromatographic system equipped with radiochemical detection (HPLC/RAM).

Anaerobic degradation in aquatic sediment systems

Darunavir was investigated for its anaerobic degradation in a 101-day aquatic sediment test, according to OECD 308 [Reference X]:

Overall, [¹⁴C]TMC114 ethanolate underwent gradual depletion from the Taunton (TR) and Weweantic (WR) sediment/water systems with a significant amount of the radioactivity accumulating as non-extractable bound residues in the sediments. Depletion rates (DT₅₀) from the TR and WR sediment/water systems were 104.9 and 74.0 days, respectively. Bound  residues accounted for 41.3% and 55.3% of the applied dose at day 101 in the TR and WR, respectively. Very little formation of [¹⁴C]CO₂ or [¹⁴C]CH₄ (<1% of the applied dose) occurred over the 101-day study. Multiple small radioactive peaks, both more polar and less polar, were observed primarily in the TR sediments. However, none accumulated to more than 5% of the applied dose.

Conclusion for degradation: Darunavir is slowly degraded in the environment.

Abiotic degradation

Hydrolysis: -

Photolysis: -

Bioaccumulation

Partition coefficient octanol/water:

The partition coefficient octanol/water was determined using the shaking flask method. [Reference VIII]

log D_ow = 2.4 (pH = 4, 7 and 9)

Bioconcentration factor (BCF):

No data available

Conclusion for bioaccumulation: Darunivir has low potential for bioaccumulation.

Excretion (metabolism)

-

PBT/vPvB assessment

	PBT-criteria	Results for Darunavir
Persistence	Half-life in freshwater: DT50 > 40 days Half-life in sediment: DT50 > 120 days	DT50, sediment/water system = 104.9 days
Bioaccumulation	BCF > 2000	-
Toxicity	Chronic NOEC < 10 µg/L	NOECalgae = 43 mg/L NOECdaphnia = 19 mg/L NOECfish = 9.4 mg/L

Conclusion for PBT-assessment:

According to the established EU-criteria Darunavir should not be regarded as a PBT substance.

References

1. McLaughlin SP., TMC114 Ethanolate – Activated sludge respiration inhibition, Springborn Smithers Laboratories, Study TMC114-NC318 (SSL 13844.6103), July 2005.

2. Hogerg JR., TMC114 Ethanolate – Acute toxicity to water fleas (Daphnia magna) under static conditions, Springborn Smithers Laboratories, Study TMC114-NC323 (SSL 13844.6108), September 2005.

3. Hogerg JR., TMC114 Ethanolate – Acute toxicity to rainbow trout (Oncorhynchus mykiss) under static conditions, Springborn Smithers Laboratories, Study TMC114-NC324 (SSL 13844.6109), August 2005.

4. Hoberg JR., TMC114 Ethanolate – Acute toxicity to freshwater green alga (Pseudokirchneriella subcapitata), Springborn Smithers Laboratories, Study TMC114-NC322 (SSL 13844.6107), September 2005.

5. Sayers LE., TMC114 Ethanolate – Full life-cycle toxicity test with water fleas (Daphnia magna) under static renewal conditions, Springborn Smithers Laboratories, Study TMC114-NC313 (SSL 13844.6114), June 2006.

6. Cafarella MA., TMC114 Ethanolate – Early life-stage toxicity test with fathead minnow (Pimephales promelas), Springborn Smithers Laboratories, Study TMC114-NC314) (SSL 13844.6115), June 2006.

7. Gledhill WE., TMC114 Ethanolate – Determination of the ready biodegradability by CO2 evolution modified Sturm test, Springborn Smithers Laboratories, Study TMC114-NC320 (SSL 13844.6105), August 2005.

8. Jacobs A., TMC114 – Solubility, pKa, log D, log P, Janssen Pharmaceutica N.V., Report No. PC-CHAR 05-007, July 4, 2005.

9. Gledhill, W.E., Determination of the Aerobic Transformation of [14C]TMC114 Ethanolate in Aquatic Sediment Systems, Springborn Smithers Laboratories, Study TMC114-TiDP3-NC332 (SSL 13844.6112), February 28, 2007.

10. Gledhill, W.E., Determination of the Anaerobic Transformation of [14C]TMC114 Ethanolate in Aquatic Sediment Systems, Springborn Smithers Laboratories, Study TMC114-TiDP3-NC335 (SSL 13844.6116), March 16, 2007.

11. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm