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

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 = 0.004099725 µg/L

Where:

A = total actual API sales in Sweden for the most recent year 29.925 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 IX)

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (guideline e.g. OECD 201):

Algal growth inhibition test with the green alga (Pseudokirchneriella subcapitata)

[Reference I]:

EγC₅₀ 72 h (yield) > 29.3 mg/L

NOECγ (yield) = 29.3 mg/L

E_rC₅₀ 72 h (growth) > 29.3 mg/L

NOEC_r (growth) = 29.3 mg/L

Crustacean (Daphnia magna) (water-flea) (guideline e.g. OECD 211):

Acute toxicity

Not available

Chronic toxicity

Reproduction test with water-flea (Daphnia magna) (OECD 211) [Reference II]:

NOEC 21 days = 17.48 mg/L (Reproduction)

Fish:

Acute toxicity

Not available

Chronic toxicity

Fish early life stage test with fathead minnow (Pimephales promelas) (OECD 210) [Reference III]:

NOEC 28 days = 4.84 mg/L (growth, weight)

Other ecotoxicity data:

Activated sludge respiration inhibition test (OECD 209) [Reference IV]

EC₅₀ 3h > 1000 mg/L

NOEC 3h ≥ 1000 mg/L

PNEC (µg/l) = lowest NOEC/10, where 10 is the assessment factor used. NOEC for fathead minnow Pimephales promelas of 4.84 mg/L has been used for this calculation since it is the most sensitive of the three tested species.

PNEC = 4.84 mg/L/10 = 484 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.004099725 /484 = 0.000008470506

Conclusion for environmental risk:

The calculated PEC/PNEC ratio is < 0.1.

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

Degradation

Biotic degradation

Ready biodegradation

Cobicistat was investigated for its ready biodegradation in a 28-day CO₂-evolution test according to OECD 301B [Reference V]:

Result: Not readily biodegradable.

Simulation studies:

Aerobic degradation in aquatic sediment systems:

Cobicistat was investigated for its aerobic degradation in a 100-day aquatic sediment test, according to OECD 308 [Reference VI].

Under aerobic water/sediment conditions, cobicistat degraded at a slow rate. Total system cobicistat residues decreased from an average of 97 and 98% of applied radioactivity on day 0 to 72 and 66% AR (excluding non-extractable residues) at day 100 for aerobic silt loam and sand sediments, respectively.

Disappearance time of 50% AR (DT50) and disappearance time of 90 % AR (DT90) of the test item were estimated using the combined [14C]-GS-9350 values (expressed as % applied Gilead Sciences Ref. No. TX-216-2048 Page 34 Test Facility Study No. 810165 radioactivity) obtained from the surface water and sediment extract phases at each sampling timepoint.

DT₅₀ values of 241 and 171 days and DT₉₀ values of 801 and 568 days were obtained for the total system dissipation of cobicistat in the silt loam and the sand sediments respectively.

The values obtained indicate the dissipation of the test item from the total system but will also include incorporation of the test item into sediments in a non-extractable form.

For surface water dissipation, DT₅₀ values of 5.6 and 12 days and DT₉₀ values of 19 and 40 days were obtained for silt loam and sand sediment systems respectively. Based on negligible mineralization in both systems, degradation DT values were greater than the 100 day duration of the study.

Determination of Single First Order (SFO) Kinetics: the rate of disappearance of GS-9350 in two aerobic sediment systems was determined for the reported data using kinetic analysis. Optimisation of model parameters, including estimation of parameter standard errors, was performed using the software KinGUI version 1.1.

Conclusion for degradation:

Cobicistat is potentially persistent.

Abiotic degradation

Hydrolysis: -

Photolysis: -

Bioaccumulation

Partition coefficient octanol/water:

The partition coefficient octanol/water of cobicistat was determined according to OECD 117 [Reference VII]

Log P_ow = 3.05, 4.00 and 4.10 at pH 5, 7 and 9 respectively.

Bioconcentration factor (BCF):

The bioconcentration and depuration characteristics of cobicistat in the rainbow trout in a flow through system were examined according to OECD 305 [Reference VIII].

BCF_k,_low dose = 1.67

BCF_k,_high dose = 1.37

The BCF value of the low and high dose indicates that cobicistat has low potential to bioconcentrate in the rainbow trout.

Conclusion for bioaccumulation: Cobicistat has low potential for bioaccumulation

Excretion (metabolism)

-

PBT/vPvB assessment

	PBT-criteria	Results for BDQ
Persistence	Half-life in freshwater: DT50 > 40 days Half-life in sediment: DT50 > 120 days	DT50,water = 5.6-12 days DT50,system = 171-241 days
Bioaccumulation	BCF > 2000	BCFk = 1.67 (low dose) and 1.37 (high dose)
Toxicity	Chronic NOEC < 10 µg/L	NOECalgae = 29.3 mg/L NOECdaphnia = 17.48 mg/L NOECfish = 4.84 mg/L

Conclusion for PBT-assessment:

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

References

1. Knight B. Determination of Acute Toxicity (EC₅₀) of GS-9350 to Algae (72 h). OECD 201. Gilead Report No. TX-216-2038. September 2011.

2. Knight B. The Effect of GS-9350 on Daphnia magna Reproduction (21 Day Semi-Static Test). OECD 211. Gilead Report No. TC-216-2036. November 2011.

3. Knight B. The Effect of GS-9350 on the Early Life Stages of the Fathead Minnow (Continuous Flow). OECD 210. Gilead Report No. TC-216-2037. November 2011.

4. Knight B. GS-9350: Activated Sludge Respiration Inhibition Test. OECD 209. Gilead Report No. TX-216-2034. September 2011.

5. Hall B. E. GS-9350: Determination of Ready Biodegradation by the CO₂ Evolution (Modified Sturm) Test. OECD 301. Gilead Study No. TX-216-2035. June 2011.

6. Bell S. The Aerobic Transformation of [¹⁴C]-GS-9350 in Two Aquatic Sediment Systems. OECD 308. Gilead Report No. TX-216-2048. March 2012.

7. Ballco S. and Allan G. The Determination of the Partition Coefficient (Log Pow) of GS-9350 to Meet the Requirements of the OECD Guidelines for Testing of Chemicals, Section 1, No. 117 “Partition Coefficient”. Gilead Report No. TX-216-2040. March 2011.

8. Knight B. Bioconcentration of [¹⁴C]-GS-9350 in Rainbow Trout. OECD 305. Gilead Report No. TX-216-2049. April 2012.

9. 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