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) = 1.5*10^-6 *A(100-R)

PEC = 0.0001 μg/L

Where:

A = 1 kg (total sold amount API in Sweden year 2021, data from IQVIA) (Ref. I)

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 10 *10⁶ 

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Pseudokirchneriella subcapitata) (OECD 201) (Reference. III): 

EC₅₀ 72h > 81 µg/L

NOEC 72h = 81 µg/L

No effects noted for any endpoint

Crustacean, water flea (Daphnia magna) (OECD 211) (Ref. IV): 

Chronic toxicity

NOEC 21d = 840 µg/L

No effects noted for any endpoint (reproduction, growth rate)

Fish, fathead minnow (Pimephales promelas) (OECD 210) (Ref. V): 

Chronic toxicity

NOEC 32d = 2.3 µg/L (larval survival)

PNEC = 0.23 μg/L (2.3 µg/L / 10 based on the most sensitive NOEC for the fathead minnow and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0001 /0.23 = 0.0006 , i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of elbasvir has been considered to result in insignificant environmental risk.

Biotic degradation

Inherent degradability

37% degradation (loss of parent in activated sludge) in 28 days (OECD 314D) (Ref. VI)

Conversion to CO₂ occurred at 14.5% AR in the biotic activated sludge test solutions. At Day 28 in the aerobic system, 62.9% of the AR remained as parent molecule. Four regions of radioactivity and a polar region were observed in the HPLC analyses of the biotic sludge in addition to the parent peak. The overall primary biodegradation half-life of [¹⁴C] elbasvir in the biotic sludge was calculated to be 45 days.

Sediment Transformation (OECD 308) (Ref. VII):

1.4 - 2% to CO₂ in 99 days

DT₅₀ (total system) = 43 - 91 days

No major degradates (≥ 10% AR) were identified.

At each sampling interval, duplicate incubation vessels per sediment/water system were removed from incubation chamber and water layers were separated from sediment layers. Two layers were analyzed separately for [¹⁴C]elbasvir and degradates. The sediment was then extracted once with acetonitrile:purified reagent water:trifluoroacetic acid (90:10:0.1, v:v:v), once with acetonitrile:purified reagent water:trifluoroaoacetic acid (80:20:0.5, v:v:v) and once with acetonitrile:purified reagent water:trifluoroacetic acid (50:50:1.0, v:v:v). The water and sediment extracts were radioassayed by LSC and then analyzed by high performance liquid chromatography with radiochemical detection (HPLC/RAM) to quantify [¹⁴C]elbasvir and degradation products in the fractions. Radioactivity in the post extracted solids (sediment bound) was quantified by combustion analysis and the liquid volatile organic traps were radioassayed by LSC.

The transformation of elbasvir in sediments and natural water was assessed in two different aerobic water/sediment systems at a temperature of 20 ± 2 °C continuously in the dark for 100 days. Average material balance ranged from 95.4 to 103% AR over the course of the 100-day study.

The DT₅₀ (half-life) of elbasvir in the water phase was 14 and 19 days for the Taunton River and Weweantic River aerobic test systems. The DT₅₀ (half-life) of elbasvir in the sediment extractable phase was estimated to be > 100 days for the Taunton River and Weweantic River aerobic test systems. The DT₅₀ (half-life) of [¹⁴C]elbasvir in the total water/sediment test systems ranged from 43 to 91 days for the aerobic test systems.

Evidence of primary biodegradation was observed for [¹⁴C]elbasvir in the aerobic water/sediment test systems, and no major metabolites (≥ 10% AR) were identified.

Ultimate biodegradation of [¹⁴C]elbasvir was observed in the aerobic samples with evolution of 14CO2 reaching an average maximum of 1.25 and 1.99% AR for the Taunton River and Weweantic River aerobic test samples, respectively, at Day 100. Radioactivity was not detected in the volatile organic compound traps for the aerobic test systems accumulatively at Day 100 in the Weweantic River samples and was negligible (0.107 %AR) in the Taunton River samples.

Justification of chosen biotic degradation phrase:

Since half-life < 120 days for total system, elbasvir is slowly degraded in the environment.

Bioaccumulation

Bioconcentration Factor (OECD 305) (Ref. VIII): 

BCF = 73.2 (low concentration)

BCF = 48.2 (high concentration)

Justification of chosen bioaccumulation phrase:

Since BCF < 500, elbasvir has low potential for bioaccumulation.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2022 (data 2021)”.

   
   

2. 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

   
   

3. Smithers Viscient, 2014. MK-8742: 72-hour Acute Toxicity with the Freshwater Green Alga, Pseudokirchneriella subcapitata, Following OECD Guideline 201. Study 359.6797, 31 July 2014.

   
   

4. Smithers Viscient, 2014. MK-8742: Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Flow-Through Conditions Following OECD Guideline 211. Study 359.6799, 4 Dec 2014.

   
   

5. Smithers Viscient, 2015. MK-8742: Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas). Study 359.6798, 27 February 2015.

   
   

6. Smithers Viscient, 2015. [14C]-MK-8742 - Determination of the Biodegradability of a Test Substance in Activated Sludge Following OECD Guideline 314. Study 359.6806, 29 January 2015.

   
   

7. Smithers Viscient, 2015. [14C]-MK-8742 - Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308. Study 359.6805, 28 January 2015.

   
   

8. Smithers Viscient, 2015. [14C]-MK-8742 - Flow-Through Bioconcentration and Metabolism Study with Bluegill Sunfish (Lepomis macrochirus). Study 359.6806, 2 February 2015.

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 = 0.0004 μg/L 

Where:

A = 2.8 kg (total sold amount API in Sweden year 2021, data from IQVIA) (Ref. I).

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 10 *10⁶ 

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Pseudokirchneriella subcapitata) (OECD 201) (Reference III): 

EC₅₀ 72h > 10 mg/L

NOEC 72h = 10 mg/L

No effects noted for any endpoint (yield and growth rate)

Crustacean, water flea (Daphnia magna) (OECD 211) (Ref. IV): 

Chronic toxicity

NOEC 21d = 5 mg/L (reproduction, growth)

Fish, fathead minnow (Pimephales promelas) (OECD 210) (Ref. V): 

Chronic toxicity

NOEC 32d = 0.98 mg/L

No effects noted for any endpoint (hatching, survival, growth)

PNEC = 98 μg/L (0.98 mg/ L/ 10 based on the most sensitive NOEC for the fathead minnow and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0004/98 = 3.9 E-06 , i.e. PEC/PNEC ≤ .1 which justifies the phrase "Use of grazoprevir has been considered to result in insignificant environmental risk.

Biotic degradation

Inherent degradability

66% degradation (loss of parent in activated sludge) in 28 days (OECD 314D) (Ref VI)

Very little (2%) conversion to CO₂. At Day 28, in the aerobic system, 33.9% of the AR remained as parent molecule. Six regions of radioactivity and a polar region were observed in the HPLC analyses of the biotic sludge in addition to the parent peak. Two metabolites M1 and M2 were measured in concentrations greater than 10% by Day 28 (identified in the OECD 308 study, below). The overall primary biodegradation half-life of grazoprevir in the biotic sludge was calculated to be 20 days.

Sediment Transformation (OECD 308) (Ref. VII):

0.9-1% to CO₂ in 99 days

DT₅₀ (total system) = 59-76 days

At each sampling interval, duplicate incubation vessels per water/sediment system were removed from each incubation chamber and the water layers were separated from sediment layers. The water layer from each system was analyzed separately for [14C]grazoprevir and degradates without any concentration step. The sediment was then extracted once with acetonitrile, once with 90:10 acetonitrile:purified reagent water (v:v) and once using 90:10:0.1 acetonitrile:purified reagent water:formic acid (v:v:v) for a total of three extractions. The water and sediment extracts were radioassayed by LSC and then analyzed by high performance liquid chromatography with radiochemical detection (HPLC/RAM) to quantify [14^C]grazoprevir and degradation products in the fractions. Radioactivity in the post extracted solids (sediment bound, PES) was quantified by combustion analysis and the liquid volatile organic traps were radioassayed by liquid scintillation counting (LSC).

The DT₅₀ (half-life) of grazoprevir in the water phase was 18.52 and 31.29 days for the Taunton River and Weweantic River aerobic test systems, respectively. The DT₅₀ (half-life) of grazoprevir in the sediment phase was 110.4 and 64.68 days for the Taunton River and Weweantic River aerobic test systems, respectively. The DT₅₀ (half-life) of [14C]grazoprevir in the total water/sediment test systems was 76.25 and 59.09 days for the Taunton River and Weweantic River aerobic test systems, respectively.

Evidence of primary biodegradation was observed for [14^C]grazoprevir in the aerobic water/sediment test systems.

Two major peaks (>10% AR) were observed in some of the chromatograms for both extractable sediment fractions at a retention time of approximately 26 and 27 minutes. % AR in extractable sediments remained steady or slightly increased from Day 66 on to the end of the study (i.e., no further degradation of M1 or M2 was noted).

Proposed structures for observed major degradates M1 and M2 were determined by LC-MS/MS. A proposed transformation pathway for [14^C] grazoprevir was determined based on these proposed structures and HPLC-RAM analysis. It is proposed that the parent material hydrolyzes to form M2, which in turn forms M1 by hydrolysis and/or metabolism. Additionally, parent molecule directly forms M1 by hydrolysis.

Justification of chosen biotic degradation phrase:

Since half-life < 120 days for total system, grazoprevir is slowly degraded in the environment.

Bioaccumulation

Bioconcentration Factor (OECD 305) (Ref. VIII): 

BCF = 3.09 (low concentration)

BCF = 7.62 (high concentration)

Justification of chosen bioaccumulation phrase:

Since BCF < 500, grazoprevir has low potential for bioaccumulation.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2022 (data 2021)”.

   
   

2. 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

   
   

3. Smithers Viscient, 2014. "MK-5172 − 72-Hour Toxicity Test with the Freshwater Green Alga, Pseudokirchneriella subcapitata, Following OECD Guideline 201" Study No.359.6812, SV, Wareham, MA, USA, 25 August 2014.

   
   

4. Smithers Viscient, 2014. "MK-5172 – Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static Renewal Conditions Following OECD Guideline #211" Study No.359.6814, SV, Wareham, MA, USA, 10 July 2014.

5. Smithers Viscient, 2015. "MK-5172 – Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas)" Study No.359.6853, SV, Wareham, MA, USA, 7 January 2015.

   
   

6. Smithers Viscient, 2015. "[14C]MK-5172 – Determination of the Biodegradability of a Test Substance in Activated Sludge Based on OECD Method 314B," Study No. 359.6822, SV, Wareham, MA, USA, 12 February 2015.

   
   

7. Smithers Viscient, 2015. "[14C]MK-5172 – Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308," Study No. 359.6821, SV, Wareham, MA, USA, 11 February 2015.

   
   

8. Smithers Viscient, 2014. "[14C]MK-5172 – Flow-Through Bioconcentration and Metabolism Study with Bluegill Sunfish (lepomis macrochirus)" Study No.359.6819, SV, Wareham, MA, USA, 29 Dec 2014.