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 = 0.014 μg/L

Where:

A = < 100 kg (maximum estimated 5 year sales in Sweden, data blinded for confidentiality)

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. I)

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

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

EC50 72h > 1.4 mg/L (growth rate)

NOEC 72h = 1.4 mg/L (growth rate)

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

Crustacean, water flea (Daphnia magna) (OECD 202) (Ref. III):

EC₅₀ 48h > 2.0 mg/L

NOEC 48h 2.0 mg/L

No effects noted for endpoint (immobilisation)

Fish, rainbow trout (Oncohynchus mykiss) (OECD 203) (Ref. IV)

LC₅₀ 96h > 2.0 mg/L

NOEC 96h 2.0 mg/L

No effects noted for endpoint (mortality)

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

LOEC 32d > 3.9 mg/L

NOEC 32d =3.9 mg/L

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

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

Chronic toxicity

LOEC 21d = 11 mg/L (reproduction)

NOEC 21d = 5.3 mg/L (reproduction)

Insect larvae, midge (Chironomid) (OECD 218) (Ref. VII)               

Chronic toxicity

EC₅₀ 28d > 870 (development)

EC₁₀ 28d = 740 (development)

PNEC = 140 μg/L (1.4 mg/ L/ 10 based on the most sensitive NOEC for the daphnia and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.014 /140 = 0.000098, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of gefapixant has been considered to result in insignificant environmental risk.

Biotic degradation

Biodegradation in Activated Sludge (OECD 314B)      (Ref VIII)

18.9% to CO₂ in 28 days

           

The biodegradability of [¹⁴C]gefapixant was determined following OECD Guideline 314B at a concentration of approximately 1.0 mg/L and a temperature of 22 ± 2 °C for 28 days in activated sludge. Activated sludge samples were analyzed at time 0 and 1, 3, 7, 14, 21, and 28 days after dosing to determine primary biodegradation. At each sampling interval, the aqueous sludge samples were extracted and analyzed by liquid scintillation counting (LSC) and high-performance liquid chromatography with radiometric detection (HPLC-RAM) to evaluate primary degradation.  Dissolved organic carbon (DOC) measurements were also made to evaluate ultimate biodegradation of the positive control reference substance.

[14C]gefapixant underwent partial primary and ultimate biodegradation over the course of the 28-day study.  The material balance (based on LSC analysis of the sludge and trapping solutions) of the biotic activated sludge test solution ranged from 105 to 108% applied radioactivity (AR). The material balance (based on LSC analysis of the sludge and trapping solutions) of the abiotic activated sludge test solution ranged from 105 to 109% AR. Ultimate biodegradation (conversion to CO2) occurred at 18.9% AR in the biotic activated sludge test solution and did not occur in the abiotic activated sludge solution.

The primary biotic biodegradation DT₅₀, DT₇₅ and DT₉₀ were determined to be 74.0, 148 and 246 days, respectively. The overall rate constant (ke) was determined to be 0.00937 day^-1.

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

DT₅₀ (total system) = 195-499 days  

The aerobic transformation of [¹⁴C]gefapixant in two aquatic sediment systems was investigated according to OECD Guideline 308. Test samples consisted of 50 g sediment (dry weight equivalent) aliquots, which were flooded with 150 mL of corresponding overlying water in a glass screw cap vessel.  The test vessels were connected to volatile trapping solutions, and incubated under aerobic conditions in the dark at 20 ± 2 °C.  [¹⁴C]gefapixant was applied at a nominal concentration of 0.6 µg/mL.

Water/sediment samples were analyzed at 0, 7, 14, 28, 55, and 101 days of incubation for the Taunton River (TR) and Weweantic River (WR) test systems.  Water/sediment samples were extracted and analyzed by liquid scintillation counting (LSC) and high-performance liquid chromatography with radiometric detection (HPLC-RAM) for determination and profiling of extracted residues.  The post-extraction solids (PES) were combusted and analyzed by LSC for determination of non-extractable residues.  The volatile trapping solutions were analyzed by LSC for determination of ¹⁴CO2 and volatile organics.  Non-extractable residues in representative PES samples were additionally characterized by extraction with polar and non-polar solvent.  Representative volatile trapping solutions were additionally characterized by barium chloride precipitation.

Average material balance ranged from 94.5 to 100% applied radioactivity (AR) over the course of the study for both the TR and WR test systems. Ultimate biodegradation of [¹⁴C]gefapixant was observed in the aerobic samples with evolution of ¹⁴CO₂ reaching an average maximum of 5.60 and 5.01% AR for the TR and WR aerobic test samples at day 101, respectively.  Negligible amounts of radioactivity were observed in the ethylene glycol trapping solutions at day 101 for both aerobic test samples.

The rate of transformation of [¹⁴C]gefapixant was determined using non-linear kinetics following FOCUS Kinetics guidelines calculated using Computer Assisted Kinetic Evaluation (CAKE) software. The DT₅₀ and DT₉₀ values at 20°C as well as corresponding half-lives at 12^oC were calculated per Focus, 2014. Results are presented in Table 1.

Evidence of primary biotransformation was observed for [¹⁴C]gefapixant in the water/sediment test systems. There were no major transformation products (≥10% AR) over the course of the study. Minor regions of radioactivity represented less than 10% AR in the water and sediment extracts and were not characterized further.

Justification of chosen biotic degradation phrase:

Since half-life >120 days for total system, gefapixant is potentially persistent.

Bioaccumulation

Partitioning coefficient (OECD 107) (Ref. X):

Log P_ow = 0.777 at pH 7

Justification of chosen bioaccumulation phrase:

Since log P_ow < 4, gefapixant has low potential for bioaccumulation.

References

1. European Chemicals Agency, 2024.  Guidance on information requirements and chemical safety assessment.  Available at: https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment (Accessed 02 July 2024). 

2. Softcheck KA. MK-7264 – 72-hour toxicity test with the freshwater green alga, Pseudokirchneriella subcapitata following OECD guideline 201. Wareham (MA): Smithers Viscient; 19 April 2017. Study No. 359.7021.

3. Fournier AE. MK-7264 – Acute toxicity to water fleas (Daphnia magna) under static conditions following OECD guideline 202.  Wareham (MA): Smithers Viscient; 3 November 2016. Study No. 359.7024.

4. Fournier AE. MK-7264 – Acute Toxicity to rainbow trout (Oncorhynchus mykiss) under static conditions following OECD guideline 203.  Wareham (MA): Smithers Viscient; 21 October 2016. Study No. 359.7025.

5. Urann K. MK-7264 – Early life-stage toxicity test with fathead minnow (Pimephales promelas) following OECD guideline 210 and OCSPP guideline 850.1400. Wareham (MA): Smithers Viscient; 17 October 2018. Study No. 359.7063.

6. Mason JA. MK-7264 – Full life-cycle toxicity test with water fleas (Daphnia magna) under static-renewal conditions OECD guideline 211. Wareham (MA): Smithers Viscient; 17 July 2018. Report No. 359.7064.

7. Malcom CA. MK-7264 - Toxicity test with sediment-dwelling midges (Chironomus riparius) under static conditions, following OECD Guideline 218. Wareham (MA): Smithers Viscient; 28 May 2019. Report No. 359.7096.           

8. Dubey P. [¹⁴C]MK-1439 - [14C]MK-7264 – Determination of the biodegradability of a test substance in activated sludge based on OECD method 314B. Wareham (MA): Smithers Viscient; 24 September 2018. Study No. 359.7060.

9. Kang S. [¹⁴C]MK-7264 – Aerobic transformation in aquatic sediment systems following OECD guideline 308. Wareham (MA): Smithers Viscient; 7 December 2018. Study No. 359.7067.

10. Smithers, 2017.  "MK-7264 - Determining the Partitioning Coefficient (n-Octanol/Water) by the Shake-Flask Method Following OECD Guideline 107" Study No. 359.7022, Smithers Viscient, Wareham, MA, 10 July 2017.