Detaljerad miljöinformation

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (µg/L)    

= (A x 1 000 000 000 x (100 – R)) ÷ (365 x P x V x D x 100)

            = (1.5810 x 1 000 000 000 x (100 – 0)) ÷ (365 x 10 000 000 x 200 x 10 x 100)

            = 0.00022 µg/L

           

Where:

A = 1.5810 kg (total amount of selpercatinib sold in Sweden 2022, data from IQVIA).  This number is not adjusted for metabolism

R = Assumed 0% removal rate in a sewage treatment plant

P = 10 000 000 population of Sweden

V = 200 L of wastewater per capita per day (ECHA, 2017a)

D = 10 dilution of wastewater by surface water flow (ECHA, 2017a)

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Algae (Raphidocelis subcapitata)

(OECD 201) (Study 151P-106A, 2020)

            EC₅₀ 72 hr (growth rate) >1700* µg/L

            NOEC 72 hr (growth rate) 1700* µg/L

Crustacean (Daphnia magna)

            Acute toxicity

            EC₅₀ 48 h (immobilization) 1300 µg/L

(OECD 202) (Study 151A-165, 2021)

            Chronic toxicity

            NOEC 21 days (most sensitive endpoints -immobile neonates) = 97 µg/L

(OECD 211) (Study 151A-167, 2021)

Fish (Pimephales promelas)

            Acute toxicity

            LC₅₀ 96 h (mortality) = >1900* µg/L

(OECD 203) (Study 151A-166, 2021)

            Chronic toxicity

NOEC 4 d embryos + 28 d post-hatch (most sensitive endpoints: -length, wet and dry weight) = 160 µg/L

(OECD 210) (Study 151A-168, 2021)

*highest concentration tested

Calculation of PNEC

PNEC = 9.7 µg/L

PNEC (µg/L) = lowest NOEC ÷ 10. NOEC of 97 µg/L is the lowest of three chronic toxicity values in aquatic species. 10 is the assessment factor used because long-term results were available from three trophic levels: fish, daphnids and algae.

Environmental Risk Classification (PEC/PNEC Ratio)

PEC/PNEC = 0.00022 µg/L ÷ 9.7 µg/L = 0.000022

The PEC/PNEC ratio of less than 0.1 justifies the phrase: “Use of selpercatinib has been considered to result in insignificant environmental risk.”

Degradation

Biotic Degradation

Inherent degradability: 

¹⁴C-Selpercatinib was aerobically incubated with activated sewage sludge for 28 days at 20°C (OECD 314B). The disappearance half-life (DT50) was estimated to be 3.46 days. After 28 days, multiple transformation products (all more polar than selpercatinib) were observed totaling 35.7% of the applied radioactivity. Only one transformation product was greater than 10% of applied radioactivity. 37.6% of applied radioactivity was unextractable from the sludge. Less than 1% of applied radioactivity evolved as ¹⁴CO₂. (Study 151E-149, 2020).

Simulation studies:

Transformation of ¹⁴C-selpercatinib was evaluated over 100 days in two static, aerobic water-sediment systems at 20°C (OECD 308). After 100 days, almost all radioactivity had partitioned to sediment and less than 1% had evolved as ¹⁴CO_2. After 100 days, approximately 69 and 77% of the applied radioactivity (sediment 1 and sediment 2, respectively) could be extracted from the sediment using four sequential extractions with 1% NH₄OH in tetrahydrofuran. Initial extraction efficiency was at least 94%. Most of the radioactivity that could be extracted from the system at Day 100 was identified as selpercatinib while 15 and 17% of applied radioactivity was identified as multiple polar transformation products. No single transformation product was more than 10% of applied radioactivity. The remainder of the applied radioactivity (approximately 27 and 16%) was unextractable despite supplemental extractions with solvents of varying polarity and dielectric constants (water, acetone, ethyl acetate and hexane). Therefore, these unextractable residues are considered to be not bioavailable. For the two water-sediment systems, the disappearance half-life values (DT50) of selpercatinib from the total system were 127 and 159 days. (Study 151E-150, 2022)

Abiotic Degradation

Hydrolysis:

Selpercatinib is hydrolytically stable. Less than 10% of selpercatinib was degraded when incubated at 50°C in sterile, anoxic aqueous buffers at pH 4, 7 and 9 in the dark (OECD 111). (Study 151E-151, 2022) 

Justification of the degradation phrase:

There was some evidence of biotransformation of selpercatinib in biotic degradation studies. Selpercatinib does not meet the criteria for inherent biodegradability. Additionally, the DT50 values are >120 days from the total system in the OECD 308 simulation test. Therefore, selpercatinib is potentially persistent.

Bioaccumulation

Bioconcentration factor (BCF):

The bioaccumulation potential of selpercatinib in fish was experimentally determined using two concentrations of selpercatinib (separated by a factor of 10). The growth-corrected, lipid-normalized kinetic BCF values for selpercatinib are 98 and 42 L/kg (low and high concentration, respectively). (OECD 305) (Study 151A-186, 2022)

Justification of the bioaccumulation phrase:

Because the BCF is less than 500 L/kg, selpercatinib has low potential for bioaccumulation.

Excretion (metabolism)

Selpercatinib undergoes some metabolism in humans following oral administration. No removal by human metabolism was used to calculate the PEC.

PBT/vPvB Assessment

Selpercatinib is potentially persistent. Selpercatinib is potentially toxic since it meets CLP Hazard Statement Code H360 (toxic to reproduction in mammals) (ECHA, 2017b). According to established EU criteria, selpercatinib does not meet the criteria for bioaccumulative (ECHA 2017a). Therefore, selpercatinib is not a PBT or vPvB substance.

References

ECHA, European Chemicals Agency. 2017a. Guidance on information requirements and chemical safety assessment. Chapter R.11: PBT/vPvB Assessment and Chapter R.16: Environmental Exposure Estimation. 

ECHA, European Chemicals Agency. 2017b. Guidance on the Application of the CLP Criteria. Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures. Draft Version 5.0.

Study 151P-106A, 2020. LY3527723 – A 72-Hour Toxicity Test with the Freshwater Green Alga (Raphidocelis subcapitata) Following OECD Guideline 201.

Study 151A-165, 2021. LY3527723 – A 48-Hour Static Acute Toxicity Test with the Cladoceran (Daphnia magna) Following OECD Guideline 202.

Study 151A-166, 2021. LY3527723 – A 96-Hour Static-Renewal Acute Toxicity Test with the Fathead Minnow (Pimephales promelas) Following OECD Guideline 203.

Study 151A-167, 2021. LY3527723 – A Semi-Static Life-Cycle Toxicity Test with the Cladoceran (Daphnia magna) Following OECD Guideline 211 - Amended.

Study 151A-168, 2021. LY3527723 – An Early Life-Stage Toxicity Test with the Fathead Minnow (Pimephales promelas) Following OECD Guideline 210.

Study 151E-149, 2020. Biodegradation of ¹⁴C-LY3527723 in Activated Sludge Following OECD Guideline 314B.

Study 151E150, 2022. Aerobic Transformation of ¹⁴C LY3527723 in Aquatic Sediment Systems Following OECD Guideline 308 - Amended.

Study 151E-151, 2022. [¹⁴C]LY3527723: An Evaluation of Hydrolysis as a Function of pH Following OECD Guideline 111 - Amended.

Study 151A-186, 2022. LY3527723 – An Aqueous Exposure Bioaccumulation Test with the Bluegill (Lepomis macrochirus) - OECD Guideline 305.