Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The 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 = 0.000274 μg/L

Where:

A = 2 kg (Forecasted sales data of < 2 kg five years after launch.)

R = 0 % removal rate as a concervative estimate.

P = number of inhabitants in Sweden = 10 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default)¹

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default)¹

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies (all concentrations below are presented as fedratinib base)

Algae (Selenastrum capricornutum) (OECD 201)³

EC₅₀ 72 h (growth rate) = 84 µg/L

EC₁₀ 72 h (growth rate) = 8.4 µg/L

Crustacean (Daphnia magna)

Chronic Toxicity (OECD 211)⁴

NOEC 21 days (survival/body length/reproduction) = 2700 µg/L

Fish (Fathead Minnow; Pimephales promelas)

Chronic Toxicity (OECD 210)⁵

NOEC 28 days/30 days post hatch (larvae growth) = 1000 µg/L

The PNEC for aquatic organisms is based on the lowest NOEC of 8.4 µg /L, noted in the algae toxicity study. An assessment factor of 10 is applied to the ecotoxicity base set of three chronic studies.

PNEC_aquatic = 8.4/10 = 0.84 µg/L

Environmental Risk Classification (PEC/PNEC Ratio)

PEC/ PNECaquatic = 0.000274/0.84 = 3.26 x 10^-4. PEC/ PNECaquatic < 0.1 which justifies the phrase “Use of fedratinib has been considered to result in insignificant environmental risk”

Degradation

Biotic degradation

Ready Degradability (OECD 301B)⁶:

0% to 1% degradation over 28 days; not readily biodegradable

Simulation Studies (OECD 308)⁷:

The fate of fedratinib was studied in two natural aquatic sediment systems. Two freshly sampled water/sediment systems were used in this study: Schoonrewoerdse Wiel (SW) and Van Esschenven (EV). They were significantly different based on the texture and percentage organic carbon of the sediment. In both aerobic sediment systems fedratinib declined in the water phase over time (< 2% of initial concentration from Day 30 onwards) and increased in the sediment phase (36-66% of initial radioactivity after 100 days). Individual transformation products did not exceed 10 % of applied radioactivity in both systems. Mineralization was not a major route of degradation: less than 4% of applied radioactivity was recovered as CO₂. In both test systems negligible organic volatiles were detected (< 1%). Bound residues increased to 52% (SW) and 22% (EV) of applied radioactivity on Day 63 and then decreased to 43% (SW) and 14% (EV) at the end of the incubation period (Day 100). Mean mass balances ranged between 94% and 103% of applied radioactivity. The half-life (DT₅₀) of fedratinib in water layer at 12°C for sediment SW and EV was 3.4 and 0.2 days, respectively. The total system half-life (DT₅₀) of fedratinib at 12°C for sediment SW and EV was 47 and 319 days, respectively. The sediment extractions were performed using a shaker table at 250 rpm for 10 minutes with with 80/10/10 (v/v/v) methanol/water/25% ammonia. Acidic and alkaline extractions were also performed for selected post-extraction sediment samples of test systems with significant bound residues (> 10% of applied radioactivity) in order to characterize the nature of the bound residues. Non-extractable residues were determined by combustion-LSC.

Based on the OECD 301B study, fedratinib is not readily biodegradable. Based on the DT₅₀s determined in the OECD 308 study and the 2012 FASS guidance for pharmaceutical companies v 2.0, the phrase “fedratinib is potentially persistent” is justified.

Bioaccumulation

Bioconcentration factor (OECD 305)⁹:

The bioaccumulation factor (BCF; steady-state, total residue) was 57 ± 15 L/kg and 29 ± 8.5 L/kg at 4.6 μg base/L and 46 μg base/L, respectively.

Partitioning Coefficient (OECD 107)⁸:

LogDow values at pH 5, 7 and 9 was reported as -0.3, 2.1 and > 3.1, respectively.

Justification of chosen bioaccumulation phrase:

Since BCF < 500, the phrase “fedratinib has low potential for bioaccumulation” is justified.

Soil Sorption/Desorption

Determination of the Koc Coefficient (OECD 106)¹⁰

An OECD 106 study was conducted in three soils with varying characteristics (pH, organic carbon, clay content and soil texture) and two sludges from different wastewater treatment plants. Kocs in the three soils at equilibrium ranged from 69034-757834 L/kg. The Kocs in the two sludges at equilibrium were 2210 and 2574 L/kg.

Excretion (metabolism):

Following a single oral administration of [14C]-fedratinib at 200 mg, fedratinib represented approximately 80% of the total circulating radioactivity and the metabolites constitute minor portion of the circulating radiaoactivity². The pharmacological activity of the metabolites is not known. Excretion via feces accounted for the major elimination pathway of the administered dose. On average, 76.9% of the dose was excreted in feces and 5.15% in the urine. Concentrations of radioactivity in expired air were low. No removal is used as a worst case scenario for the PEC calculation above.

PBT/vPvB Assessment

Fedratinib does not meet the criteria to be considered a PBT or vPvB substance.

References

1. 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

2. Celgene Corporation, 2018. Investigator’s brochure - Fedratinib. Edition Number 8, 27 Jul 2018.

3. Augusiak, J.A., 2021. Freshwater Algal Growth Inhibition Test with Fedratinib. Charles River Laboratories Den Bosch BV report 20203718. 13 October 2021.

4. Wagenaars, S.M.A., 2020. Daphnia Magna, Reproduction Test with Fedratinib (Semi-Static). Charles River Laboratories Den Bosch BV report 20203717, 29 July 2020.

5. Augusiak, J.A., 2020. Fish early-life stage toxicity test with Fedratinib (flow-through). Charles River Laboratories Den Bosch BV report 20203719. 24 August 2020.

6. Timmer, N., 2019. Determination of 'Ready' Biodegradability: Carbon Dioxide (CO₂) Evolution Test (Modified Sturm Test) of Fedratinib. Charles River Laboratories Den Bosch BV report 20203714. 23 September 2019.

7. Brands, C.M.J., 2021. Aerobic Transformation of Fedratinib in Aquatic Sediment Systems. Charles River Laboratories Den Bosch BV report 20203715. 16 April 2021.

8. Volic N., 2018. Determination of Physico-Chemical Properties of Fedratinib. Charles River Laboratories Den Bosch BV report 20150967. 16 November 2018.

9. Augusiak, J.A., 2021. Bioaccumulation in Fish with Fedratinib (Flow-Through, Aqueous Exposure). Charles River Laboratories Den Bosch BV report 20262380. 29 October 2021.

10. Jacobs, L., 2021. Adsorption/Desorption of C¹⁴-Fedratinib on Three Soils and Two Sludges. Charles River Laboratories Den Bosch BV report 20203712. 4 June 2021.