Detaljerad miljöinformation

Environmental risk: Hazardous environmental properties. 

Degradation: According to the established EU criteria, midostaurin should be regarded as a PBT substance. 

Bioaccumulation: According to the established EU criteria, midostaurin should be regarded as a PBT substance. 

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) = 1.37*10^-6 * 0.44 * 100 = 0.00006 μg/L

Where:

A = 0.4424 kg midostaurin (total sold amount API in Sweden year 2021, data from IQVIA).

R = 0 % removal rate.

P = number of inhabitants in Sweden = 10 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata):

NOEC 72 h (growth rate) = 0.27 µg/L (OECD201) (IES Study 20160356)

Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) = 13.0 µg/L (OECD202) (NOTOX Project 383186)

Chronic toxicity

NOEC 21 days (parental mortality and reduced reproduction rates) = 5.0 µg/L (OECD 211) (RCC Study Number B29586)

Fish:

Acute toxicity (Oncorhynchus mykiss, rainbow trout)

LC50 96 h (mortality) = 25.0 µg/L (OECD203) (NOTOX Project 398227)

Chronic toxicity (Danio rerio, zebrafish)

NOEC 34 days (egg development, hatching rate, survival of larvae and juvenile fish) = 14.0 µg/L (OECD 210) (RCC Study Number B29608)

Other ecotoxicity data:

Bacterial respiration inhibition

NOEC 3 h > 1000 mg/L (activated sludge respiration inhibition) (OECD209) (IES Study 20160358)

Sediment-dwelling organisms (Chironomus riparius, non-biting midge)

NOEC 28 days = 100.0 mg/kg dry weight (OECD 218) (Harlan Laboratories Study C11772)

PNEC derivation:

PNEC = 0.027 μg/L

PNEC (μg/L) = lowest NOEC or EC₁₀ / 10, where 10 is the assessment factor used if three chronic toxicity studies from three trophic levels are available. The NOEC for algae growth inhibition has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00006 μg/L / 0.027 μg/L = 0.002, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of midostaurin has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Simulation studies:

DT₅₀ (total system) > 1000 days (OECD 308). (Harlan Laboratories Study C11715)

For each system, the water and sediment phases were separated and the sediments were extracted with acetonitrile followed by acetonitrile/water (4:1, v/v). In Addition, Soxhlet extraction with acetonitrile/water (4:1, v/v) for four hours was performed on the sediments from days 7 onwards.

Total recoveries of the applied radioactivity (material balances) averaged 95.5 ± 2.0% and 96.5 ± 1.4% in the river and pond systems, respectively.

Complete mineralisation of midostaurin and formation of organic volatiles was insignificant. In both aquatic systems two major metabolites could be detected in the sediment extracts, with metabolite M1 reaching maxima of 18.6 % and 22.9 % of applied activity in the two systems on day 55. M1 was identified as a hydroxylated metabolite of midostaurin. Metabolite M2 achieved its maximum on day 115 with 9.4 % and on day 55 with 16.4 % of applied radioactivity in the river and pond system, respectively.

In the aquatic systems the amount of non-extractable radioactivity increased to a value of 9.7% and 11.6% on day 115 for the river and pond systems respectively.

Further harsh extractions using acidic reflux conditions extracted a maximum of 3.7% of the applied radioactivity from sediment on day 115.

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, midostaurin can be classified as ‘Midostaurin is potentially persistent' (DT₅₀ for total system > 120 days)

Bioaccumulation

Partitioning coefficient:

log Kow = 4.26 at pH 6.71 (Harlan Laboratories Study C11704)

Bioconcentration in fish:

Lipid-normalised kinetics BCF (BCF_L,k) = 1867 – 2684 L/kg

Kinetics BCF (BCF_k) = 549 – 789 L/kg

Steady-state BCF (BCF_ss) = 495 – 756 L/kg (Harlan Laboratories Study C11726)

Justification of chosen bioaccumulation phrase:

Since the lipid-normalised kinetics BCF > 500, midostaurin has high potential for bioaccumulation.

Excretion (metabolism)

Midostaurin is metabolized by CYP3A4 mainly via oxidative pathways and the major plasma components included midostaurin and two major active metabolites. O-demethylation, oxidation at benzene ring, oxidation at pyrrolidinine ring, amide bond hydrolysis, and N-demethylation were the major pathways of metabolism in man, leading to formation of 16 metabolites. The Human Mass Balance study results indicate that fecal excretion is the major route of excretion (78% of the dose), and mostly as metabolites (73% of the dose) while unchanged midostaurin accounts for 3% of the dose. Only 4% of the dose is recovered in urine. (RYDAPT^® (midostaurin) Core Data Sheet)

PBT/vPvB assessment

Midostaurin has been found to be persistent with the half-life determined in the study on transformation in water/sediment systems exceeding 1000 days. As shown in the bioconcentration study in rainbow trout, midostaurin can be considered bioaccumulative based on the maximum BCF_L,k of 2684 L/kg. Moreover, midostaurin fulfils the criteria for toxicity with a NOEC of 0.27 µg/L determined for the green algae species Pseudokirchneriella subcapitata. Therefore, midostaurin shows hazardous environmental properties. According to the established EU criteria, midostaurin should be regarded as a PBT substance.

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• IES Study 20160356. PKC412-NXA.003 – Effect on Pseudokirchneriella subcapitata in a 72-hour algal growth inhibition test. Final report: 10. April 2017.

• NOTOX Project 383186. Acute toxicity study in Daphnia magna with midostaurin (semi-static). Final report: 14. January 2004.

• RCC Study Number B29586. PKC412 DS Effect on survival and reproduction of Daphnia magna in a semi-static test over three weeks. Final report: 19. March 2008.

• NOTOX Project 398227. 96-hour acute toxicity study in rainbow trout with midostaurin. Final report: 13. May 2005.

• RCC Study Number B29608. PKC412 DS Toxic effects to zebra fish (Brachydanio rerio) in an early-life stage toxicity test. Final report: 19. March 2008.

• IES Study 20160358. PKC412-NXA.003 – Toxicity to activated sludge in a respiration inhibition test. Final report: 14. March 2017.

• Harlan Laboratories Study C11772. PKC412 DS Effects of PKC412 DS on the development of sediment-dwelling larvae of Chironomus riparius in water-sediment systems with spiked sediment. Final report: 29. April 2010.

• Harlan Laboratories Study C11715. PKC412 DS: Route and rate of degradation of 14C-PKC412 DS in aerobic aquatic sediment systems. Final report: 31. March 2011.

• Harlan Laboratories Study C11704. PKC412-NXA.003 Determination of the partition coefficient (n-octanol / water). Final report: 24. February 2009.

• Harlan Laboratories Study C11726. [14C]-PKC412 DS: Bioconcentration flow-through test in the rainbow trout (Oncorhynchus mykiss). Final report: 02. November 2011.

• RYDAPT^® (midostaurin) Core Data Sheet Version 2.0. 14 December 2017.