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) = 0.000737 μg/L

Where:

A = 4.915 kg ribociclib succinate (total sold amount API in Sweden year 2018, data from IQVIA).

R = 0 % removal rate.

P = number of inhabitants in Sweden = 9 *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):

EC10 72 h (growth rate) = 0.71 mg/L (OECD201) (Will Research Project 504754)

Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) > 33.0 mg/L; highest concentration tested due to substance’s water solubility limit (OECD202) (Wil Research Project 504755)

Chronic toxicity

NOEC 21 days (growth of parental daphnids) = 1.4 mg/L; (OECD 211) (Wil Research Project 508584)

Fish:

Acute toxicity (Cyprinus carpio, carp)

LC50 96 h (mortality) = 38.0 mg/L (OECD203) (Wil Research Project 504756)

Chronic toxicity (Pimephales promelas, fathead minnow)

NOEC 33 days (fish larvae length) = 1.0 mg/L (OECD 210) (Wil Research Project 508583)

Other ecotoxicity data:

Bacterial respiration inhibition

EC₅₀ 3 h > 1000 mg/L (activated sludge respiration inhibition) (OECD209) (Wil Research Project 504753)

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

NOEC 28 days (emergence rate and development rate) = 1000.0 mg/kg dry weight (OECD 218) (Charles River Laboratories Den Bosch Project 509180)

PNEC derivation:

PNEC = 71.0 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 EC₁₀ for algae growth inhibition has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000737 μg/L / 71.0 μg/L = 0.00001, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of ribociclib has been considered to result in insignificant environmental risk."

Degradation 

Biotic degradation

Ready degradability:

5-14 % degradation in 28 days, not readily biodegradable (OECD301B). (Wil Research Project 504757)

Simulation studies:

DT₅₀ (total system) = 0.31 – 0.35 days (OECD 308). (Wil Research Project 508585)

Extraction of sediment with acetonitrile/water or methanol/water did not release more than 5% of the applied activity. Therefore harsh conditions were required to be able to extract LEE011-BBA from the sediment. The sediment phase was extracted four times with 100 mL 80/20 methanol/1M NaOH. Approximately half of the combined extracts (200 mL) were centrifuged and a subsample of approximately 6 mL was ultra-centrifuged. Prior to HPLC analysis the subsamples were acidified. In the sediment extracts 85% (SW) and 88% (SL) of applied radioactivity was recovered and in the final concentrated samples 83% (SW) and 85% (SL) of applied radioactivity was recovered.

In both test systems negligible organic volatiles were detected (≤ 0.1%). Up to 11% of applied activity was recovered as CO₂ in the SL system and maximum 2% of applied activity in the SW system. Non-extractable residues accounted for 34% of applied activity in the SL system and 44% of applied activity in the SW system at the end of the incubation period (100 days).

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, ribociclib can be classified as ‘Ribociclib is degraded in the environment' (DT₅₀ for total system ≤ 32 days)

Bioaccumulation

Partitioning coefficient:

log D at pH 4 < -0.8

log D at pH 7 = 0.6

log D at pH 9 = 2.2 (OECD107) (Wil Research Project 504758)

Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, ribociclib has low potential for bioaccumulation.

Excretion (metabolism)

Following oral administration of a single 600 mg dose of [¹⁴C] ribociclib to humans, ribociclib was extensively metabolized, with the unchanged drug accounting for 17.3% and 12.1% of the dose in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 13.9% and 3.74% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤2.78% of the administered dose).

Ribociclib is eliminated mainly via the feces, with a small contribution from the renal route. In 6 healthy male subjects, following a single oral dose of [¹⁴C] ribociclib, 91.7% of the total administered radioactive dose was recovered within 21 days; feces were the major route of excretion (69.1%), with 22.6% of the dose recovered in the urine. (KISQALI^®/™, KRYXANA^®/™ (ribociclib) Core Data Sheet)

PBT/vPvB assessment

Ribociclib has low potential for bioaccumulation based on the screening criteria for B and is degraded in the environment based on total system DT50s obtained in a simulation study following OECD308. Ribociclib can therefore not be considered a potential 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

• Wil Research Project 504754. Fresh water algal growth inhibition test with LEE011-A4 (=LEE011-NXA). Final report: 29. August 2014.

• Wil Research Project 504755. Acute toxicity study in Daphnia magna with LEE011-A4 (=LEE011-NXA) (static). Final report: 29. August 2014.

• Wil Research Project 508584. Daphnia magna, reproduction test with LEE011-BBA (semi-static). Final report: 01. September 2015.

• Wil Research Project 504756. 96-hour acute toxicity study in carp with LEE011-A4 (=LEE011-NXA) (static). Final report: 29. August 2014.

• Wil Research Project 508583 Fish early-life stage toxicity test with LEE011-BBA (flow-through). Final report: 28. October 2015.

• Wil Research Project 504753 Activated sludge respiration inhibition test (carbon and ammonium oxidation) with LEE011-A3. Final report: 22. May 2014.

• Charles River Laboratories Den Bosch Project 509180 Sediment-water Chironomid toxicity test using sediment spiked with LEE011-BBA. Final report: 26. July 2016.

• Wil Research Project 504757 Determination of ‘ready’ biodegradability: carbon dioxide (CO₂) evolution test (modified Sturm test) of LEE011-A4. Final report: 17. April 2014.

• Wil Research Project 508585 Aerobic degradation of LEE011-BBA in two water/sediment systems. Final report: 29. July 2016.

• Wil Research Project 504758 Determination of physico-chemical properties of LEE011-BBA. Final report: 05. January 2015.

• KISQALI^®/™, KRYXANA^®/™ (ribociclib) Core Data Sheet Version 2.0 & 2.1. 04 July 2019.