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) = 1.37*10^-6 * 45.6 kg * 100 = 0.000767 μg/L = 0.767 ng/L

Where:

A =5.5991 kg ruxolitinib phosphate (total sold amount API in Sweden year 2022, data from IQVIA).

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0, if no data is available.

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) (OECD 201) (NOTOX Project 495601):

ErC50 72 h (growth rate) = 15’000 μg/L

NOEC = 1’000 μg/L

Crustacean (Daphnia magna):

Acute toxicity

EC50 48 h (immobilization) = 13’000 μg/L (OECD 202) (NOTOX Project 495598)

Fish (Cyprinus carpio):

Acute toxicity

LC50 96 h (lethality) = 15’000 μg/L (OECD 203) (NOTOX Project 495598)

PNEC = 13.0 μg/L

The PNEC (μg/L) is based on the lowest EC50/1000, where 1000 is the assessment factor used if acute data for 3 trophic levels is available. EC50 for Daphnia magna has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000767 μg/L / 13.0 μg/L = 0000059, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of ruxolitinib has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

4-22 % degradation in 28 days (OECD 301B). (NOTOX Project 495602)

Justification of chosen degradation phrase:

Ruxolitinib is not readily biodegradable. The phrase “Ruxolitinib is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = 2.3-2.4 at pH 7 (EC440/2008 A.8; OECD 107). (NOTOX Project 495597)

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

Following a single oral dose of [¹⁴C]-labeled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism with 74% of radioactivity excreted in urine and 22% excretion via feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity. (Novartis Core Data Sheet, 2017).

PBT/vPvB assessment

According to the established EU criteria, ruxolitinib cannot be regarded as a PBT/vPvB substance, as it has low potential for bioaccumulation and is not toxic.

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

• NOTOX Project 495601. Final report: 17 June 2011.

• NOTOX Project 495598. Final report: 17 June 2011.

• NOTOX Project 495598. Final report: 17 June 2011.

• NOTOX Project 495602. Final report: 17 June 2011.

• NOTOX Project 495597. Final report: 19 April 2011.

• Novartis Core Data Sheet, JAKAVI® (ruxolitinib), Version 2.3, 12 May 2017.