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 * 0.14 * 100 = 0.000019 μg/L = 0.019 ng/L

Where:

A = 0.140572148 kg trametinib (total sold amount API in Sweden year 2021, 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 (Selenastrum capricornutum) (OECD 201):

NOEC 72 h (growth rate) = 0.04 mg/L (not toxic up to the limit of water solubility) (GlaxoSmithKline Report No 2011N119092_00)

Crustacean (Waterflea, Daphnia magna):

Chronic toxicity

NOEC 21 days = 0.013 mg/L (OECD 211) (not toxic up to the limit of water solubility) (GlaxoSmithKline Report No 2012N139247_00)

Fish (Zebrafish, Danio rerio):

Chronic toxicity

NOEC 28 days (fish body length and dry weight) = 0.004 mg/L (OECD 210) (GlaxoSmithKline Report No 2012N134344_00)

PNEC = 4.0 μg/L / 10 = 0.4 µg/L = 400 ng/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used, if chronic toxicity values for 3 trophic levels are available. NOEC from fish early life-stage toxicity (OECD 210) 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 = 0.019 ng/L / 400.0 ng/L = 0.0000475 i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of trametinib has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

No data available

Justification of chosen degradation phrase:

As no data on degradation is available for trametinib, the following classification is chosen: The potential for persistence of trametinib cannot be excluded, due to lack of data.

Bioaccumulation

Partitioning coefficient:

Log Kow = 4.04 (OECD 107) (GlaxoSmithKline Report No 2011N117817_00)

Justification of chosen bioaccumulation phrase:

Since log Kow > 4, trametinib has high potential for bioaccumulation.

Excretion (metabolism)

Total dose recovery is low after a 10-day collection period (<50%) following administration of a single oral dose of radiolabeled trametinib as a solution, due to the long half-life. Drug-related material was excreted predominantly in the feces (≥81% of recovered radioactivity) and to a small extent in urine (≤19%). Less than 0.1% of the excreted dose was recovered as parent in urine. (Novartis Core Data Sheet, MEKINIST^® (trametinib))

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

• GlaxoSmithKline Report No 2011N117817_00: GSK1120212B: Determination of partition coefficient (n-octanol:water). Final report: 20 May 2011.

• GlaxoSmithKline Report No 2011N119092_00: GSK1120212B: Algal growth inhibition test. Final report: 17 June 2011.

• GlaxoSmithKline Report No 2012N139247_00: GSK1120212B: Daphnia magna reproduction test. Final report:  08 May 2012.

• GlaxoSmithKline Report No 2012N134344_00: GSK1120212B: Fish early life stage toxicity test. Final report: 06 March 2012. 

• Novartis Core Data Sheet for MEKINIST^®(trametinib), Version 2.2, 06 August 2019