Detaljerad miljöinformation

etailed 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) = 1.37*10^-6*A*(100-R)

PEC = 1.37*10^-6* 21.0234 *100 = 0.00288 μg/L

Where:

A = 21.0234 kg dabrafenib mesylate (total sold amount API in Sweden year 2021, data from IQVIA).

R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10 *10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Pseudokirchneriella subcapitata):

IC50 96h (biomass) = 280 μg/L (OECD 201) (Reference 4)

NOEC = 220 μg/L

Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 105 μg/L (OECD 211) (Reference 5)

Fathead minnow (Pimephales promelas):

Chronic toxicity

NOEC 28 days (reproduction) = 1,740 μg/L (OECD 210) (Reference 6)

Other ecotoxicity data:

Chironomid (Chironomus riparius)

NOEC 28 days (reproduction) = 75,840 μg/kg (OECD 218) (Reference 7)

Microorganisms in activated sludge

EC50 3 hours (Inhibition) = 370,300 μg/L (OECD 209) (Reference 3)

PNEC = 105.0 μg/L / 10 = 10.50 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for water flea (= 105 ug/L) 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 = 0.00288 μg/L / 10.50 μg/L = 0.00027, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of dabrafenib has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

32% degradation in 28 days, not readily biodegradable. (OECD 301B) (Reference 8)

81% primary degradation in 28 days.

Simulation studies:

Water-sediment study:

50% (DT₅₀) degradation in 162-307 days (OECD 308) (Reference 9)

One significant Unknown WS-1 (> 10%) transformation product identified, C₂₃H₁₈O₂N₅F₃S₂. WS-1 was detected at 14% at day 59 but declined to 3% by the end of the study.

Non-extractable residue = 17.10% - 31.10%

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

Dabrafenib is not readily biodegradable nor inherently biodegradable. This substance is predicted to degrade in water sediment systems ≥ 120 days. However, non-extractable residues represent > 15% of the total material. The phrase “Dabrafenib is potentially persistent” is thus chosen.

Bioaccumulation

Bioconcentration factor (BCF):

Rainbow trout (Oncorhynchus mykiss)

BCF < 10 (OECD 305) (Reference 10)

Justification of chosen bioaccumulation phrase:

Since BCF < 500, the substance has low potential for bioaccumulation.

Excretion (metabolism)

The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidized via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can be decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolized by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hrs while the carboxy- and desmethyl-metabolites exhibited longer half-lives (21-22 hours). Mean metabolite to parent AUC ratios following repeat-dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib; while the activity of carboxy-dabrafenib is not likely to be significant.

Terminal half-life following an intravenous single microdose is 2.6 hours. Dabrafenib terminal half-life after a single dose is 8 hours due to absorption-limited elimination after oral administration (flip-flop pharmacokinetics). IV plasma clearance is 12 L/hr. After an oral dose, the major route of elimination of dabrafenib is metabolism, mediated via CYP3A4 and CYP2C8. Dabrafenib related material is excreted primarily in faeces, with 71 % of an oral dose recovered in faeces and 23 % in urine as metabolites only. (Reference 2)

PBT/vPvB assessment

Dabrafenib does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Dabrafenib does not fulfil the criteria for PBT and/or vBvP based on a BCF < 500.

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

2. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Tafinlar (Dabrafenib mesilate) 50mg and 75mg hard capsules. GlaxoSmithKline, March 2014.

3. Graham R and Alderman D. GSK2118436B: Activated Sludge Respiration Inhibition Test (Carbon and Ammonium Oxidation). Report No.8236109. Covance Laboratories Limited, July 2011.

4. Last G, Burke J, Flenely A and Jakes M. GSK2118436B: Inhibition of Growth to the Alga Pseudokirchneriella subcapitata. Report No. 8236106. Covance Laboratories Limited, April 2012.

5. Last G, Burke J, Flenely A and Jakes M. GSK2118436B: Chronic effects to Daphnia magna. Report No. 8236107. Covance Laboratories Limited, April 2012.

6. Last G, Burke J, Flenely A and Jakes M. GSK2118436B: Fish Early Life Stage Test (Pimephales promelas). Report No. 8236108. Covance Laboratories Limited, April 2012.

7. Last G and Jakes M. GSK2118436B: Sediment-Water Chironomus riparius Toxicity Test using Spiked Sediment. Report No. 8250285. Covance Laboratories Limited, April 2012.

8. Burwood C. GSK2118436B: Assessment of Inherent Biodegradability by Measurement of Carbon Dioxide Evolution with Specific Analysis. Report No. 8236103. Covance Laboratories Limited, May 2012.

9. Fletcher T, Dixon K, Gilbert J. [14C]-GSK2118436B: Degradation in Water-Sediment Systems under Aerobic Conditions. Report No. 8236105. Covance Laboratories Limited, April 2012.

10. Swales S. [14C]-GSK2118436B: Fish Bioconcentration Study. Report No. 8246812. Covance Laboratories Limited, April 2012.