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)

Where:

A = 0.96 kg (total sold amount API in Sweden year 2020, 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 = 10x10⁶

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

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Ref. I)

Based on the above formula and data the PEC was calculated as 0.00013 μg/L.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Latin name): Not available

Crustacean (Latin name): Not available

Acute toxicity

Not available

Chronic toxicity

Not available

Fish (Latin name): Not available

Acute toxicity

Not available

Chronic toxicity

Not available

Other ecotoxicity data: Not available

Environmental risk classification (PEC/PNEC ratio)

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of Cabozantinib-(S)-Malate is unlikely to present a risk to the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit (0.01 μg/L). As a result, no studies were conducted to determine the fate or the aquatic ecotoxicity of Cabozantinib-(S)-Malate, following release to the environment.

As Cabozantinib-(S)-Malate is considered potentially persistent in and there have been no ecotoxicity studies conducted, it is not possible to rule out potential chronic toxicity to aquatic species. Therefore, the phrase ‘Risk of environmental impact of Cabozantinib-(S)-Malate cannot be excluded’ is applicable.

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of Cabozantinib-(S)-Malate is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 μg/L.

Enligt den europeiska läkemedelsmyndigheten EMA:s riktlinjer för miljöriskbedömning av läkemedelssubstanser (EMA/CHMP/SWP/4447/00), bedömdes det vid registreringstillfället vara osannolikt att användningen av Cabozantinib-(S)-Malate kommer att medföra en miljörisk, då det förväntas att användningen ger en koncentration i miljön (PEC) som bli lägre än tröskelvärdet 0,01 μg/L.

Degradation

Biotic degradation

Ready degradability:

Information on ready biodegradability of Cabozantinib-(S)-Malate is not available.

Inherent degradability:

Information on inherent biodegradability of Cabozantinib-(S)-Malate is not available.

Simulation studies:

STP simulation studies and/or test results in water, sediment and total system are not available for Cabozantinib-(S)-Malate.

Abiotic degradation

Hydrolysis:

Information on hydrolysis is not available.

Photolysis:

Information on photolysis in water is not available

As Cabozantinib-(S)-Malate is not readily biodegradable, and simulation studies are not available, the default value R = 0 was used for removal rate. However, this is considered to represent a worst-case approach for Cabozantinib, as modelling results using SimpleTreat suggest that within STP about 10% is removed to sludge, and 90% is emitted to the effluent water (EPIWIN 18% emitted; 82% removed in sludge and <1% biodegraded)

Photodegradation

In the atmosphere Cabozantinib could be removed by chemical reaction with radicals, by photolysis and by wet or dry deposition. The degradation time is assumed to be limited by the reaction with the hydroxyl radical (OH•). The rate coefficient (k_OH) was estimated using AOPWIN in EpiSuite.

k_OH = 194.2 x 10^-12 cm³/molecule-sec at 298 K corresponding to a half-life of 0.028 days.

Adsorption to soil

Estimations via EpiSuite show K_OC values of 3.01 x 10⁵ L/kg (log K_OC = 5.5) (MCI Method) and 6835 L/kg (log K_OC = 3.8) (KOW Method).

Using the log Pow and the recommended QSAR of the TGD for hydrophobics in EUSES, results in a K_OC of 18685.3 L/kg.

Weight of Evidence approach, geometric mean of QSAR results: K_OC = 33798.9 L/kg (log K_OC = 4.53)

Thus, Cabozantinib is potentially immobile in soils and sediments (according to P.J. McCall et al.,1981) (Ref II)

Volatilisation

Distribution of cabozantinib between air and water (Henry’s law constant - HLC) was estimated using HENRYWIN in EpiSuite.

HLC = 7.36 X 10^-16 Pa-m³/mol) HENRYWIN (V3.20):

The estimated values indicate low volatility of cabozantinib.

Justification of chosen degradation phrase:

Based on the information that Cabozantinib-(S)-Malate is not readily biodegradable, and reliable simulation studies are not available, the phrase “Cabozantinib-(S)-Malate is potentially persistent” is thus chosen.

Bioaccumulation

Bioconcentration factor (BCF):

Bioconcentration of ¹⁴C-Cabozantinib-(S)-Malate in Bluegill (Lepomis macrochirus) was investigated in a flow-through system according to the OECD Test Guideline 305 and under GLP (Ref III). Bioconcentration was evaluated at two nominal concentrations 1.0 μg/L (low dose) and 10.0 μg/L (high dose). Measured concentrations throughout testing ranged from approximately 75.0 to 88.8% of the nominal (low dose) and 72.2 to 102% of the nominal (high dose). Overall mean measured concentrations were 82% and 85% of nominal (0.82 and 8.5 μg/L). The fish were exposed to ¹⁴C-Cabozantinib-(S)-Malate in water for 25 days (uptake phase), followed by a 55-day depuration period with no exposure. Fish and exposure media were sampled seven times during the uptake phase ( days 0, 1, 3, 7, 14, 21 and 24) and 8 times during the depuration phase (on days 1, 3, 7, 10, 14, 21, 28 and 42 of the test) and analysed for ¹⁴C-Cabozantinib-(S)-Malate by liquid scintillation counting (LSC). There were two mortalities in the solvent control, 5 mortalities in the low treatment group and 4 mortalities in the high treatment group which were considered to incidental and not test substance related. Overall mortality over the duration of the test was 6%. One fish in the low treatment group was observed to be lethargic. Steady state concentrations of ¹⁴C-Cabozantinib-(S)-Malate in fish were achieved after approximately 24 days of exposure at both concentrations. The steady state bioconcentration factor (BCF_SS) was 280 and 266 for the low and high dose, respectively (whole fish), 118 and 152 for the low and high dose, respectively (edible portion) and 418 and 373 for the low and high dose, respectively (non-edible portion). Based on these data, Cabozantinib-(S)-Malate is considered not bioaccumulative.

Partitioning coefficient:

The n-octanol/water partition coefficient was determined using the slow-stir method OECD Test Guideline 123 (Ref IV). The partition coefficient (as log D_OW) was reported to be 7510 equivalent to a log D_OW of 3.88 at pH 5 and 142000 equivalent to a log D_OW of 5.15 at pH 7.4.

Justification of chosen bioaccumulation phrase:

Since BCF < 500, Cabozantinib-(S)-Malate has low potential for bioaccumulation.

Excretion (metabolism)

Cabozantinib is a highly permeable compound with a generally rapid absorption after oral administration. Absolute bioavailability of the malate salt of cabozantinib administered via an oral capsule is moderate to high in dog and rat, respectively. There are four major metabolites, of which the 6-desmethyl half-dimer sulphate (M2a) and the monohydroxysulphate (M4) are the most important (Ref V)). The pharmacological activity of the metabolites is not known. As a worst-case scenario it is assumed, for the purpose of this classification, that 100% of excreted metabolites have the same ecotoxicity as the parent carbozantinib.

PBT/vPvB assessment

According to the established EU criteria, Cabozantinib-(S)-Malate is not PBT or vPvB

All three properties, i.e., ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Ref VI). Cabozantinib-(S)-Malate does not fulfil the criterion for B based on a BCF<2000.

References

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

II. McCall P.J., Laskowski D.A., Swann R.L., and Dishburger H.J., (1981), “Measurement of sorption coefficients of organic chemicals and their use, in environmental fate analysis”, in Test Protocols for Environmental Fate and Movement of Toxicants. Proceedings of AOAC Symposium, AOAC.

III. Wildlife International (2015). Study Report 750A-102 – Cabozantinib (S)-Malate: An aqueous exposure bioaccumulation test with the bluegill (Lepomis macrochirus).

IV. Wildlife International (2013). Study Report 750C-102 – Determination of the 1-octanol/water partition coefficient of Cabozantinib (s)-Malate by the slow-stirring method

V. European Medicines Agency (EMA). Committee for Medicinal products for Human Use (CHMP) 2016. CHMP Public Assessment report: Cabometyx.

VI. European Chemicals Agency (ECHA) 2017. Guidance on Information Requirements and Chemical Safety Assessment Chapter R.11: PBT/vPvB Assessment. Version 3.0. Reference: ECHA-17-G-12-EN.