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Bayer

Filmdragerad tablett 200 mg
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Miljöpåverkan (Läs mer om miljöpåverkan)

Sorafenib

Miljörisk: Användning av sorafenib har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning: Sorafenib är potentiellt persistent.
Bioackumulering: Sorafenib har hög potential att bioackumuleras.


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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) = 1.5*10-6*A(100-R)

Where:

A = 20.4996 kg (total sold amount API in Sweden year 2015, data from IMS Health).
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 = 9 *106 

V (L/day) = volume of waste water per capita and day = 200 (ECHA default)

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

PEC = 0.0031 μg/L


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae growth inhibition study

Demodesmus subspicatus

NOEC /72 h (growth rate) = ≥0.536 µg/L (guideline OECD 201) (1)

Crustacea chronic toxicity study

Daphnia magna reproduction study

≥ 0.860 µg/L (NOEC/21d; reproduction, mortality) (guideline OECD 211) (2)

Fish chronic toxicity study

Fathead minnow (Pimephales promelas), early life-stage test (guideline OECD 210) (3)

<1.0 µg/L (NOEC/28d; length, weight, mortality),  1.0 µg/L (LOEC/28d; length, weight, mortality)
0.47 µg/L (EC10/28d; weight),
0.32 µg/L (EC10/28d; length)
0.17 µg/L (EC10/28d; mortality)

Microorganisms

Activated sludge, respiration inhibition test

>32 mg/L (EC50, 30min), (guideline OECD209) (4)

The lowest EC10 (fish ELS test, mortality) of 0.17 µg/L is used for deriving the PNEC.

PNEC = 0.17 x 0.1 [AF] = 0.017 µg/L


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0.0031/0.017 = 0.2 , i.e. PEC/PNEC 0.1-1.0, which justifies the phrase Use of sorafenib has been considered to result in low environmental risk.


Biodegradation

Sorafenib is not readily biodegradable; OECD 301F (5).

Sorafenib (as tosylate) was studied for aerobic biodegradability in water in a manometric respiration test according to guideline OECD 301F. Sorafenib was introduced into the test system at a concentration of 200 mg/L as theoretical oxygen demand. There was no degradation after 28 days. The reference substance (sodium diacetate) was degraded to more than 60 % within 14 days and the toxicity control did not indicate an inhibiting effect on microorganisms.

Sorafenib showed no degradation in a water-sediment system (OECD 308) (6).

The transformation of [14C] sorafenib in sediments and natural water was assessed in two different aerobic sediment/water systems at a temperature of

19-23 °C over 114 days continuously in the dark. Radioactivity of [14C] sorafenib in sediment was quantified by combustion analysis and radioassay. The water fraction was measured by liquid scintillation counting (LSC). Hydrochloric acid was added to the soda lime fraction and evolving 14CO2 was absorbed in a scintillation cocktail and analysed by LSC. The distribution of [14C] sorafenib to the sediment compartment and the disappearance from the water fraction was determined by plotting the radioactivity over time. The half-lives of [14C] sorafenib were 0.5 and 0.6 days for the two sampling locations in the overlying water. The total mass balance accumulated to 98.2 and 99.9 % for the tow sampling locations (day 29). Towards the end of the incubation period, only 74.0 and 75.4 % of the total radioactivity was recovered. This is most likely due to the binding of test material to the glass surface of the test vessels. Only slight ultimate biodegradation was observed in the test systems. The accumulative amount of evolved 14CO2 for the both test systems was 0.3 and 0.4 % of the applied radioactivity. In both aquatic/sediment systems the major part of the introduced test material was found in the sediments (up to 99 %).

Sorafenib is potentially persistent.


Bioaccumulation

The octanol/water partition coefficient (logPow) was determined with 3.7 according to OECD117 (7).

In a fish bioaccumulation test, bluegill sunfish (Lepomis macrochirus) were exposed to sorafenib (C-14 labelled) over 26 days at concentrations of 0.04 µg/l and 0.032 µg/L.

The BCFs was determined with 5300 for the higher concentration and >7300 for the lower concentration, where no steady-state was reached (8).

This justifies that sorafenib has a high potential for bioaccumulation.


Excretion (metabolism)

Sorafenib is excreted in unmetabolized form and as metabolites such as glucoronides and coboxylic acid.


References

  1. Growth inhibition test with sorafenibtosylate (BAY54-9085) on the green-algae Desmodesmus subspicatus. Bayer Schering Pharma AG, Nonclinical Drug Safety, Report no. A42279, study no. TOXT2078665, 2009

  2. Reproduction study of sorafenibtosylate (BAY54-9085) in Daphnia magna. Bayer Schering Pharma AG, Nonclinical Drug Safety, Report no. A42837, study no. TOXT3079089, 2009

  3. Early life-stage test of sorafenibtosylate (BAY54-9085) in the fathead minnow (Pimephales promelas). Bayer Schering Pharma AG, Nonclinical Drug Safety, Report no. A44229, study no. TOXT5079595, 2009

  4. Respiration inhibition test of sorafenibtosylate (BAY54-9085) on activated sludge microorganisms. Bayer Schering Pharma AG, Nonclinical Drug Safety, Report no. A44292, study no. TOXT7079605, 2009

  5. Study on the biodegradability of sorafenibtosylate (BAY54-9085) in the manometric respiration test. Bayer Schering Pharma AG, Nonclinical Drug Safety, Report no. A41886, study no. TOXT9078635, 2009

  6. Aquatic sediment study (aerobic) with [C14] sorafenibtosylate ([C-14] BAY54-9085). Bayer Schering Pharma AG, Nonclinical Drug Safety, Report no. A42733, study no. TOXT7078697, 2009

  7. Sorafenib tosylate/ (BAY54-9085)/ Report on physicochemical properties/ partition coefficient n-octanol/water (HPLC method). Bayer Schering Pharma AG, Analytical Development Physical Chemistry, Report no. Bayer Schering Pharma AG, Nonclinical Drug Safety, Report no. A44292, study no. 08100223, 2008

  8. Bioaccumulation study of sorafenib in fish (Lepomis macrochirus). Bayer Schering Pharma AG, Nonclinical Drug Safety, Report no. A51426, study no. TOXT7082142, 2009

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