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Filmdragerad tablett 40 mg
(Ljusrosa filmdragerade tabletter, ovala med en längd på 16 mm och en bredd på 7 mm, präglade med ”BAYER” på ena sidan och ”40” på den andra sidan.)

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ATC-kod: L01XE21
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Miljöinformation

Miljöpåverkan

Regorafenib

Miljörisk: Särskilt miljöfarliga egenskaper
PBT/vPvB-klass: I enlighet med EU:s fastställda kriterier ska substansen betraktas som en PBT/vPvB-substans


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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 = amount sold (0.92064 kg)
R = Removal rate (0)
P = number of inhabitants= 9*106
V = Volume of wastewater per capita/day = 200L (ECHA default)
D = dilution factor of wastewater by surface water flow = 10 (ECHA default)

Total amount in kg: 0.92064 kg (year 2018) (data from IQVIA)
PEC Sweden: 1.5*10-6*0.92064 kg (100-0) = 0.00014 µg/L


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus):

NOEC /72 h (growth rate) = 0.13 µg/L, LOEC /72h (growth rate) = 0.69 µg/L (guideline OECD 201) (1)


Crustacean (waterflea Daphnia magna):

Chronic toxicity

NOEC /21 days (survival of parent) = 10.5 µg/L, LOEC /21 days = 27.7 µg/L (guideline OECD 211) (2)

Fish:


Chronic toxicity (fathead minnow Pimephales promelas)

NOEC 28 days post hatch (survival) 0.007 µg/L, LOEC / 28 days post hatch (survival) 0.02 µg/L (guideline OECD 210) (3)


Microorganisms

Activated sludge respiration inhibition

NOEC/3 h (respiration) >40000 µg/L (5)

PNEC: Lowest chronic NOEC 0.007 µg/L; assessment factor 10
0.1 x 0.007 µg = 0.0007 µg/L


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio [µg/L]: 0.00014: 0.0007 = 0.2


The calculated PEC/PNEC ratio is ≤ 1. Hence, risk assessment procedures would indicate that “regorafenib” would have low long-term risk to the environment. However, the half-life in the environment is >120 days, the BCF is >2000 and the chronic toxicity is <0.01 mg/L (NOEC). “regorafenib” should therefore be regarded as a PBT substance, according to the ECHA Guidance criteria, and as such the current PEC/PNEC ratio may underestimate the potential for long-term risks to aquatic organisms.


Degradation

Biotic degradation

Regorafenib is not ready biodegradable; OECD 301F (5). Regorafenib was studied for aerobic biodegradability in water in a manometric respiration test according to guideline OECD 301F. Regorafenib was introduced into the test system at a concentrations of 200 mg/L as theoretical oxygen demand. There was 0% 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.

The transformation of Regorafenib was studied a water-sediment system (OECD 308) (7).

The transformation of [14C] Regorafenib in sediments and natural water was assessed in two different aerobic sediment/water systems at a temperature of 19-23 °C over 100 days continuously in the dark. Radioactivity of [14C] Regorafenib 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] Regorafenib to the sediment compartment and the disappearance from the water fraction was determined by plotting the radioactivity over time. The total mass balance accumulated to 104% and 113% for both sampling locations, respectively. No ultimate biodegradation was observed in the test system. Regorafenib disappeared from the water phase within 24 hours to more than 50%. In sediments, the [14C] Regorafenib fraction remained on a level between 67 and 107% with no time dependency. Therefore, it can be concluded that Regorafenib was not degraded within 100 days in the aquatic sediment system.

The overall degradation half-life from the system was >120 days. Therefore, the degradation half-life above 120 days justifies the phrase: Regorrafenib is potentially persistent.


Abiotic degradation

Hydrolysis:

Not determined due to low water solubility


Bioaccumulation

Partitioning coefficient:

Log Pow 3.7 at pH7 [OECD 117] (6)

In a fish bioconcentration study (7) with Regorafenib, fish (bluegill sunfish Lepomis macrochirus) were exposed to 14C-labeled regorafenib at two concentrations (nominally 0.16 and 1.6 µg/L) and additionally to the control for a period of 28 days. Subsequently, the fish were depurated over a period of 14 days. Two replicate tanks for the test concentrations and one tank for the control were used. Concentration in water and fish tissue were analysed by radioassay.

The BCFss (bioconcentration factor at steady state) was 2874 and 4444 for group 2 and 3, respectively. Based on lipid normalized (6%) values, the BCFss was 2653 and 4102 for group 2 and 3, respectively


Justification of chosen bioaccumulation phrase:

The bioconcentration factor of >500 justifies the phrase: Regorafenib has a high potential for bioaccumulation.


According to the established EU criteria, the compound should be regarded as a PBT substance.


References

  1. Growth inhibition test with Regorafenib (BAY 73-4506) on green algae (Desmodesmus subspicatus). Nonclinical Drug Safety, Bayer Pharma AG, study no. T102316-3, report no. PH-39194 (2016)

  2. Reproduction study of Regorafenib (BAY 73-4506) in Daphnia magna. Nonclinical Drug Safety, Bayer Pharma AG, study no. T102349-7, report no. PH-37250 (2013)

  3. Early-Life-Stage-Test Fish with Regorafenib (BAY 73-4506). Nonclinical Drug Safety, Bayer Pharma AG, study no. T100932-5, report no. PH-38249 (2014)

  4. Respiration inhibition test of Regorafenib (BAY 73-4506) on activated sludge micro-organisms. Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TOXT8081559, report no. A51602 (2011)

  5. Respiration inhibition test of Regorafenib (BAY 73-4506) on activated sludge micro-organisms. Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TOXT3082139, report no. A51400 (2011)

  6. Aquatic-sediment study (aerobic) with Regorafenib[BAY 73-4506(14-C)]. Nonclinical Drug Safety, Bayer HealthCare AG, study no. TOXT1082461, report no. A53445 (2012)

  7. Bioconcentration flow-through fish test with Regorafenib [BAY73-4506(14-C)]. Nonclinical Drug Safety, Bayer HealthCare AG, study no. TOXT9082937, report no. A57715 (2012)