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Gadovist®

Bayer

Injektionsvätska, lösning 1 mmol/ml
(klar, färglös till blekt gul lösning)

Paramagnetiskt kontrastmedel för magnetisk resonanstomografi (MRT)

Aktiv substans:
ATC-kod: V08CA09
Utbytbarhet: Ej utbytbar
Läkemedel från Bayer omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Gadobutrol (vattenfri)

Miljörisk: Användning av gadobutrol (vattenfri) har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Gadobutrol (vattenfri) är potentiellt persistent.
Bioackumulering: Gadobutrol (vattenfri) har låg 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 =  81.94073 kg (total sold amount API in Sweden year 2018, 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 = 9 *106

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

D = factor for dilution of wastewater by surface waterflow = 10 (ECHA default)

PEC = 0.012 μg/L


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus):

Growth inhibition
NOEC/72 h = 937 mg/L
LOEC/72 h = 2062 mg/L (guideline OECD 201) (1)


Crustacean (waterflea Daphnia magna):

Acute toxicity

EC50 /48 h (immobilization) >1000 mg/L (guideline OECD 202) (2)

Chronic toxicity

NOEC /21 days (immobilization, reproduction) ≥ 1 mg/L
LOEC /21 days > 1 mg/L (guideline OECD 211) (3)


Fish:

Acute toxicity (Zebrafish Danio rerio)

LC50 /96 h (mortality) = >100 mg/L (guideline OECD 203) (4)

Chronic toxicity (Fathead minnow Pimephales promelas)

Early life-stage test (Hatching, mortality growth) (guideline OECD 210) (5)
NOEC /28 days ≥ 1 mg/L
LOEC >10 mg/L


Different microorganisms
(Pseudomonas putida, Azotobacter beijerinckii, Apergillus niger, Caetomium globosum, Nostoc ellipsosporum) 

Growth inhibition test

Minimum inhibitory concentration (MIC) /<1-10 days (growth) > 1000 mg/L (guideline FDA TAD 4.02) (6)

PNEC = 100 μg/L (Lowest NOEC Daphnia magna >1000 µg/L; AF 10)


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0,012/100 = 0,00012, i.e. PEC/PNEC <0,1 which justifies the risk phrase "Use of Gadobutrol has been considered to result in insignificant environmental risk."


Degradation

Biotic degradation

Ready degradability: not ready biodegradable

The aerobic biodegradability of gadobutrol in water was investigated in accordance with the FDA guideline FDA TAD 3.11 (7). In a modified CO2-evolution test over 28 days, which was preceded by a pre-adaptation period of 14 days, the test compound attained 4 % biodegradation according to the CO2 production in three replicates, therefore it is possible that little amounts of Gd in the sediment resulted from that solution. At the end of the incubation, there was a slight increase of the Gd concentration in the sediment that was supposed to be related to the introduced substance.

Since Gadobutrol is not ready degradable and gadolinium containing contrast agents are generally known as stable complexes, the phrase “Gadolbutrol is potentially persistent in the environment” is applicable.


Abiotic degradation

Hydrolysis:

Gadobutrol is hydrolytically stable (8)


Bioaccumulation

Partitioning coefficient:

Log POW -5.4 (Shake flask method, FDA TAD 3.02) (9)

Justification of chosen bioaccumulation phrase:

Since log POW was -5.4, the substance was considered to have a low potential for bioaccumulation.

Excretion (metabolism)

Gadobutrol is introduced unmetabolized as parent compound (contrast agent).


PBT/vPvB assessment

Gadobutrol is not PBT/vPvB, because the log POW was lower than 4.5 and it is not toxic.


References

  1. Growth inhibition test of Gadobutrol on the green algae Chlorella vulgaris. Nonclinical Drug Safety, Schering AG, Report no. AM32, Study no. TX96038 (1996).

  2. Acute immobilization test of gadobutrol with Daphnia magna. Experimental Toxicology, Schering AG, Report no. AK12, Study no. TX94.066 (1994).

  3. Reproduction study of Gadovist® (ZK 135079) in Daphnia magna. Nonclinical Drug Safety, Bayer Schering Pharma AG, Report no. A30908, Study no. TXST20050144 (2005).

  4. Acute toxicity of Gadovist® (ZK 135079) to the Zebrafish Danio rerio. Nonclinical Drug Safety, Bayer Schering Pharma AG, Report no. A29954, Study no. TXST20050265 (2005).

  5. ZK135079: Early life-stage toxicity test with fathead minnow (Pimephales promelas) under flow-through conditions. Nonclinical Drug Safety, Bayer Schering Pharma AG, Report no. A51566, study no. T3078909EXT; Springborn Smithers study no.1121.003.122 (2005)

  6. Microbial growth inhibition test of gadobutrol with Pseudomonas putida, Azotobakter beijerinckii, Aspergillus niger, Chaetomium globosum, and Nostoc ellipsosporum. Schering AG, Experimental Toxicology, Report no. AB91, Study no. TX94.084 (1994)

  7. Study of aerobic biodegradation of gadobutrol. Schering AG, Experimental Toxicology, Report no. AC43, Study no. TX94.064 (1994).

  8. The rate of hydrolysis of gadobutrol (ZK 135079). Schering AG, General Physical Chemistry, Report no. L391, study no. 94/070 (APC), (1994)

  9. The octanol/water partition coefficient of gadobutrol (ZK 135079). Schering AG, General Physical Chemistry, Report no. L388, Study no. 91/180 (APC) (1991)