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Gadovist®

MiljöinformationReceptstatusFörmånsstatus
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?

Miljöpåverkan (Läs mer om miljöpåverkan)

Gadobutrol (vattenfri)

Miljörisk: Användning av gadobutrol har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Gadobutrol är potentiellt persistent.
Bioackumulering: Gadobutrol 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)
= 1.5*10-6*43,9253[kg]*100

Where:

A =  43.9253 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 wastewater per capita and day = 200 (ECHA default)

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

PEC = 0.00659 μg/L


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus):

NOEC/72 h (growth inhibition, growth rate) 937 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 /21d (reproduction) = ≥ 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)

NOEC 28d (post hatch) (hatching, survival, weight, length) ≥ 10 mg/L (guideline OECD 210) (5)

Microorganisms (bacteria, yeast, mold, green algae, blue-green algae)

MIC (minimal inhibitory concentration) >1000 mg/L (guideline USA 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: 0.00659/100 = 0.000659, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase Use of gadobutrol has been considered to result in insignificant environmental risk.


Degradation

Biotic degradation

Ready degradability: Not readily 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.


An investigation of the aerobic biodegradability of Gadovist® in a laboratory scale sewage treatment plant (LSSTP) was conducted according to DIN 38412 part 26 and DIN 38414 part 2 (8) (7) and confirmed these results. The test substance gadobutrol was continuously dosed into a LSSTP for 49 days. Additionally, a control LSSTP was operated without dosage of test substance. The LSSTPs were inoculated with activated sludge from a municipal sewage treatment plant. Prior to the dosing with the test substance the activated sludge was adapted for 49 days in the plants. Synthetic sewage was continuously added to the LSSTPs as concentrate. The elimination of gadobutrol from the sewage was determined with a HPLC/UV method specific for gadobutrol. Degradation of the synthetic sewage concentrate as a measure for the function of the LSSTP was determined by measurement of the dissolved organic carbon (DOC) in the inflow and the effluent of the LSSTPs. Degradation of the synthetic sewage to more than 80 % is a quality criteria for a stable run. During the adaptation phase, where a continuous supply of synthetic sewage concentrate was performed, the degradation in the LSSTPs was between 87.8 and 99.8%. It was therefore concluded, that the activated sludge was viable and active for the whole time of the experiment. On average, sludge growth and sludge index did not differ between control and dosed plant. It could be concluded that gadobutrol had no inhibitory effects on the sludge biocoenosis. The test compound gadobutrol was not degraded after 47 days of incubation. After flocculation with FeCl3, only 24 % of the test substance could be detected in the effluent.


Abiotic degradation

Hydrolysis:

Stable (pH 4, 7, 9, 25ºC) (FDA TAD 3.09) (9)

The studies on biodegradability in the screening assay and the waste water treatment plant simulation test and the abiotic degradation showed that gadobutrol is recalcitrant to microbiological activity and chemical transformation in the environment.

Gadobutrol is potentially persistent.


Bioaccumulation

Partitioning coefficient:

Log POW -5.4 (FDA TAD 3.02) (10)

Justification of chosen bioaccumulation phrase:

The log POW of -5.4 justifies the phrase:

Gadobutrol has low potential for bioaccumulation.

Excretion (metabolism)

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


PBT/vPvB assessment

Gadobutrol is not PBT/vPvB.


References

  1. Growth inhibition test of gadobutrol on the green algae Chlorella vulgaris. Schering AG, Experimental Toxicology, Report no. AM32, Study no. TX96038

  2. Acute immobilization test of gadobutrol with Daphnia magna. Schering AG, Experimental Toxicology, Report no. AK 12, Study no. TX94066

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

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

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

  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. TX94084

  7. Study of aerobic biodegradation of gadobutrol. Schering AG, Experimental T oxicology, Report no. AC43, Study no. TX94067

  8. Study on the biodegradability of Gadovist (gadobutrol, ZK 135079) in a laboratory scale sewage treatment plant. Bayer Schering Pharma AG, Non-clinical Drug Safety, Report no. A33289, Study no. TXST20060119

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

  10. The n-octanol/water partition coefficient of gadobutrol (ZK 135079). Schering AG, General Physical Chemistry, report no. L388, study no. 91/180 (APC)