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Visipaque

GE Healthcare

Injektionsvätska, lösning 270 mg I/ml
(Klar, från färglös till blekgul injektionsvätska)

Dimeriskt, icke-joniskt röntgenkontrastmedel för intravaskulärt och intratekalt bruk samt för användning i kroppskaviteter

Aktiv substans:
ATC-kod: V08AB09
Utbytbarhet: Ej utbytbar
Läkemedel från GE Healthcare omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Jodixanol

Miljörisk: Användning av jodixanol har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Jodixanol är potentiellt persistent.
Bioackumulering: Jodixanol har låg potential att bioackumuleras.


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Detaljerad miljöinformation

1. ENVIRONMENTAL ISSUES

Visipaque contains the active moiety, iodixanol, an iodinated dimeric molecule that contains six iodine atoms, present in the formulation at a concentration of 270 or 320 mg I/mL. The major route of Visipaque administration to patients is by intravascular injection, and this will provide an entry path for iodixanol into the environment. There is no measurable metabolism of iodixanol in the human body. It is rapidly distributed to the extracellular fluid, does not penetrate cells, and is excreted unchanged in the urine at a rate that is governed by the glomerular filtration rate (GFR). The mean elimination half-life is 2 hours, with approximately 80% of the administered dose recovered unmetabolized in the urine within 4 hours, and 97% within 24 hours after intravenous injection in healthy volunteers. Only about 1.2% of the injected dose is excreted in faeces within 72 hours. For the purposes of environmental assessment, therefore, it can be assumed that patients will excrete in the urine and faeces 100% of the administered iodixanol into the environment via the sewage system and the publicly owned treatment works (POTWs) as the intact molecule.

  • Water Solubility: Freely soluble in water (>1 g/ml) [3]

  • Dissociation Constants: Not Applicable

  • Octanol/Water Partition coefficient (log Pow): -4.05 [3]

  • *Vapour Pressure: 1E-015 mm Hg

  • *Henry's Law Constant: 2.04E-021 Atm-m3/mol

  • * Air-water partition coefficient: 8.34E-020

*calculated values (7)


Biodegradability (2)

The biodegradability and depletion was measured according to iso/dis 9408 water quality - evolution in an aqueous medium of the "ultimate" aerobic biodegradability of organic compounds - method by determining the oxygen demand in a closed respirometer.

Biodegradability of iodixanol was measured over 28 days in a two phase system (air/water), with the test item as the sole carbon source for the micro-organisms from activated sludge according to OECD Guideline 301 (2). The degradation was measured by the oxygen consumption [BOD, biochemical oxygen demand], as well as the dissolved carbon [DOC] removal. Although a low but significant BOD was recorded, iodixanol is classified as "not readily degradable" according to the OECD criteria, which requires a DOC removal of 70% in 28 days to be classified as "readily degradable". With regard to the Fass guidance (2012), this data would result in a classification of “The substance is potentially persistent”, or in Swedish, “Läkemedlet är potentiellt persistent.”

Test

Test concentration

BOD28

DOC-removal

Biodegradability

100 mg/L

4

2%


Bioaccumulation potential (3)

Bioaccumulation of organic compounds is closely linked to physical chemical properties such as water solubility and lipophilicity. The partitioning of the substance between water and an organic phase such as octanol is taken to be a measure of bioaccumulation potential. The octanol/water coefficient (log Pow) was determined to be -4.05 (3). The partition coefficients of iodixanol were determined by the addition of 1-octanol to a solution of iodixanol. The amount of iodixanol in the alcohol phase was determined by direct measurement of the UV absorbance at 245nm. Such a low octanol/water coefficient value indicates a low potential for bioaccumulation. With regard to the Fass guidance (2012), the following statements are appropriate for iodixanol; The substance has low potential for bioaccumulation. In Swedish: Jodixanol har låg potential att bioackumuleras.


Environmental Concentrations:


A first estimate of the predicted environmental concentration in surface waters receiving the discharge of sewage facilities was calculated according to the formula:


PEC (μg/L) = A x 109 x (100-R)/(365 x P x V x D x 100)


Where A = 6186,868 kg (amount sold in Sweden in 2019, data from IQVIA)


R (%) = removal rate = 0;


P = number of inhabitants = 9 x 106


V = volume of waste water per capita and day = 200 l (ECHA default) (8)


D = factor for dilution of waste water by surface water = 10 (ECHA default) (8)


This results in the following estimate of PECwater for iodixanol:


PECwater = 6186,868 kg x 109 x 100/(365 x 9 x 106 x 200 x 10 x 100) = 0,9417 μg/L


Based on the medical use of the agent (primarily intravascular administration), followed by rapid urinary excretion of the unchanged molecule, iodixanol will enter the aquatic environment via the sewage system and the publicly owned treatment works (POTWs). Once having entered the aquatic environment, measurements of biodegradability and depletion indicate that the rate of depletion will be slow. Potential for accumulation in the terrestrial compartment is low, as although iodixanol is water soluble, it has a low octanol/water partition coefficient and is therefore not expected to bioconcentrate or to be adsorbed onto biosolids to an appreciable extent. Potential for accumulation in the atmospheric compartment is also low due to its medical use as an intravascularly administered agent, and its physical chemical properties which show that it will not volatilize significantly.


Estimation of the predicted no effect concentration (PNEC):


This is based on the following formula:


PNEC = EC/AF, where EC is the lowest value of the LC50 or EC50 from acute toxicity tests in aquatic organisms, and AF, the assessment factor, is set at 1,000.


The tests conducted were in accordance with the Tier 2 testing as defined by the FDA guideline (1) and comprised the aquatic base set of (a) a fish acute toxicity test, (b) an aquatic invertebrate acute toxicity test, and (c) an algal species bioassay. The effects of iodixanol on aquatic organisms has been tested for bioaccumulation potential (log Pow), biodegradability and depletion, and toxicity to algae, daphnia and fish according to the OECD Guidelines for Testing of Chemicals.


Fish, Acute Toxicity Test (4)

Acute toxic effects on fish were tested according to OECD 203, "Fish Acute Toxicity Test" (OECD 1984). The test system was young Atlantic salmon (Salmo salar). Treatment was for 4 days, and the end point of toxicity was the number of fish killed. No toxicity was observed at the highest concentration of 1000 mg/L, therefore the Fish 96 hour LC50 was > 1000 mg/L.


Daphnia sp. Acute Immobilisation Test (5)

This invertebrate test was carried out according to ISO 6341 Water Quality – Determination of the inhibition of the mobility of Daphnia magna Straus (Cladocera, Crustacea). The test procedure is in accordance with OECD Guideline 202 - "Daphnia sp acute immobilization test" (OECD 1984). Young Daphnia magna were exposed to iodixanol and the numbers of immobilized animals recorded at 24 and 48 hours. No toxicity was observed at the highest concentration of 2500 mg/L, therefore the Daphnia EC50 (48 hrs) was >2500 mg/L.


Alga, Growth Inhibition Test (6)

The test was carried out according to ISO 8692 Water Quality - Algal growth inhibition test. The test was also in accordance with OECD Guideline 201 "Alga, growth inhibition test (OECD 1984). The test system was exponentially growing cultures of a fresh water green alga, Selenastrum capricornutum Prinz. The test endpoint was the average growth rate in relation to control culture over 72 hours treatment. No toxicity was observed at the highest concentration of 3200 mg/L therefore the Algal EC50 (72 hrs) was >3200 mg/L.


Summary of aquatic toxicity tests:

Fish, Acute Toxicity Test Fish 96 hr LC50 = > 1000 mg/L


Daphnia sp. Acute Immobilisation Test Daphnia 24 hr EC50 (48 hrs) = >2500 mg/L.


Alga, Growth Inhibition Test Algal 72 hr EC50 = >3200 mg/L.


Since no toxicity was observed, the lowest possible LC50 seen in fish = 1000 mg/L.


PNEC (μ/L) = LC/AF = 1000000 μg/L (fish) / 1000 μg/L = 1000 μg/L


The PECwater : PNECwater = 1,024 / 1000 = 0,001


According to the Fass guidance (2012), a PEC/PNEC ≤ 0,1 provides the aquatic risk phrase of “Use of Iodixanol has been considered to result in insignificant environmental risk.”, or in Swedish “Användning av Jodixanol har bedömts medföra försumbar risk för miljöpåverkan”.


DISCUSSION


The major route of Visipaque administration to patients is by intravascular injection, there is no measurable metabolism of iodixanol in the human body, and virtually 100% of the administered dose is rapidly excreted in the urine. Iodixanol administered to patients therefore enters the aquatic environment via the sewage system and the publicly owned treatment works (POTWs) as the intact molecule. Due to its medical use as an intravascularly administered agent, and its physical chemical properties which show that it is not volatile, it is considered unlikely to enter the atmospheric compartment.


Although it is expected that the rate of degradation of iodixanol in the environment will be slow, because of the low octanol/water partition coefficient (logPow = -4.05) it is not expected to bioconcentrate. This, together with the low toxicity in the base set long-term toxicity tests in algae, Daphnia and fish, and the PEC/PNEC ≤ 0,1, supports the risk phrase of “Use of Iodixanol has been considered to result in insignificant environmental risk.”, or in Swedish “Användning av Jodixanol har bedömts medföra försumbar risk för miljöpåverkan” for iodixanol.


MITIGATION MEASURES


The tier 2 aquatic base set comprising fish, Daphnia and algae demonstrated that the no-effect level for toxicity divided by the EIC was several orders of magnitude greater than the assessment factor of 100. It is therefore concluded that no further testing of iodixanol is required.


ALTERNATIVES TO THE PROPOSED ACTION

No alternative courses of action are considered necessary.


REFERENCES


(1) FDA Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications. July 1998, CMC 6, Revision 1


(2) Biodegradability of organic compounds in aquatic medium. ISO/DIS 9408. Norwegian Institute for Water Research, NIV A. Lab Code B00511. 1992


(3) Eivindvik, K., Sjøgren, C.E. Physicochemical properties of Iodixanol. Acta Radiol. 36 (Suppl 399): 32-38, 1995.


(4) Fish, acute toxicity. OECD 203. Norwegian Institute for Water Research, NIVA. 1992


(5) Daphnia acute immobilisation test. ISO 6341, OECD 202. Norwegian Institute for Water Research, NIVA. Lab Code B005/1. 1992


(6) Alga, growth inhibition test. ISO DIS 8692, OECD 201. Norwegian Institute for Water Research, NIVA. Lab Code B00511. 1992


(7) STP Fugacity Model: Predicted fate in a wastewater treatment facility using Biowin/EPA draft method. U.S. Environmental Protection Agency: Exposure Assessment Tools and Models. EPI Suite v3.l2. 2000.


(8) 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