Detaljerad miljöinformation

1. ENVIRONMENTAL RISK ASSESSMENT

Omnipaque will be distributed to hospitals and clinics in the market area to be used as a diagnostic agent in patients for intravenous, intra-arterial and intrathecal use, and for use in body cavities. Use of the finished product in patients will provide an entry path into the environment, via the sanitary sewage system. Iohexol is excreted unchanged in the urine. No metabolites have been detected (2).

Iohexol has not been found to be biodegradable by aerobic microorganisms, and did not exert any growth-inhibitory effect or toxicity on algae or Daphnia at a concentration of 3,200 mg/l. A limit test on fry of trout (Salmo rutta) showed no mortality of fish at an exposure to 1,000 mg/l of iohexol (1). These studies are detailed as follows:

The biodegradability of iohexol was measured over 28 days (1) 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 301F, 1993. The degradation was measured by the oxygen consumption (BOD, biochemical oxygen demand, expressed as mg oxygen uptake per mg test compound), as well as the dissolved organic carbon (DOC) removal. The results of this study indicated that iohexol is “not readily biodegradable” according to the OECD criteria, which require a DOC removal of 70% and a BOD of 60% in 28 days to be classified as “readily biodegradable”.

Table 1. Summary of the test results for biodegradability of iohexol

Test	Test concentration	BOD28	DOC-removal
Biodegradability	100 mg/L	0,01 mg/mg	None

As iohexol is not biodegradable by aerobic microorganisms, it is expected that the rate of degradation will be slow, i.e. iohexol is potentially persistent. With regard to the Fass guidance document, this data would result in a classification of “The substance is potentially persistent”, or in Swedish, “Läkemedlet är potentiellt persistent.”

The molecular weight of iohexol is 821.14. The solubility of iohexol in water is more than 1 g/ml at 4°C and 20°C. The bioaccumulation potential of iohexol was assessed according to OECD Guideline 107, 1981, “Partition coefficient (n-octanol/water), flask shaking method”. Substances with logPow values >4 are considered to have a significant potential for bioaccumulation. The results of this test gave a logPow value for iohexol of -0,5 indicating a low potential for bioaccumulation (1). With regard to the Fass guidance (2012), the following statements are appropriate for iohexol; The substance has low potential for bioaccumulation. In Swedish: Johexol har låg potential att bioackumuleras.

A first estimate of the predicted environmental concentration (PEC) 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 = 53218,24 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) (3)

D = factor for dilution of waste water by surface water = 10 (ECHA default) (3)

This results in the following estimate of PECwater for iohexol:

PECwater = 53218,24 kg x 10⁹ x 100/(365 x 9 x 10⁶ x 200 x 10 x 100) = 8,100189 μg/L

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 base set toxicity tests comprise 1) algae, growth inhibition test, 2) Daphnia sp. toxicity test, 3) fish, acute toxicity test.

The growth inhibitory effect of iohexol on a fresh water green alga, Selenastrum capricornutum Prinz, was determined according to OECD Guideline 201, 1984. No toxicity was observed at the highest concentration of 3200 mg/L over a period of 3 days, therefore the Algal 72 hr EC₅₀ was >3200 mg/L (1).

The potential of iohexol to cause acute immobilisation in the fresh water crustacean Daphnia magna Straus was evaluated according to OECD Guideline 202, 1984. No toxicity was observed at the highest concentration of 3200 mg/L, therefore the Daphnia 24 h EC₅₀ was >3200 mg/L (1).

The acute toxic effects of iohexol were tested on young Atlantic salmon (Salmo salar) according to OECD Guideline 203, 1984. No toxicity was observed at the highest concentration of 1000 mg/L over a period of 4 days, therefore the Fish 96 hr LC₅₀ (endpoint) was >1000 mg/L (1).

Table 2. Summary of the test results for aquatic toxicity tests with iohexol

Tests	Results
Alga, Growth Inhibition Test	Algal 72 hr EC50 was >3200 mg/L
Daphnia sp. Acute Immobilisation Test	Daphnia 48 hr EC50 was >3200 mg/L
Fish, Acute Toxicity Test	Fish 96 hr LC50 was >1000 mg/L

The PECwater : PNECwater = 5,60 / 1000 = 0,0056. According to the Fass guidance (2012), a PEC/PNEC ≤ 0,1 provides the aquatic risk phrase of “Use of iohexol has been considered to result in insignificant environmental risk.”, or in Swedish “Användning av johexol har bedömts medföra försumbar risk för miljöpåverkan”.

REFERENCES

1) Norwegian Institute for Water Research, NIVA. Report No 0-93268, 1993.

2) Holtz E. Omnipaque (iohexol) solution for injection X-ray contrast medium. Toxico-Pharmacological Expert Report. December 20 2000.

3) 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