Detaljerad miljöinformation

PEC/PNEC = 0.009/8.6 = 0.0011

PEC/PNEC ≤ 0.1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is based on following data and calculated using the equation outlined in the fass.se guidance (Ref 1):

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

PEC (µg/L) = 1.37*10^-6*A*(100-R)

A (Kg/year) = 65.9603 kg total sold amount API in Sweden year 2023, data from IQVIA.

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization,

hydrolysis or biodegradation) = 0

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 (default, Ref. 1)

D = factor for dilution of wastewater by surface water flow = 10 (default, Ref. 1)

(Note: The factor 10⁹ converts the quantity used from kg to μg)

PEC = 1.37 * 10^{-6 *} 70.1 * (100-0) = 0.009 µg/L

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of budesonide is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 μg/L.

Metabolism and excretion

After oral inhalation budesonide undergoes an extensive degree (>90%) of biotransformation to metabolites of low corticosteroid activity on first passage through the liver. The activity of the major metabolites, 6β-hydroxy-budesonide and 16α-hydroxy-prednisolone, is less than 1% of the parent compound. The plasma elimination half-life is approximately 4 hours. No or trace amounts of unchanged drug were found in the urine after intravenous administration (Ref. 2).

Only trace amounts of budesonide are excreted unchanged in the urine of patients. As such, environmental exposure of budesonide resulting from patient use is expected to be negligible; however, the PEC does not take into consideration metabolism and therefore provides a worst-case exposure scenario.

PNEC (Predicted No Effect Concentration)

Ecotoxicity Data

Study Type	Method	Result	Reference
Toxicity to green algae, Pseudokirchinella subcapitata, growth inhibition test	OECD 201	72 hour NOEC (growth rate) = 5.6 mg/L 72 hour LOEC (growth rate) = 8.6 mg/L 72 hour EC50 (growth rate) > 8.6 mg/L 72 hour NOEC (biomass) = 5.6 mg/L 72 hour LOEC (biomass) = 8.6 mg/L 72 hour EC50 (biomass) > 8.6 mg/L	3
Acute toxicity to the giant water flea, Daphnia magna	OECD 202	48 hour EC50 (immobility) >14 mg/L	4
Acute toxicity to Rainbow Trout, Oncorhynchus mykiss	OECD 203	96 hour LC50 (mortality) > 13 mg/L	5

NOEC No Observed Effect Concentration

LOEC Lowest Observed Effect Concentration

EC50 the concentration of the test substance that results in a 50% effect

LC50 the concentration of the test substance that results in a 50% mortality

Environmental risk classification (PEC/PNEC ratio)

Short-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. For all three species, the EC50 values were greater than the highest test concentration and the limit of solubility of budesonide in the test medium. Therefore, to obtain a worst case PNEC value, the lowest limit of solubility of budesonide in the test media, reported for the algal study, is used. The PNEC is based on the lowest >EC50 value 8.6 mg/L (equivalent to 8600 µg/L) and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref. 6).

PNEC = 8600 /1000 = 8.6 μg/L

Environmental risk classification (PEC/PNEC ratio)

PEC = 0.009 µg/L

PNEC = 8.6 µg/L

PEC/PNEC = 1.1 x 10^-3

The PEC/PNEC ratio is < 0.1 which justifies the phrase "Use of budesonide has been considered to result in insignificant environmental risk".

In Swedish: “Användning av budesonid har bedömts medföra försumbar risk för miljöpåverkan” under the heading “Miljörisk”.

Environmental Fate Data

Budesonide is extensively metabolized (>90%), and only trace amounts of budesonide are excreted unchanged in the urine of patients. As such, environmental exposure of budesonide resulting from patient use is expected to be negligible. Budesonide cannot be considered as readily biodegradable and based on the octanol-water partition coefficient the risk of bioaccumulation in aquatic organisms is low.

Environmental Fate Data for Budesonide

Study Type	Method	Result	Reference
Aerobic biodegradation	OECD301E	Degradation after 7 days <8% Not readily biodegradable	7

Degradation

Biotic degradation

Budesonide is not biologically readily biodegradable (Ref. 7). Since data from further degradation tests is lacking, the phrase ‘Budesonide is potentially persistent’ is used under the heading Biodegradation.

In Swedish: ”Läkemedlet är potentiellt persistent” under the heading ”Nedbrytning”.

Bioaccumulation

Budesonide is not ionisable within the environmentally relevant pH range. The Log octanol-water partition coefficient is 3.3, measured at pH 7.4. Since Log P < 4, budesonide has low potential to bioaccumulate and the phrase “Budesonide has low potential for bioaccumulation” is assigned.

In Swedish: Budesonid har låg potential att bioackumuleras” under the heading ’Bioackumulering’.

Physical Chemistry Data

Study Type	Method	Result	Reference
Solubility Water	Unknown	14 mg/L at 25 °C	8
Octanol-Water Partition Coefficient	Unknown	Log Kow = 3.3

References

1. Fass.se (2021). Environmental classification of pharmaceuticals at www.fass.se: Guidance for pharmaceutical companies https://www.fass.se/pdf/Environmental_classification_of_pharmaceuticals-120816.pdf.pdf

2. Investigator’s Brochure. Drug Substance Budesonide/formoterol. Project Code D5890000000. Edition Number 9. Date 31 May 2016.

3. Budesonide: Toxicity to the green alga Selenastrum capricornutum. Bowles A.J. Brixham Environmental Laboratory Report BL8078/B. May 2005.

4. Budesonide: Acute toxicity to Daphnia magna. Bowles A.J. Brixham Environmental Laboratory Report BL8079/B. May 2005.

5. Budesonide: Acute toxicity to rainbow trout (Oncorhynchus mykiss). Bowles A.J. Brixham Environmental Laboratory Report BL8080/B. May 2005.

6. ECHA (European Chemicals Agency) 2008. Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

7. Nedbrytbarhetsförhållanden för läkemedelssubstansen A002. Institutet för vatten- och luftvårdsforskning (IVL). IVL-rapport A92017. (Safety Assessment rapport SR99433-01).

8. Budesonid - preformuleringsrapport. Report no. 83 – 014. Draco, Lund, Sweden. 1 February 1983.