Detaljerad miljöinformation

PEC/PNEC = 0.00904 µg/L / 0.09 µg/L = 0.1004

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is based on the 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)

PEC                 = 1.37* 10^-6 * 65.9603* (100-0)

= 0.00904µg/L

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

                        = 65.9603 kg/year

R (%)               = removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation = 0 (default)

P                      = number of inhabitants in Sweden = 10*10⁶ (default, Ref 1)

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

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

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

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. Unchanged budesonide has not been detected in urine (Ref 2). However the PEC does not take into consideration metabolism and therefore provides a worst-case exposure senario.

Ecotoxicity Data

Study Type	Method	Result	Reference
Activated sludge, respiration inhibition test	OECD 209	3 hour EC50 >1000 mg/L 3 hour NOEC = 1000 mg/L	3
Toxicity to green algae, Selenastrum capricornutum 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	4
Growth inhibition study Pseudokirchneriella subcapitata (previously Selenastrum capricornutum)	OECD 201	72 hour NOEC (growth rate) = 7.9 mg/L 72 hour LOEC (growth rate) > 7.9 mg/L 72 hour EC50 (growth rate) > 7.9 mg/L 72 hour NOEC (biomass) = 7.9 mg/L 72 hour LOEC (biomass) > 7.9 mg/L 72 hour EC50 (biomass) > 7.9 mg/L	5
Daphnia magna reproduction test under semi-static conditions	OECD 211	21 day NOEC = 3.36mg/L 21 day LOEC = 6.95mg/L	6
Acute toxicity to the giant water flea, Daphnia magna	OECD 202	48 hour EC50 (immobility) >14 mg/L 48 hour NOEC (immobility) = 3.8mg/L	7
Acute toxicity to Rainbow Trout, Oncorhynchus mykiss	OECD 203	96 hour LC50 (mortality) > 13 mg/L 96 hour NOEC (mortalitiy) = 13mg/L	8
Life-cycle toxicity test with the Zebrafish, Danio rerio	OECD review paper on fish lifecycle tests / OPPTS 850.1500	180/181 day NOEC(Male wet weight and length; F0 larval survival) = 0.9µg/L 180/181 day LOEC(Male wet weight and length; F0 larval survival) = 2.8µg/L	9
Toxicity to sediment dwelling midge, Chironomus riparius	OECD 218	28 day NOEC(development/emergence) = 890 mg/Kg (sediment dry weight) 28 day LOEC(development/emergence) > 890 mg/Kg (sediment dry weight)	10

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

PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. The PNEC is based on the chronic toxicity to Zebrafish (Danio rerio), the most sensitive species, and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 11).

PNEC = 0.9 µg/L /10 = 0.09 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00904 µg/L / 0.09 µg/L = 0.1004

This justifies the use of:

Use of budesonide has been considered to result in low environmental risk.

In Swedish: Användning av budesonid har bedömts medföra låg risk för miljöpåverkan.

Environmental Fate Data

Study Type	Method	Result	Reference
Determination of ready biodegradability	OECD301F	Mean degradation after 28 days = 2.2 % Not readily biodegradable	12
Adsorption/desorption to sediments, soils and sludge	OECD106	Mean ± SD Kd (ads) (5 soils) = 34.6 ± 16.6 Mean ± SD Koc (ads) (5 soils) = 1629 ± 1734	13
Aerobic transformation in aquatic sediment systems	OECD308	HOM DT50 (water) = 6.9 days LOM DT50 (water) = 6.45 days HOM DT50 (total system) = 18.1 days* LOM DT50 (total system) = 12.5 days HOM 14CO2 (98 DAT) = 54.8% AR LOM 14CO2 (98 DAT) = 86.2% AR <15% of applied radioactivity remaining as parent compound (0% in water + 3.8%* in sediment) at the end of the study	14

* Results calculated for the sum of [4-14C]budesonide and M23 as [4-14C]budesonide could not be sufficiently separated from its metabolite M23 by the HPLC method employed.

Degradation

The aerobic biodegradation of budesonide was assessed according to the OECD 301F Test. Results of this test indicates that budesonide is not readily biodegradable.

The adsorption and desorption of budesonide to five soils of differing characteristics was assessed in accordance with the OECD 106 Test Guideline. The reported Kd values ranged from 20 to 66 L/kg, with a derived mean of 34.6 L/kg. The corresponding Koc values were reported as ranging from 394 to 5049 L/kg with a derived mean of 1629 L/kg. Based on these results, budesonide is not expected to partition significantly to sludge solids during sewage treatment processes.

The degradation of budesonide in aquatic sediment systems was investigated according to the OECD 308 Test Guideline.The degradation of radiolabeled budesonide was investigated in a low organic matter (LOM) content (river) versus a high organic matter (HOM) content (pond) water-sediment system under both, aerobic and anaerobic conditions, over a 98-day testing period. Only the results for the aerobic test vessels are discussed here. The test item was applied to the water layer and, at day 0, 94.3% and 91.5% of applied radioactivity (AR) were present in the water of the LOM and HOM vessels, respectively. The amount of radiolabel in the water layer decreased to 7.8% AR (LOM) and 9.6% AR (HOM) at 98 days after treatment (DAT).

The amount of radioactivity associated with the sediment phase peaked at 30 DAT (49% AR in LOM, 69% in HOM) and subsequently decreased to 19% AR in LOM and 37% AR in HOM by the end of the study. The amount of budesonide parent remaining in the total system test was 1.9% (in LOM). In the HOM pond system, budesonide could not be sufficiently separated from metabolite M23, and therefore could not be quantified separately. At 98 DAT the amount of budesonide + M23 was 3.8% AR. The study showed significant mineralization, with cumulative ¹⁴CO₂ accounting for 86.2% AR and 54.8% AR in the LOM and HOM systems, respectively. All mass balances were acceptable.

Four major metabolites (>10% AR) were found in all systems (water and sediment in both river and pond systems) as either major or minor metabolites. These were identified by mass spectrometry. The total system degradation half-life of budesonide in the LOM (river) system was 12.5 days. In the HOM (pond) system, due to poor chromatographic separation, the degradation half-life of budesonide was calculated from the sum of budesonide and M23 and a conservative total system DT₅₀ of 18.1 days was derived.

As the highest DT₅₀ values reported passes the criteria of DT₅₀ ≤ 32d for the total system, and less than 15% budesonide was remaining as the parent compound at the end of the study the following phrase is therefore assigned:

Budesonide is degraded in the environment

In Swedish: Budesonide bryts ned i miljön.

Physical Chemistry Data

Study Type	Method	Result	Reference
Solubility Water	Unknown	14 mg/L at 25oC	15
Octanol-Water Partition Coefficient	OECD107	Log Pow = 3.45	16

Budesonide is not ionisable within the environmentally relevant pH range.  The Log octanol-water partition coefficient is 3.45, measured at pH 7.19.  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.

Bioaccumulation Data

Study Type	Method	Result	Reference
Bioaccumulation in tissues of carp, Cyprinus carpio	OECD305	BCFL at 3μg/L = 9 ± 3 Not bioaccumulative in fish	17

A fish bioconcentration study was conducted in carp, Cyprinus carpio, according to the OECD 305 Test Guideline. During the uptake phase, fish were exposed at nominal concentrations of 0.3 and 3.0 μg/L for 28 days. A steady state concentration was reached for both test concentrations after 3 days of exposure. The whole body bioconcentration factor at steady state (BCFss) was normalised for the lipid content and reported as 8 ± 3 at 0.3 μg/L and 9 ± 3 at 3.0 μg/L of budesonide. In the absence of any significant uptake, a depuration period was not required.

As a BCF < 500 was determined, the phrase:

“Budesonide has low potential for bioaccumulation” is assigned.

In Swedish: Budesonid har låg potential att bioackumuleras.

References

1. Fass.se (2012).  Environmental classification of pharmaceuticals at www.fass.se: Guidance for pharmaceutical companies https://www.fass.se/pdf/Environmental_classification_of_pharmaceuticals-120816.pdf

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

3. Budesonide: Activated sludge respiration inhibition test. R Harrigan & P Curtis-Jackson. Brixham Environmental Laboratory Report No BR0451/B. May 2011

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

5. Budesonide: Toxicity to green algae Pseudokirchneriella subcapitata determined in a growth inhibition study. Erica Tediosi, Desirée Garagna. ChemService S.r.l. Controlli e Ricerche Report 165/2013. July 2013.

6. Budesonide: Daphnia magna reproduction test under semi-static conditions. Erica Tediosi. ChemService S.r.l. Controlli e Ricerche Report 164/2013. September 2013.

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

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

9. Budesonide: A flow-through life-cycle toxicity test with the zebrafish (Danio rerio). Easton study number 123A-139. Eurofins EAG Agroscience, LLC. Maryland, USA. May 2023.

10. Sediment-water chironomid toxicity test using sediment spiked with Budesonide. M.J.E. Desmares-Koopmans, Bachelor, ERT. Charles River Laboratories Den Bosch B.V. Project 509587. July 2016.

11. 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

12. Budesonide: Ready biodegradability in a manometric respirometry test. Erica Tediosi ChemService S.r.l. Controlli e Ricerche Report CH-166/2013. July 2013

13. Budesonide: Determination of the adsorption / desorption coefficient Koc. Stefano Paronuzzi Ticco. ChemService S.r.l. Controlli e Ricerche Report 190/2013. September 2013.

14. [4-¹⁴C]Budesonide – Degradation in Two Different Aquatic Systems under Aerobic and Anaerobic Conditions. Dr. Rafal Piskorski. Innovative Environmental Services (IES) Ltd. May 2016.

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

16. Budesonide: Determination of the partition coefficient (n-octanol/water). Simona Nichetti. ChemService S.r.l. Controlli e Ricerche Report 169/2013. June 2013.

17. Bioaccumulation in fish with Budesonide (flow-through, aqueous exposure). L.M. Bouwman, MSc. Charles River Den Bosch B.V. Project 509585. August 2016

Detaljerad miljöinformation

PEC/PNEC = 0.000160 μg/L /94 μg/L = 1.71x10^-6

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)

PEC = 1.37*10^-6 *1.171*(100-R)                            

= 0.000160 µg/L

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

= 1.171 kg

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

hydrolysis or biodegradation)

= 0 (default)

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 waste water by surface water flow

= 10 (default, Ref 1)

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

(Note: Whilst formoterol is metabolised in the body, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as parent formoterol).

Metabolism and excretion

Formoterol is rapidly absorbed and inactivated via conjugation reactions to form O‑demethylated and deformylated metabolites. Pharmacokinetic studies report that 62% of the administered dose is recovered in urine and 24% in faeces, with urinary excretion of unchanged formoterol accounting for between 4 and 8% of the nominal dose (Ref. 2)

Ecotoxicity Data

Study Type	Method	Result	Reference
Toxicity to green algae, Selenastrum capricomutum, growth inhibition test	OECD201	72 hour NOECgrowth rate = 30 mg/L 72 hour LOECgrowth rate = 60 mg/L 72 hour EC50growth rate = 94 mg/L 72 hour NOECbiomass = 15 mg/L 72 hour LOECbiomass = 30 mg/L 72 hour EC50biomass = 46 mg/L	3
Acute toxicity to Daphnia magna	OECD202	48 hour NOEC = 55 mg/L 48 Hour EC50 = 144 mg/L	4
Acute toxicity to rainbow trout, Oncohynchus mykiss	OECD203	96 hour NOEC = 120 mg/L 96 hour EC50 > 120 mg/L	5

Predicted No Effect Concentration (PNEC)
Short-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the lowest relevant EC50 value, which was reported for the growth rate of the green algae (Selenastrum capricomutum), 94 mg/L (equivalent to 94,000 µg/L) and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref. 6).

PNEC = 94 000/1000 µg/L = 94 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC = 0.000160 µg/L

PNEC = 94 µg

PEC/PNEC = 1.71 x 10^-6

The PEC/PNEC ratio decides the wording of the aquatic environmental risk phrase, and the risk phrase for PEC/PNEC ≤ 0.1 reads as follows:“Use of formoterol fumarate dihydrate has been considered to result in insignificant environmental risk”. 

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

Environmental Fate Data

Study Type	Method	Result	Reference
Aerobic biodegradation	ISO 8727-1984E	20.6% biodegradation after 28 days. Not readily biodegradable	7

Physical Chemistry Data

Study Type	Method	Result	Reference
Octanol-water distribution coefficient	OECD 107	LogDOW @ pH 5 = -0.837 LogDOW @ pH 7 = 0.0633 LogDOW @ pH 9 = 0.0896	8
Water solubility	-	pH 6.4 at RT = 1.5g/L	9
Dissociation Constant	Potentiometric titration	pKa = 7.9 (Phenol) pKa = 9.2 (Amine)	9

Biodegradation

Based on the data above and lack of further studies, the phrase “Formoterol fumarate dihydrate is potentially persistent” is chosen.

In Swedish: “Formoterol fumarat dihydrat är potentiellt persistent ” under the heading ”Nedbrytning”.

Bioaccumulation

As formoterol fumarate dihydrate is ionisable within the environmentally relevant range, the octanol-water partition coefficient was measured at pH 5,7 and 9. As the LogD_OW results are all below 4, the phrase: ‘Formoterol fumarate dihydrate has low potential for bioaccumulation’ is therefore assigned.

In Swedish: ”Formoterol fumarat dihydrat har låg potential att bioackumuleras” under the heading ”Bioackumulering”.

References

1. Fass.se (2012). Environmental classification of pharmaceuticals at www.fass.se: Guidance for pharmaceutical companies https://www.fass.se/pdf/Environmental_classification_of_pharmaceuticals-120816.pdf

2. AstraZeneca Investigator’s Brochure Oxis® Turbuhaler® Edition 1 October 2003 Doc ID-000218391

3. Formoterol Fumarate Dihydrate: Toxicity to the green alga Selenastrum capricornutum. Brixham Environmental Laboratory, AstraZeneca, UK. Report BL8081 (2005).

4. Formoterol Fumarate Dihydrate: Acute toxicity to Daphnia magna. Brixham Environmental Laboratory, AstraZeneca, UK Report BL8082 (2005).

5. Formoterol Fumarate Dihydrate: Acute toxicity to Rainbow Trout (Oncorhynchus mykiss). Brixham Environmental Laboratory, AstraZeneca, UK. Report BL8083 (2005).

6. [ECHA] European Chemicals Agency.  Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0). February 2016.

7. Toxicon test report 59/93, “A026”. Toxicon, Landskrona, Sweden. January 1994.

8. Determination of the n-octanol/Water Partition Coefficient of Formoterol Fumarate by the Shake Flask Method, 123K-104, EAG, Inc., Easton, Maryland 2017

9. AstraZeneca S.1.3 General Properties Formoterol fumarate dihydrate micronized. Version 2.0 April 2014. Doc ID-000355139