Detaljerad miljöinformation

PEC/PNEC = 0.000050 μg/L /94 μg/L = 0.5*10^-7

PEC/PNEC ≤ 0.1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The PEC is based on the following calculation:

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 *0.34*(100-0)

= 0.000050 µg/L

Where;

A (kg/year) = total sold amount API in Sweden year 2020, data from IQVIA  

= 0.34 kg

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 L/day (Ref 1)

D = factor for dilution of waste water by surface water flow

= 10 (Ref 1)

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

Metabolism and excretion

The major part of the dose of formoterol fumarate dihydrate is eliminated via metabolism. After inhalation, 8-13% of the delivered dose is excreted unmetabolised in the urine. (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 test have been undertaken for species from three trophic levels, based on internationally accepted guidelines. The most sensitive species of these is the green alga, Pseudokirchneriella subcapitata (formerly known as Selenastrum capriocornutum), and the growth rate end point has been applied. Therefore, the PNEC is based on the growth rate results (EC50) from the toxicity to P subcapitata study, and an assessment factor of 1000 is applied in accordance with ECHA guidance (Ref 6).

PNEC = 94 000/1000 = 94 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000050 µg/L /94 µg/L = 0.5*10^-7

PEC/PNEC ≤ 0.1 

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	20.5% biodegradation after 28 days. Not readily biodegradable	6

Physical Chemistry Data

Study Type	Method	Result	Reference
Octanol-water distribution coefficient	Shake flask	pH 5 logDOW = 0.146 pH 7 logDOW = 1.18 pH 9 logDOW = 7.85	7
Dissociation Constant	Potentiometric titration	pKa = 7.9 (Phenol) pKa = 9.2 (Amine)	8

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

Partition coefficient Octanol/Water

Log D = 1.18 at pH 7

Since Log D < 4 the phrase ‘Formoterol fumarate dihydrate has low potential for bioaccumulation’ is assigned.

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

References

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

2. Determination of absolute pulmonary bioavailability of formoterol when given via Turbuhaler® to healthy volunteers. Report No. 37-CR-3004. January 1995.

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. A026: Biodegradability. Report no: 59/93, Toxicon, Landskrona, Sweden. 10 January 1994

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

8. Marketing, S1-03 general Properties, Formoterol Fumarate Dihydrate. AstraZeneca report BD4179 (2009).

Detaljerad miljöinformation

PEC/PNEC = 0.00012 µg/L / 33.0 µg/L = 0.0000036 = 3.6 x 10^-6

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The 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 *0.8938*(100-0)

= 0.00012 µg/L

Where;

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

= 0.8938 kg

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

P                      = number of inhabitants in Sweden = 10 x 10⁶

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

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

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

Metabolism and excretion

Following inhalation, up to 23% of the delivered dose was found in urine as parent drug (Ref. 2).

Ecotoxicity Data

Study Type	Method	Result	Reference
Toxicity to green algae, Pseudokirchneriella subcapitata	OECD 201	72h ErC50 (growth rate) > 100mg/L NOEC = 7.5mg/L	3
Acute toxicitiy to the giant water flea, Daphnia magna	OECD 202	48h EC50 = 33.0mg/L
Acute toxicity to the Zebrafish, Danio rerio	OECD 203	96h LC50 > 100mg/L

Predicted No Effect Concentration (PNEC)

Short term data is available for species from three trophic levels. The PNEC is therefore based on the lowest EC50, for Daphnia magna, with an assessment factor of 1000 applied in accordance with ECHA guidance (Ref. 4).

PNEC = 33.0 mg/L / 1000 = 33.0 μg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00012 µg/L / 33.0 µg/L = 0.0000036 = 3.6 x 10^-6

As the PEC/PNEC ratio is ≤ 0.1, the following risk statement in assigned:

Use of glycopyrronium bromide has been considered to result in insignificant environmental risk.

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

Environmental Fate Data

Study Type	Method	Result	Reference
Ready biodegradability	OECD 301A	0% degradation in 28 days Not readily biodegradable	3
Octanol water partition coefficient	OECD 107	Log DOW = -2.1
Octanol water partition coefficient	OECD 107	LogDOW, pH 7 = -1.63	5

Biodegradation

Based on the results of the OECD 301A study and since no additional relevant environmental fate data is available, the following phrase is applied: Glycopyrronium bromide is potentially persistent.

In Swedish: Glykopyrronium bromid är potentiellt persistent.

Bioaccumulation

As the measured LogD_OW < 4 at pH 7, the following phrase applies: Glycopyrronium bromide has low potential for bioaccumulation.

In Swedish: Glykopyrronium bromid 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. Annex 1: SmPC for SEEBRI™ BREEZHALER^® (Glycopyrronium bromide), Novartis Europharm Limited. December 2021.

3. Fass.se - Glykopyrroniumbromid Accord. Miljöpåverkan (Miljöinformationen för glykopyrron är framtagen av företaget Novartis). Accessed 14 Jan 2025.

4. 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  

5. 123K-102. Determination of the n-octanol/Water Partition Coefficient of Glycopyrronium by the Shake Flask Method. Project Number 123K-102. EAG, Inc. Easton, Maryland 21601. January 2018