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