Detaljerad miljöinformation

PEC/PNEC = 0.00015 μg/L /94 μg/L = 1.6*10^-6 → PEC/PNEC = ≤ 0.1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is based on following data:

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

PEC (µg/L) = 1.5*10^-6*A*(100-R)

A (kg/year) = total sold amount API in Sweden year 2017, data from IQVIA (former IMS Health and Quintiles). 

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

hydrolysis or biodegradation) = 0 if no data is available.

P = number of inhabitants in Sweden = 9 *10⁶

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

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

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

A =  1.00 kg

R = 0

PEC = 1.5 * 10^-6 * 1.00 * (100-0) = 0.00015 μg/L

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

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

^{Note 1: Concentrations were confirmed by analysis, and results expressed as nominal.}

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 = 0.00015 µg/L /94 µg/L =1.6*10^-6

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

Note 2: This data is experimental derived but the study pre-dates current ERA regulatory requirements and may not have been undertaken to standard test guidelines.

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 = 0.41, pH 7.4 @ 25 °C (ref. 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”. 

Physical Chemistry Data

^{Note 2: This data is experimental derived but the study pre-dates current ERA regulatory requirements and may not have been undertaken to standard test guidelines.}

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. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment (Table R10.4). May 2008. 

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

8. A026: Algae, Growth inhibition test, Daphnia magna, acute immobilisation test, Fish Acute toxicity test, Biodegradability. Toxicon. Report no: 59/93 (1994)

Detaljerad miljöinformation

PEC/PNEC = 0.000042 µg/L /33.0 µg/L = 0.0000013 → PEC/PNEC ≤ 0.1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The PEC is based on the following data:

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

PEC (µg/L) = 1.5*10^-6*A*(100-R)

A (kg/year) = total sold amount API in Sweden year 2017, data from IQVIA (former IMS Health and Quintiles).

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation) = 0 if no data is available.

P = number of inhabitants in Sweden =9*10⁶

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

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

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

A= 0.2809 kg

R= 0

PEC = 1.5 * 10^-6 *0.2809 *(100-0) = 0.000042 µg/L

Metabolism 

Up to 23% of the delivered dose was found in urine as parent drug (ref 2).

Ecotoxicity Data

Predicted No Effect Concentration (PNEC)

PNEC (μg/L) = lowest EC50/1000, where 1000 is the assessment factor used if acute toxicity data for three trophic levels is available. EC50 for Daphnia magna has been used for this calculation since it is the most sensitive of the three tested species.

PNEC = 33.0 μg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000042 µg/L /33.0 µg/L = 0.0000013

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 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

Biodegradation

Based on the data above the phrase “Glycopyrronium bromide is potentially persistent” is chosen.

In Swedish: “Glykopyrronium bromidär potentiellt persistent” under the heading “Nedbrytning”.

Bioaccumulation

Since Log P < 4 the phrase “Glycopyrronium bromide has low potential for bioaccumulation” is assigned.

In Swedish: ”Glykopyrronium bromid 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. Novartis SmPC for SEEBRI™ BREEZHALER^® (Glycopyrronium bromide), July 2018

3. Fass.se

   Miljöinformationen för glykopyrron är framtagen av företaget Novartis för Enurev Breezhaler, Seebri Breezhaler, Tovanor Breezhaler, Ultibro Breezhaler, Ulunar Breezhaler, Xoterna Breezhaler

   • Harlan Laboratories Study C13436. Toxicity of NVA237 A5 to Pseudokirchneriella subcapitata in a 72-hour algal growth inhibition test. Final report: 28 January 2009.

   • Harlan Laboratories Study C13425. Acute toxicity of NVA237 A5 to Daphnia magna in a 48-hour immobilization test. Final report: 28 January 2009.

   • Harlan Laboratories Study C10040. Acute toxicity of NVA237 A5 to zebra fish (Brachydanio rerio) in a 96-hour test. Final report: 28 January 2009.

   • Harlan Laboratories Study C13447. Ready biodegradability of NVA237 A5 in a DOC Die-Away test. Final report: 09 February 2009.

   • Harlan Laboratories Study C13403. Determination of the water solubility and the partition coefficient (n-octanol/water). Final report: 15 June 2009.

4. 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