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AstraZeneca

Inhalationspulver 340 mikrogram/12 mikrogram
(vitt eller nästan vitt pulver)

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  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Aklidinium

Miljörisk: Risk för miljöpåverkan av aklidinium kan inte uteslutas då ekotoxikologiska data saknas.
Nedbrytning: Det kan inte uteslutas att aklidinium är persistent, då data saknas.
Bioackumulering: Aklidinium har låg potential att bioackumuleras.


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Detaljerad miljöinformation

The Predicted Environmental Concentration (PEC) / Predicted No Effect Concentration (PNEC) ratio has not been determined due to insufficient ecotoxicity data.


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) = 2.12 kg = total sold amount API in Sweden year 2016, data from QuintilesIMS.

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

P = number of inhabitants in Sweden = 9*106

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


PEC = 1.5 * 10-6 * 2.12 * (100-0) = 0.00032 µg/L


Metabolism and excretion

Aclidinium bromide inhalation powder is indicated as a maintenance bronchodilator treatment to relieve symptoms in patients with chronic obstructive pulmonary disease (COPD).


Following intravenous administration of 400 µg radiolabelled aclidinium bromide, approximately 1% of the dose was excreted as unchanged aclidinium bromide in the urine. Up to 65% of the dose was eliminated as metabolites in the urine and up to 33% as metabolites in the faeces (Ref 2).


Following inhalation, the urinary excretion of unchanged aclidinium was very low at about 0.1% of the administered dose, indicating that renal clearance plays a minor role in the total aclidinium clearance from plasma (Ref 3).


Predicted No Effect Concentration (PNEC)

The Predicted No Effect Concentration (PNEC) has not been determined due to insufficient data.

PNEC = Not determined.


Environmental Risk Classification (PEC/PNEC ratio)

The PEC / PNEC ratio has not been determined due to insufficient data. Therefore, the risk of environmental impact of aclidinium bromide cannot be excluded.


In Swedish: Risk för miljöpåverkan av aklidiniumbromid kan inte uteslutas då ekotoxikologiska data saknas.


Biodegradation

No environmental fate or degradation data are available. Therefore, the potential for persistence of aclidinium bromide cannot be excluded, due to lack of data.


In Swedish: Det kan inte uteslutas att aklidiniumbromid är persistent, då data saknas. 


Bioaccumulation Data

Aclidinium bromide is not ionisable within the environmentally relevant pH range. The octanol water partition coefficient, measured at pH 7.4, is low (Log Pow <4). Therefore, aclidinium bromide has low potential for bioaccumulation.


In Swedish: Aklidiniumbromid har låg potential att bioackumuleras.


Physical Chemistry Data

Study Type

Method

Result

Reference

Octanol-water distribution coefficient

OECD107, Chromatographic

Hydrophobicity Index method

log Pow = 1.9 at pH 7.4

4

Water Solubility

Not stated

0.6 g/L

5

Disassociation Constant

Estimated

pKa = 10.35

pKa = -4.8

6


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. http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

  2. Ortiz S, Flach S, Ho J, Fanying L, Caracta C.F, Garcia Gil E and Jansat J.M, 2012. Mass balance and metabolism of aclidinium bromide following intravenous administration of [14C]-aclidinium bromide in healthy subjects. Biopharmaceuticals and Drug Disposition, 33: 39–45

  3. STUDY NO. LAS-PK-12. A Randomized Multiple Dose, Placebo Controlled, Single Blind Clinical Trial to Assess the Safety, Tolerability, and Pharmacokinetics of Aclidinium Bromide Administered Twice Daily by Inhalation in Healthy Volunteers. February 2011

  4. Determination of partition coefficient in Octanol/water (logP) of Aclidinium bromide. AE-11-269-HPLC. November 2011.

  5. AstraZeneca Internal Document: Aclidinium bromide S.1.3 GENERAL PROPERTIES

  6. Drug Bank. Aclidinium bromide. Available at

    https://www.drugbank.ca/drugs/DB08897Accessed 20/07/2017

Formoterol

Miljörisk: Användning av formoterol har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Formoterol är potentiellt persistent.
Bioackumulering: Formoterol har låg potential att bioackumuleras.


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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

Endpoint

Species

Common Name

Method

Time

Result

Ref

EbC50 - Based on Area under the Growth Curve







Pseudokirchneriella subcapitata (formerly known as Selenastrum caprico-rnutum)







Green Alga







OECD 201







72 h

46 mg/L

Note 1

3

NOEC - Based on Area under the Growth Curve

15 mg/L

 Note 1

LOEC - Based on Area under the Growth Curve

30 mg/L

Note 1

ErC50 - Based on Logarithmic Growth Rate

94 mg/L

Note 1

LOEC - Based on Logarithmic Growth Rate

60 mg/L

Note 1

NOEC - Based on Logarithmic Growth Rate

30 mg/L

Note 1

EC50 – Based on Immobilisation



Daphnia magna



Giant Water Flea



OECD 202



48 h

114 mg/L Note 1

4

NOEC - Based on Immobilisation

55 mg/L

Note 1

LC50



Oncorhynchus mykiss



Rainbow Trout



OECD 203



96 h

>120 mg/L Note 1

5

NOEC - Based on Mortality & Symptoms of Toxicity

120 mg/L Note 1

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

Endpoint

Method

Test Substance Concentration

Time

Result

Ref

Partition Coefficient Octanol Water

Note 2

-

-

Log D = 0.41 @ pH 7.4

7

Percentage DOC Removal

ISO 7827-1984 (E)

40 mg /L

Dissolved Organic Carbon

28 d

20.5 %

8

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

Endpoint

Method

Test Conditions

Result

References

Solubility Water




Note 2






-



1500 mg/L @ pH 6.4





7



Dissociation Constant

pKa = 7.9 (Phenol)

Dissociation Constant

pKa = 9.2 (Amine)

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)