Detaljerad miljöinformation

Detailed background information

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R)/(365*P*V*D*100) = 1.37*10^-6*A(100–R)

PEC = 8.41 x 10^-4μg/L

Where:

A = 6.14 kg (total sold amount API in Sweden year 2023, derived from all salt forms, data from IQVIA).

R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation).

P = number of inhabitants in Sweden = 10 *10⁶

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

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

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of Beclomethasone dipropionate is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 μg/L.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

All data refers to Beclomethasone dipropionate

Algae:

No data

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 3.74 μg/L (OECD 202) (Reference 6)

Water flea (Ceriodaphnia dubia):

Chronic toxicity

No data

Bluegill sunfish (Lepomis macrochirus):

Acute toxicity

LC50 48 h (lethality) = 1,600 μg/L (OECD 203) (Reference 8)

Chronic toxicity

No data

Other ecotoxicity data:

Microorganisms in activated sludge:

EC50 3 h (inhibition) = 97,200, µg/L (OECD 209) (Reference 2)

Sediment toxicity

Blackworm (Lumbriculus variegates):

EC50 28d (lethality) > 500,000 µg/kg (OECD 218) (Reference 12)

Terrestrial toxicity

Manure worm (Eisenia foetida):

LC50 28d (lethality) > 750,000 µg/kg (TAD 4.12) (Reference 9)

PNEC cannot be calculated because data is not available for all three (algae, crustacean and fish) of the toxicity endpoints.

Environmental risk classification (PEC/PNEC ratio)

Risk of environmental impact of beclomethasone cannot be excluded, since there is not sufficient ecotoxicity data available.

Degradation

All data refers to Beclomethasone dipropionate

Biotic degradation

Ready degradability:

3% degradation in 28 days (TAD 3.11) (Reference 7)

Inherent degradability:

No Data

Soil Metabolism:

21.9-61.5% degradation in 64 days (TAD 4.12) (Reference 8)

Abiotic degradation

Hydrolysis:

50% degradation (pH 7) in 166 h (TAD 3.09) (Reference 11)

Photolysis:

No data

Justification of chosen degradation phrase:

Beclomethasone is not readily biodegradable. There are no data for inherent biodegradation. The phrase “beclomethasone is potentially persistent” is thus chosen.

Bioaccumulation

All data refers to Beclomethasone dipropionate

Bioconcentration factor (BCF):

Partitioning coefficient:

Log Pow = 3.49 (TAD 3.04). (Reference 10)

Justification of chosen bioaccumulation phrase:

Since log Pow < 4, the substance has low potential for bioaccumulation.

For the active metabolite, beclomethasone-17-monopropionate, there is low potential to bioaccumulate in aquatic organisms. Log Pow_calculated = 3.5 @ pH 7.4 (Reference 2).

Excretion (metabolism)

Beclomethasone dipropionate is a prodrug with weak pharmacological activity but once clinically administered it is extensively hydrolyzed into its active metabolite beclomethasone-17-monopropionate (Reference 3). There are two minor metabolites, beclomethasone-21-monoprppionate and beclomethasone, which are inactive. Approximately 60 % of dose is excreted in the faeces as free and conjugated polar metabolites (Reference 4).

PBT/vPvB assessment

Beclomethasone does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Beclomethasone does not fulfil the criteria for PBT and/or vBvP based on log Pow < 4.

Please, also see Safety data sheets on http://www.msds-gsk.com/ExtMSDSlist.asp.

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

2. ACD /LogD. September 2011. Advanced Chemistry Development, Inc.

3. Martin LE, et al, Clin Pharmacol Ther 15:267-275, 1974.

4. Lipworth, Br J Clin Pharmacol 42:697-705, 1996.

5. Jenkins WR. AH15720AA: Activated Sludge – Respiration Inhibition Test. Report No. WPT/94/026. Pharmaco LSR Ltd, January 1995.

6. Jenkins CA. AH15720AA: Acute Toxicity to Daphnia magna. Report No. WPT/94/026. Pharmaco LSR Ltd, December 1994.

7. Jenkins WR. AH15720AA: Biotic Degradation with Acclimatised Composite Inoculum. Modified Sturm Test. Report No. WPT/94/026. Pharmaco LSR Ltd, January 1995.

8. O’Connor J. AH15720AA: Biodegradation in Soil. Report No. WPT/94/026. Pharmaco LSR Ltd, December 1994.

9. Wetton PM and Bartlett AJ. AH15270AA: Earthworm Subacute 28-Day Toxicity Test. Report No. WPT/93/113. Safepharm Laboratories Ltd, February 1996.

10. Colwyn TC. AH15270AA: Determination of Physico-Chemical properties. Report No. WPT/94/026. Pharmaco LSR Ltd, December 1994.

11. Colwyn TC. AH15270AA: Determination of Hydrolysis as a Function of pH. Report No. WPT/94/026. Pharmaco LSR Ltd, December 1994.

12. Sewell IG and McKenzie J. Beclomethasone Dipropionate: A Prolonged Toxicity Test Using Spiked Sediment with the Oligochaete, Lumbriculus variegatus. Report No. 1127/307. Safepharm Laboratories Ltd, July 2004.

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).