Detaljerad miljöinformation

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 = 9.98 x10^-5 μg/L

Where:

A = 0.7280 kg (total sold amount API in Sweden year 2021, data from IQVIA Health).

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)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae:

No data

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 12 μg/L (OECD 202) (Reference 4)

NOEC = 12 μg/L

Chronic toxicity

No data

Fish (Pimephales promelas):

Acute toxicity

No data

Chronic toxicity

LOEC 116 days > 0.58 μg/L (OECD 210/234) (Reference 8)

NOEC = 0.58 μg/L

Other ecotoxicity data:

Microorganisms in activated sludge:

EC50 3 h (inhibition) > 1,000,000 μg/L @ 3 hrs (OECD 209) (Reference 4)

Earthworm (Eisenia foetida):

LC50 14 days (lethality) > 1,000,000 μg/kg (OECD 207) (Reference 5)

NOEC = 1,000,000 μg/Kg

PNEC = 0.58/10 = 0.058 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for one long-term NOECs but where there is a high degree of confidence that the dataset includes the most sensitive species (fish) and addresses the specific mode of action (endocrine disruption). On this basis the NOEC for fish has been used in the calculation.

PNEC Justification

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

However, fluticasone furoate is a glucocorticoid and, as such, is considered as a potential endocrine active substance and therefore the potential endocrine activity of this compound was investigated in an appropriate chronic vertebrate test system with relevant end points. Accordingly, GSK has conducted a fish early life-stage test, as per OECD 210, as a range-finder to set concentrations for an extended early life-stage test, exposing newly fertilised embryos until they reached sexual maturity (OECD 234). This study concluded that no statistically significant effects were observed between the controls and any of the test concentrations in terms of hatching success, post-hatch survival, growth, spawning ability or secondary sexual characteristics.  Due to the mode of action of fluticasone furoate and its potential to act as an endocrine active substance there is a high degree of confidence that fish is the most sensitive species and on that basis there is a strong justification for applying an AF of 10 (Reference 1).

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 9.98 x10^-5 /0.058 = 1.72 x10^-3, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of fluticasone furoate has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

No Data

Inherent degradability:

0% degradation in 28 days (OECD 302C) (Reference 7)

Soil Metabolism:

3% degradation in 64 days (OECD 304) (Reference 6)

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

Fluticasone furoate is not readily degradable or inherently degradable but it is slowly degraded in soil. The phrase “fluticasone furoate is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Kow = 2.61 at pH 7 (OECD 117) (Reference 5)

Justification of chosen bioaccumulation phrase:

Since log Kow < 4 at pH 7, the substance has a low potential for bioaccumulation.

Excretion (metabolism)

Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7 l/h) from systemic circulation principally by hepatic metabolism to an inactive 17β-carboxylic metabolite (GW694301X), by the cytochrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 17β-carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.

Elimination was primarily via the faecal route following oral and intravenous administration indicative of excretion of fluticasone furoate and its metabolites via the bile. Following intravenous administration, the elimination phase half-life averaged 15.1 hours. Urinary excretion accounted for approximately 1 % and 2 % of the orally and intravenously administered dose, respectively. (Reference 2).

PBT/vPvB assessment

Fluticasone furoate does not fulfil the criteria for PBT and/or vPvB

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Fluticasone furoate 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. Pharmacokinetic properties: Meatbolism and Elimination. Summary of Product Characteristics Avamys (fluticasone furoate). GlaxoSmithKline, January 2016.

3. Burwood CE. GW685698X: Determination of Inhibition of Respiration of Activated Sludge. Report No. 1990/363. GlaxoSmithKline, June 2004.

4. Manson P. GW685698X: Acute toxicity to Daphnia magna. Report No. 1990/369. GlaxoSmithKline, November 2004.

5. Swales S. Acute toxicity of GW685698X to the earthworm Eisenia fetida. Report No. 1990/383. GlaxoSmithKline, April 2004.

6. Krajewski M. (14C)-GW685698X: Inherent Biodegradability in Soil Report No. 1990/384. GlaxoSmithKline, June 2004.

7. Mead C and McKenzie J. GW685698X: Assessment of Inherent Biodegradability; Modified MITI (II) Test. Report No. 813/735 GlaxoSmithKline, October 2004

8. Goodband T. Extended Fish Early Life Stage Test (Pimephales promelas). Report No. 3200560. GlaxoSmithKline, March 2016.

Detaljerad miljöinformation

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 = 5.48 x 10^-6 μg/L

Where:

A = 0.04 kg (total sold amount API in Sweden year 2020, data from IQVIA). Reduction of A may be justified based on metabolism data.

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)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Pseudokirchneriella subcapitata):

IC50 96h (yield) = 420 μg/L (OECD 201) (Reference 24)

NOEC = 62.50 μg/L

Water flea:

Acute toxicity

No data

Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 3,200 μg/L (OECD 211) (Reference 35)

Rainbow Trout:

Acute toxicity

No data

Fathead minnow (Pimephales promelas):

Chronic toxicity

NOEC 28 days (reproduction) = 10,000 μg/L (OECD 210) (Reference 46)

Other ecotoxicity data:

Chironomid

No data

Microorganisms in activated sludge

No data

PNEC = 62.50/10 = 6.25 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for alga (= 62.50 ug/L) has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 5.48 x 10^-6/6.25 = 8.77 x 10^-7, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of vilanterol has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

No data

Inherent degradability:

No data

Simulation studies:

Water-sediment study:

No data

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

There are no degradation data available for Vilanterol. The phrase “The potential for persistence of Vilanterol cannot be excluded, due to lack of data” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Pow = 1.26 (OECD 107) (Reference 53)

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

In vitro studies showed that vilanterol is primarily metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate for the P-gp transporter. The primary metabolic routes for vilanterol are O-dealkylation to a range of metabolites with significantly reduced beta1- and beta2-adrenergic agonist activity. Plasma metabolic profiles following oral administration of vilanterol in a human radiolabel study were consistent with high first-pass metabolism. Systemic exposure to the metabolites is low. Plasma clearance of vilanterol following intravenous administration was 108 litres/hour. Following oral administration of radiolabelled vilanterol, mass balance showed 70% of the radiolabel in urine and 30% in faeces. Primary elimination of vilanterol was by metabolism followed by excretion of metabolites in urine and faeces. Vilanterol plasma elimination half-life following inhaled dosing for 10 days averaged 11 hours (Reference 62).

PBT/vPvB assessment

Vilanterol 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). Vilanterol does not fulfil the criteria for PBT and/or vBvP based on a log Dow < 4.

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

References

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

2. Vryenhoef H and Mullee DM. GSK573719A: Algal Growth Inhibition Test. Report No. 41104996. Harlan Laboratories Limited, July 2012.

3. Goodband TJ and Mullee DM. GSK573719A: Daphnia Magna Reproduction Test. Report No. 41104998. Harlan Laboratories Limited, July 2012.

4. Goodband TJ and Mullee DM. GSK573719A: Fish, Early-Life Stage Toxicity Test. Report No. 41104997. Harlan Laboratories Limited, July 2012.

5. Fox JM. GSK573719A: Determination of Partition Coefficient. Report No. 41104995. Harlan Laboratories Limited, May 2012.

6. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics. Anora Ellipita 55 micrograms/22 micrograms Inhalation Powder. GlaxoSmithKline, April 2016.