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 = 8.22 x 10^-6 μg/L

Where:

A = 0.06 kg (total sold amount API in Sweden year 2020, 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)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Pseudokirchneriella subcapitata):

IC50 96h (yield) = 910 μg/L (OECD 201) (Reference 2)

NOEC = 95.40 μg/L

Water flea:

Acute toxicity

No data

Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 6,250 μg/L (OECD 211) (Reference 3)

Rainbow Trout:

Acute toxicity

No data

Fathead minnow (Pimephales promelas):

Chronic toxicity

NOEC 28 days (reproduction) = 370 μg/L (OECD 210) (Reference 4)

Other ecotoxicity data:

Chironomid

No data

Microorganisms in activated sludge

No data

PNEC = 95.40/10 = 9.54 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for alga (= 95.40 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 = 8.22 x 10^-6/9.54 = 8.62 x 10^-7, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of umeclidinium 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 Umeclidinium. The phrase “The potential for persistence of Umeclidinium cannot be excluded, due to lack of data” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = 1.35 at pH 7 (OECD 107) (Reference 2)

Log Dow at pH 5 = 0.092

Log Dow at pH 7 = 1.35

Log Dow at pH 9 = 1.39

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

In vitro studies showed that umeclidinium is primarily metabolised by cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours post-dose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the drug-related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male volunteers, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours in healthy volunteers, with 3% to 4% excreted unchanged in urine at steady-state (Reference 5).

PBT/vPvB assessment

Umeclidinium 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). Umeclidinium does not fulfil the criteria for PBT and/or vBvP based on a log Dow < 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. Burke J, Last G, and Goodband T. GW642444M: Inhibition of Growth to the Alga Pseudokirchneriella subcapitata. Report No. 8240789. Covance Laboratories Limited, November 2012.

   
   

3. Burke J and Flenley A. Chronic effects of GW642444M to Daphnia magna. Report No. 8240791. Covance Laboratories Limited, April 2012.

   
   

4. Burke J, Jakes M and Goodband T. Fish Early Life Stage Test (Pimephales promelas) with GW642444M. Report No. 8240790. Covance Laboratories Limited, January 2012.
   
   

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