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 = 1.6 x 10^-3 μg/L

Where:

A = 11.6695 kg (total sold amount API in Sweden year 2021, 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 wastewater 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) > 500µg/L (TAD 3.11/OECD 202) (Reference 3)

Chronic toxicity

No data

Fish (Pimephales promelas):

Acute toxicity

No data

Chronic toxicity

LOEC 116 days > 0.58 μg/L (OECD 210/234) (Reference 9)

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 28 days (lethality) > 1000 mg/kg (TAD 4.12) (Reference 8)

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 activity). 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 propionate 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 propionate is a glucocorticoid and, as such, is considered as a potential endocrine active substance. Fluticasone propionate is a generic drug but the related compound Fluticasone furoate (exclusive GSK pharmaceutical) was investigated for potential endocrine activity 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).

Proposed Read across between Fluticasone furoate and Fluticasone propionate

While these are distinct molecules there is nevertheless an appreciable similarity between the structural and physicochemical properties of both substances which warrants consideration when evaluating the suitability of a read across – see Table 1. Structurally, these compounds are similar and share many physiochemical properties. They differ only in the nature of the 17-α ester, having either a propionate or a furoate ester. It has been recognised that it is this ester that is important in determining activity at the glucocorticoid receptor. EC50 values for glucocorticoid receptor binding of fluticasone propionate and fluticasone furoate have been reported to be 1775 and 2989 respectively, which demonstrate while values are within the same order of magnitude, fluticasone furoate binds with greater affinity (Reference 11). The log kow values for both compounds are almost identical (2.78 and 2.61 for fluticasone propionate and fluticasone furoate, respectively) indicating uptake in the fish would be very similar.

In a GSK Non-Clinical studies a comparison of the in vitro pharmacology of fluticasone propionate and fluticasone furoate, in a number of assays, has been reported and the EC50 values shown to be in the same order of magnitude. In mammalian reproduction studies, although, different routes of exposure were used (subcutaneous and inhalation), both compounds show responses, in general, between 50-100 µg/kg/day dose ranges. However, NOAEL values were not provided for all studies to make more detailed comparisons.

To provide additional rational, for the testing of one compound, both compounds have been run through ECOSAR to derive QSAR data for ecotoxicological species. The data generated show a high similarity in the predicted effect concentrations between the two compounds, for common species used in ecotoxicology. While ECOSAR, of itself, is not sufficient support in favour of read across, it nonetheless indicates there are structural motifs and similarities between the two compounds which suggest that the rationale underpinning read across is not without foundation.

From the scientific peer-reviewed literature, Kugathas et al. (Reference 10) have shown, in vitro and in vivo, for a selected number of glucocorticoids, similar responses in fish in terms of plasma glucose concentrations and anti-inflammatory responses, with effect concentrations being as low as 0.1 µg/L. Currently, the PEC values based on IMS 2015 for Fluticasone furoate (0.00013 µg/L) and Fluticasone propionate (0.004 µg/L) in the European Union are known to be less than the action limit (0.01 µg/L) for both compounds.

In summary, both Fluticasone furoate and Fluticasone propionate have similarities in their structures and in their physiochemical properties. In vivo and in vitro responses are in the same order of magnitude, as are the predicted effect concentrations for ecotoxicity species. Findings in the published literature, testing nine of the most commonly synthetic glucocorticoids prescribed in the UK in 2006, have shown EC50 glucocorticoid receptor binding values within an order of magnitude, with Fluticasone furoate displaying greater receptor affinity. Importantly, the enhanced receptor sensitivity of Fluticasone furoate compared with Fluticasone propionate represents a more conservative endpoint for assessing environmental protection whilst minimizing additional testing on vertebrates. Accordingly, it is concluded that the results of the Fluticasone furoate extended life cycle fish study are applicable to the assessment of Fluticasone propionate.

Environmental risk classification (PEC/PNEC ratio)

­PEC/PNEC = 1.6 x10^-3 /0.0058 = 0.28, i.e. ≤ 0.1 PEC/PNEC ≤ 1 which justifies the phrase “Use of fluticasone propionate has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

< 1.50% degradation in 28 days (TAD 3.11) (Reference 6)

Inherent degradability:

No Data

Soil Metabolism:

9-50% degradation in 64 days (OECD 307) (Reference 7)

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

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

Bioaccumulation

Partitioning coefficent:

Log Kow = 2.80 at pH 7 (TAD 3.02). (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 propionate does not persist in any tissue, and does not bind to melanin. The major route of metabolism is hydrolysis of the S-fluoromethyl carbothioate group, to yield a carboxylic acid (GR36264), which has very weak glucocorticoid or anti‑inflammatory activity. In all test animal species, the route of excretion of radioactivity is independent of the route of administration of radiolabelled fluticasone propionate. Excretion is predominantly faecal and is essentially complete within 48 hours.

In man too, metabolic clearance is extensive, and elimination is consequently rapid. Thus drug entering the systemic circulation via the skin, will be rapidly inactivated. Oral bioavailability approaches zero, due to poor absorption and extensive first‑pass metabolism. Therefore systemic exposure to any ingestion of the topical formulation will be low (Reference 2).

PBT/vPvB assessment

Fluticasone propionate 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 propionate 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: Metabolism and Elimination. Summary of Product Characteristics Cutivate Cream (fluticasone propionate). GlaxoSmithKline, May 2012.

3. LeLievre MK. Fluticasone propionate: Acute Toxicity to Daphnids. (Daphnia pulex) Under Static Conditions. Report No. 91-10-3943. Springborn Laboratories inc., February 1993.

4. Hartley DA. Fluticasone propionate: Activated Sludge Respiration Inhibition. Report No. 91-7-3824. Springborn Laboratories inc., November 1991.

5. Hartley DA. Fluticasone propionate: Determination of the n‑Octanol‑Water Partition Coefficient. Report No. 9‑19‑3927. Springborn Laboratories inc., December 1992.

6. Weeden DM. Fluticasone propionate: Aerobic Biodegradation in Water. Report No. 9‑28‑4382. Springborn Laboratories inc. August 1994.

7. Carter JN. CCl18781: Aerobic Biodegradation i Soil. Report No. GXO 509/931840. Huntington Research Centre, December 1993.

8. Carter JN. CCl18781: 28-Day Subacute Toxicity to the Earthworm. Report No. GXO 506/931457. Huntington Research Centre, January 1994.

9. GlaxoSmithKline Report Number 2016N274822_00. Fluticasone Furoate: Extended Fish Early Life Stage Test (Pimephales promelas) March 2016

10. Kugathas S, Sumpter JP. Synthetic glucocorticoids in the environment: first results on their potential impacts on fish. Environ Sci Technol, 2011, 45: 2377-2383.

11. GlaxoSmithKline Report Number SR2006/00001/01. The in vitro pharmacology of GW685698X, a potent and selective Glucocorticoid Receptor agonist. March 2006.

Table 1 Comparison of fluticasone propionate with fluticasone furoate

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) = 1.5*10^-6*A(100-R)

PEC = 2.10 x 10^-4 μg/L

Where:

A = 1.39 kg (total sold amount API in Sweden year 2019, 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 = 9 *10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Scenedesmus subspicatus):

IC50 96h (inhibition) = 2,800 μg/L (OECD 201) (Reference 3)

NOEC = 1,300 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 13,800 μg/L (OECD 202) (Reference 10)

Water flea (Ceriodaphnia dubia):

Chronic toxicity

NOEC 8 days (reproduction) = 1,100 μg/L (USEPA 1002) (Reference 6)

Rainbow Trout (Oncorhyncus mykiss):

Acute toxicity

LC50 96 h (lethality) = 24,000 μg/L (OECD 203) (Reference 5)

Fathead minnow, Pimephales promelas:

Chronic toxicity

No data

Other ecotoxicity data:

Microorganisms in activated sludge:

EC50 3 h (inhibition) > 688,000 μg/L (OECD 209) (Reference 10)

Terrestrial toxicity

Manure worm (Eisenia foetida):

LC50 28d = 230,000 μg/kg (TAD 4.12) (Reference 8)

PNEC = 1,100/50 = 22 μg/L

PNEC (μg/L) = lowest NOEC/50, where 50 is the assessment factor applied for two long-term NOECs. NOEC for water flea (= 1,100 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 = 2.69 x 10^-4/22 = 1.22 x 10^-5i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of salmeterol has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

No data

Inherent degradability:

50% degradation in 12.80 days (TAD 3.11). (Reference 10)

Soil metabolism:

29.9 to 49.9% degradation in 64 days (OECD 304) (Reference 9)

Abiotic degradation

Hydrolysis:

50% degradation > 1 year (TAD 3.09). (Reference 10)

Photolysis:

No data

Justification of chosen degradation phrase:

Salmeterol is not readily degradable but it is inherently primarily degradable in that removal of the parent API in the Sewage Treatment Plant is expected to a significant extent. The phrase “Salmeterol is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = 1.71 at pH 7 (TAD 3.02). (Reference 4)

Log Dow at pH 5 = 2.06

Log Dow at pH 7 = 1.71

Log Dow at pH 9 = 1.32

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

Salmeterol is extensively metabolised to a pharmacologically inactive 17 metabolite 1-hydroxy-2-naphthoic acid (xinafoate). The major route of excretion of drug related material is via the faeces, 25%-60%. (Reference 2).

PBT/vPvB assessment

Salmeterol 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).

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. Product Information: Serevent(R) Diskus(R), Salmeterol inhalation powder. GlaxoSmithKline, Research Triangle Park, NC, 2003a.

3. Vryenhoef V and McKenzie J. Salmeterol Xinafoate: Algal Inhibition Test. Report No. 1127/547. Safepharm Laboratories Limited, April 2005.

4. Hartley DR. Salmeterol hydroxynapththoate: Determination of the n-Octanol/Water Partition Coefficient following FDA Technical Assisstance Document 3.02. Report No. 92-2-4102. Springborn laboratories, Inc, April 1992.

5. Sewell IG and McKenzie J. Salmeterol Xinafoate: Acute Toxicity to Rainbow Trout. Report No. 1127/546. Safepharm Laboratories Limited, April 2005.

6. Wetton PM Salmeterol Xinafoate: Daphnid, Ceriodaphnia Dubia Survival and Reproduction Test. Report No. 1127/949. Safepharm Laboratories Limited, March 2006.

7. Sewell IG and McKenzie J. Salmeterol Xinafoate: Acute Toxicity to Rainbow Trout. Report No. 1127/546. Safepharm Laboratories Limited, April 2005.

8. Handley JW, Sewell IG and Bartlett AJ. GR33343G: Earthworm Subacute Toxicty Test. Report No. 303/678. Safepharm Laboratories Limited, May 1995.

9. Secker, RC. GR33343G: Biodegradation in Soil. Report No. WPT/94/243. Pharmaco LSR Ltd, February1995.

10. Material Safety Data Sheet for Advair HFA. SDS number 126599. GlaxoSmithKline plc, November 2008.