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 * 0.5497 * (100-R)

PEC = 0.000075 μg/L

Where:

A = 0.5497 kg (total sold amount API in Sweden year 2021, data from IQVIA).

R = 0 % removal rate (due to 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) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (OECD 201) (Harlan Laboratories Study C13436):

ErC50 72 h (growth rate) > 100 mg/L

NOEC = 7.5 mg/L

Crustacean (Daphnia magna):

Acute toxicity

EC50 48 h (immobilisation) = 33.0 mg/L (OECD 202) (Harlan Laboratories Study C13425)

Fish (Danio rerio):

Acute toxicity

LC50 96 h (lethality) > 100 mg/L (OECD 203) (Harlan Laboratories Study C10040)

PNEC = 33 μg/L

PNEC (μg/L) = lowest EC50/1000, where 1000 is the assessment factor used if acute toxicity data for three trophic levels is available. EC50 for Daphnia magna 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 = 0.000075 μg/L / 33 µg/L = 0.00000227, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of glycopyrronium bromide has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

0 % degradation in 28 days (OECD 301A) (Harlan Laboratories Study C13447) 

Justification of chosen degradation phrase:

Glycopyrronium bromide is not readily biodegradable. The phrase “Glycopyrronium bromide is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Pow = -2.1 (OECD 107). (Harlan Laboratories Study C13403)

Justification of chosen bioaccumulation phrase:

Since log P < 4, glycopyrronium bromide has low potential for bioaccumulation.

Excretion (metabolism)

Following inhalation of single and repeated once-daily doses between 50 and 200 μg glycopyrronium by healthy volunteers and patients with COPD mean renal clearance of glycopyrronium was in the range of 17.4 and 24.4 L/h. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to 20% of the dose was found in urine as parent drug. (Novartis Core Data Sheet, 2016)

PBT/vPvB assessment

According to the established EU criteria, glycopyrronium bromide cannot be regarded as a PBT/vPvB substance, as it has low potential for bioaccumulation and is not toxic.

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• Harlan Laboratories Study C13436. Toxicity of NVA237 A5 to Pseudokirchneriella subcapitata in a 72-hour algal growth inhibition test. Final report: 28 January 2009.

• Harlan Laboratories Study C13425. Acute toxicity of NVA237 A5 to Daphnia magna in a 48-hour immobilization test. Final report: 28 January 2009.

• Harlan Laboratories Study C10040. Acute toxicity of NVA237 A5 to zebra fish (Brachydanio rerio) in a 96-hour test. Final report: 28 January 2009.

• Harlan Laboratories Study C13447. Ready biodegradability of NVA237 A5 in a DOC Die-Away test. Final report: 09 February 2009.

• Harlan Laboratories Study C13403. Determination of the water solubility and the partition coefficient (n-octanol/water). Final report: 15 June 2009.

• Novartis Core Data Sheet, SEEBRI™ BREEZHALER^® (Glycopyrronium bromide, NVA237), Version 2.1, 19 May 2016.

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) = 1.37*10^-6 * 0.4935 kg * 100 = 0.000068 μg/L = 0.0676 ng/L

Where:

A = 0.4935 kg indakaterol maleat (total sold amount API in Sweden year 2023, data from IQVIA).

R = 0 % 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 = 10 * 10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus) (92/69/EC (L383) C.3) (CETA Study Nr.: 37/02/23, Report Nr. 1803/L):

EC50 72 h (growth rate) > 100.0 mg/L

Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilization) > 100.0 mg/L (92/69/EEC (L.383) C.2) (CETA Study Nr.: 1/03/22, Report Nr. 2066/L)

Fish:

Acute toxicity (Piecilia reticulata, guppy)

LC50 96 h (mortality) > 100.0 mg/L (OECD203) (CETA Study Nr.: 37/02/21, Report Nr. 1807/L)

Other ecotoxicity data:

Bacterial respiration inhibition

EC₅₀ 3 h > 300.0 mg/L (activated sludge respiration inhibition) (87/302/EEC Part C) (ARC Study No.: NOV30)

PNEC derivation:

PNEC = 100.00 μg/L

PNEC (μg/L) = lowest EC50/1000, where 1000 is the assessment factor used, based on the fact that three acute toxicity studies are available, covering three trophic levels. An EC50 of 100 mg/L is used for this calculation, based on the fact that no acute toxic effects were observed in fish, Daphnia and algae at the highest tested concentration of 100.0 mg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000068 μg/L / 100.0 μg/L = 0.00000068, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of indacaterol has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

0 % degradation in 28 days, not readily biodegradable (OECD301D). (CETA Study Nr.: 37/02/25, Report Nr.: 1811/L)

Justification of chosen degradation phrase:

Indacaterol is not readily biodegradable. Therefore, the phrase "Indacaterol is potentially persistent" is chosen.

Bioaccumulation

Partitioning coefficient:

Log P = -0.74 at 20.1°C (EC440/2008 A.8 8). (NOTOX Project 491643)

Justification of chosen bioaccumulation phrase:

Since log P < 4, indacaterol has low potential for bioaccumulation.

Excretion (metabolism)

In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). (Novartis Core Data Sheet Onbrez® Breezhaler®).

PBT/vPvB assessment

Indakaterol has low potential for bioaccumulation. Indakaterol can therefore not be considered a potential PBT substance.

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• CETA Study Nr.:37/02/23, Report Nr. 1803/L. Alga, growth inhibition test. Final report: 15.09.2004

• Study No.: 1/03/22, Report No.: 2066/L. Daphnia, acute immobilisation test. Final report: 15.09.2004

• CETA Study Nr: 1807/L, Report Nr.: 37/02/21. Fish, acute toxicity test. Final report: 15.09.2004

• Study project Nr.: NOV30, Report No: ARC- -UL-0561. Activated sludge respiration inhibition test. Final report: November 2002.

• CETA Study Nr.: 37/02/25, Report Nr.: 1811/L. Determination of ready biological degradability - closed bottle test. Final report:15.09.2004.

• NOTOX Project 491643. Determination of physico-chemical properties of indacatarol maleate. Final report: 21.08.2009.

• Novartis Core Data Sheet Onbrez® Breezhaler® and related products (indacaterol maleate). Version 2.1. 30. September 2013.

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) = 1.37*10^-6 * 57.249 * (100-45.98) = 0.0042 μg/L = 4.2ng/L

Where:

A = 57.249 kg mometasonfuroat (sum of 39.3068 kg mometasonfuroat and 18.5614 kg mometasonfuroatmonohydrat, equaling 17.94 kg mometasonfuroat) (total sold amount API in Sweden year 2022, data from IQVIA).

R = 45.98 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation, as predicted by SimpleTreat 4.0 using a K_d,sludge value of 1937 L/Kg as concluded in Smithers Viscient, Study No., 359.6435, and a first order degradation constant of 0.00094 h^-1 as derived from Smithers Viscient, Study No., 359.6446).

P = number of inhabitants in Sweden = 10 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008).

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (OECD 201) (Smithers Viscient, Study No., 359.6386)

NOEC 72 h (growth rate) = 3.2 mg/L

Crustacean (Daphnia magna, waterflea):

Chronic toxicity

NOEC 21 d (reproduction) = 0.34 mg/L

LOEC 21 d > 0.34 mg/L (OECD 211) (Smithers Viscient, Study No. 359.6439)

Fish (Pimephales promelas, fathead minnow):

Chronic toxicity

NOEC 32 d (growth) = 0.14 μg/L

LOEC = 0.22 μg/L (OECD 210) (Smithers Viscient, Study No. 359.6440)

Fish (Danio rerio, zebrafish):

Chronic toxicity

NOEC 65 d (slight change in sex ratio) = 0.00313 μg/L = 3.13 ng/L

LOEC = 0.010 μg/L = 10 ng/L (OECD 234) (IES Ltd, Study No. 20210269)

PNEC Derivation:

PNEC = 0.313 ng/L

PNEC (μg/L) = lowest NOEC (3.13 ng/L)/10, where 10 is the assessment factor used when long-term results from at least three species representing three trophic levels are available. The NOEC for the fish sexual development test in zebrafish (Danio rerio) has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 4.2 ng/L / 0.313 ng/L = 13.54, i.e. PEC/PNEC > 10 which justifies the phrase "Use of mometasone has been considered to result in high environmental risk."

Degradation

Biotic degradation

Ready degradability:

<5 % ultimate biodegradation in 28 days, not readily biodegradable. The half-life for primary biodegradation was calculated to be 31 days, and the elimination rate constant was 0.0226 days^-1 (OECD 314B) (Smithers Viscient, Study No. 359.6446).

The fate and degradation of [14C]mometasone in two water-sediment systems was assessed in an OECD 308 study (Smithers Viscient, Study No. 359.6445).

Radioactivity associated with the sediment phase was extracted once with acetonitrile, then 0.1% hydrochloric acid in acetonitrile, and finally with acetonitrile:purified reagent water:hydrochloric acid 80:20:0.1, (v:v:v).

Mometasone rapidly dissipated from the water phase. Evidence of primary degradation was observed. One major peak (>10% AR) was detected in some of the chromatograms as a shoulder of the parent peak. Several minor regions of radioactivity (<10% AR) were observed in some of the chromatograms. The cumulative amount of evolved 14CO2 2.6% and 3.0% AR in the two water-sediment systems at Day 100. The average amount of sediment-bound residue as 10.6% and 11.2% AR in the two water-sediment systems at Day 100. No radioactivity was detected as volatile organic at Day 100. Average material balance ranged from 92.0 to 97.2% AR throughout the 100-day study.

The half-life of [14C]mometasone in the total water-sediment test systems ranged from 81 to 105 days.

Overall, the evidence from this study shows that mometasone is expected to be slowly degraded in the environment.

Justification of chosen degradation phrase:

Based on the half-life in the total water-sediment test system, the phrase “Mometasone is slowly degraded in the environment” is thus chosen.

Bioaccumulation

Bioconcentration factor (BCF):

BCF: 104.9 - 107.1 L/Kg (OECD 305). (Smithers Viscient, Study No. 359.6497)

Partitioning coefficient:

logK_ow = 4.68 (pH 7) (OECD 107) (Smithers Viscient, Study No., 359.6385)

Justification of chosen bioaccumulation phrase:

Since BCF < 500, the following statement is used for mometasone: Mometasone has low potential for bioaccumulation.

Excretion (metabolism)

The portion of an inhaled mometasone furoate dose that is swallowed and absorbed in the gastrointestinal tract undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. In human liver microsomes, mometasone furoate is metabolized by CYP3A4. After intravenous bolus administration, mometasone furoate has a terminal elimination T1/2 of approximately 4.5 hours. A radiolabelled, orally inhaled dose is excreted mainly in the feces (74 %) and to a lesser extent in the urine (8 %) (ATECTURA® BREEZHALER® Novartis CDS 2020).

PBT/vPvB assessment

Mometasone does not fulfil the screening criteria for a bioaccumulative substance and can therefore not be considered a potential PBT substance.

References

• ATECTURA® BREEZHALER® Novartis CDS 2020

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• Smithers Viscient, 2011. "[14C]Mometasone - Determining the Adsorption Coefficient (Koc) Following OECD Guideline 106," Study No. 359.6435, SV, Wareham, MA, 09 June 2011.

• IES Ltd, 2023. "Mometasone furoate – Fish Sexual Development Test with Zebrafish (Danio rerio)," Study No. 20210269, Switzerland, 25 May 2023.

• Smithers Viscient, 2011. "Mometasone Furoate – Determining the Partition Coefficient (n-Octanol/Water) by the Flask-Shaking Method Following OECD Guideline 107," Study No., 359.6385, SV, Wareham, MA, USA, 10 March 2011.

• Smithers Viscient, 2011. "[14C]Mometasone - Determination of the Biodegradability of a Test Substance in Activated Sludge Based on OECD Method 314B," Study No. 359.6446, SV, Wareham, MA, 01 September 2011.

• Smithers Viscient 2011. "Mometasone Furoate – Activation Sludge Respiration Inhibition Test Following OECD Guideline 209," Study No., 359.6441, SSL, Wareham, MA, USA 25 April 2011

• Smithers Viscient 2011. " Mometasone Furoate - Acute Toxicity to the Freshwater Green Alga, Pseudokirchneriella subcapitata," Study No., 359.6386, SV, Wareham, MA, USA 28 January 2011.

• Smithers Viscient, 2012. "Mometasone Furoate - Full Life-Cycle Toxicity Test with Water Fleas, (Daphnia magna), Under Flow-Through Conditions Following OECD Guideline #211," Study No. 359.6439, SV, Wareham, MA, 1 May 2012.

• Smithers Viscient, 2012. "Mometasone Furoate – Early Life-Stage Toxicity Test with Fathead Minnow, Pimephales promelas, Following OECD Guideline #210," Study No. 359.6440, SV, Wareham, MA, 21 May 2012.

• Smithers Viscient, 2011. “[14C]Mometasone – Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308”. Study No. 359.6445, SV, Wareham, MA, 6 September 2011.

• Smithers Viscient, 2012. "[¹⁴C]Mometasone - Flow-Through Bioconcentration and Metabolism Study with Bluegill Sunfish (Lepomis macrochirus) Following OECD Guideline 305," Study No. 359.6497, SV, Wareham, MA, 21 May 2012.