Miljöpåverkan
Linagliptin
Miljörisk:
Användning av linagliptin har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning:
Linagliptin bryts ned långsamt i miljön.
Bioackumulering:
Linagliptin har låg potential att bioackumuleras.
Läs mer
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) = 1.52*10-6*A *(100-R) = 3,78*10-3 µg/L
Where:
A = 24,82 kg (total sold amount API in Sweden 2019, data from IQVIA).
R = 0 % removal rate.
P = number of inhabitants in Sweden = 9 *106
V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (I)
D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (I)
Predicted No Effect Concentration (PNEC)
PNEC = 320 μg/L
The PNEC has been derived from the lowest NOEC (Daphnia magna, 21d) of 3.2 mg/L. An assessment factor of 10 is used based on the availability of a NOEC for algal growth inhibition in combination with chronic toxicity studies for the other two trophic levels in accordance with ECHA Guidelines (I).
Ecotoxicological studies
Algea (Green algea, Pseudokirchneriella subcapitata) (OECD 201, GLP) (II)
EC50 72h (growth rate) = 49 mg/L
NOEC 72h (growth rate) = 4.1 mg/L
EC50 72h (biomass) = 16 mg/L
NOEC 72h (biomass) = 4.1 mg/L
Crustacean (Water flea, Daphnia magna)
Chronic toxicity (OECD 211, GLP)(III):
NOEC 21d (parental mortality) = 3.2 mg/L
LOEC 21d (parental mortality) = 10 mg/L
Fish (Zebrafish, Danio rerio)
Chronic toxicity (OECD 210, GLP)(IV):
NOEC 35d = ≥ 12.0 mg/L (no effects, highest dose tested)
Other ecotoxicity data
Respiration inhibition of activated sludge (OECD 209, GLP)(V):
EC50 3h = 792 mg/L
NOEC 3h = 210 mg/L
Environmental risk classification (PEC/PNEC ratio)
PEC/PNEC = 3,78*10-3/320 = 1,18 x 10-5, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of Linagliptin has been considered to result in insignificant environmental risk.”
Degradation
Biotic degradation
Ready degradability:
In a 28d ready biodegradability study (OECD 301A, GLP) 0% biodegradation of Linagliptin was observed (VI). Based on these data Linagliptin is not readily biodegradable.
Inherent degradability:
No data on inherent biodegradability.
Simulation studies:
In an OECD 308 study (GLP)(VII), the following dissipation rates (DT50) were determined in two aquatic freshwater systems, river and pond:
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Freshwater: 0.8 days (river) and 1.1 (pond)
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Sediment: 110 days (river) and 42.2 (pond)
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Total system: 5.2 days (river) and 1.6 (pond)
At the end of the study (day 100), 22.7% (river) and 4.4% (pond) of the applied radioactivity was remaining as parent compound in the two systems, respectively. The amount of non-extractable radioactivity in the sediment was high for both test systems with bound residues accounting for up to 50.9% (river) and 72.4% (pond) at day 100. Several minor degradation products were detected, none individually exceeding 10% of the applied radioactivity.
After removing the water phase from the test system, the sediment was submitted to up to four extraction steps using acetonitrile/water (4:1; v/v) at room temperature until less than 5% of the radioactivity applied was recovered. Extractions at room temperature were performed in a shaker at about 200-250 strokes per minute each for about 30 minutes. The radioactivity in the individual extracts was quantified by LSC (duplicate aliquots). Soxhlet extraction using acetonitrile/water (4:1; v/v) for 4 hours was additionally performed on the extracted sediments (except for day 0). This extraction method was performed if more than 10% of the applied radioactivity remained non-extractable. All extracts containing more than 2% of the radioactivity applied were combined and concentrated in a rotary evaporator at about 30 °C. The concentrated extracts were measured by LSC for recovery and submitted to HPLC and/ or TLC analysis. The amount of solvent used was in general about 1 mL/g sediment (wet weight basis). Reflux extraction with acetonitrile/0.1 M HCl (1:1; v/v) for at least four hours was conducted followed additionally by organic matter fractionation for one interval of the river and pond test system (day 100, duplicate determination). The radioactivity content in the reflux extracts was determined by LSC. The reflux extracts were analysed by HPLC. After all extractions, the residual sediments were dried, weighed, homogenised and their radiocarbon content was determined by LSC after combustion of up to 1.0 g aliquots.
The mineralisation of the test item and the formation of other organic volatiles was very low, accounting for < 1.5% or < 0.1% during the 100 days of incubation. In conclusion, Linagliptin rapidly dissipated from the water phase by adsorption to the sediment of both systems. Once in the sediment, its degradation proceeds at a very slow rate, mainly via the formation of bound residues and the formation of minor metabolites. Since Linagliptin has a DT50 of ≤ 32d, but > 15% remaining as parent compound at the end of the study in the river system, Linagliptin is considered to be slowly degraded in the environment.
Abiotic degradation
Hydrolysis: No significant degradation was observed at pH 7 and 9 at 25°C after 28 days. At pH of 12.8 and 2.2 a total of 4.3% and 11.3% impurities, respectively, was observed (VIII).
Photolysis: After 22 hours of artificial light irradiation (Suntest) a total of 4% impurities were observed (VIII).
Justification of chosen degradation phrase:
Linagliptin was not readily biodegradable (OECD 301A, GLP). Further, in an OECD Guideline 308 simulation study, Linagliptin was slowly degraded in the environment. In abiotic degradation studies, Linagliptin did not undergo significant degradation by hydrolysis or photolysis. Based on these combined data, Linagliptin is considered to be slowly degraded in the environment.
Bioaccumulation
Bioconcentration factor (BCF):
No data on bioconcentration in fish.
Partitioning coefficient:
The n-octanol/water partition coefficient was in an OECD Guideline 122 (GLP) study determined to -1.6 at pH 5.0, 0.1 at pH 7.0 and 1.5 at pH 9.0, respectively (IX).
Justification of chosen bioaccumulation phrase:
Based on the data from the OECD Guideline 122 study n-octanol/water partition coefficients of -1.6 to 1.5 at pH 5 to 9, Linagliptin is considered to have low potential for bioaccumulation.
Excretion (metabolism)
After both oral and intravenous administration, the majority of Linagliptin (~90%) was excreted unchanged in the urine and feces (X). Thus, the environmental risk assessment should be performed on the data of the parent compound.
PBT/vPvB assessment
Linagliptin is considered not to fulfil the criteria for PBT or vPvB.
References
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European Chemicals Agency (ECHA), 2008. Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterization of dose[concentration]-response for environment.
http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf
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Boehringer Ingelheim GmbH internal report U08-0276-01, 2008
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Boehringer Ingelheim GmbH internal report U09-0013-01, 2008
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Boehringer Ingelheim GmbH internal report U08-0289-01, 2008
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Boehringer Ingelheim GmbH internal report U08-0277-01, 2008
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Boehringer Ingelheim GmbH internal report U08-0278-01, 1997
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Boehringer Ingelheim GmbH internal report U08-0279-01, 2008
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Boehringer Ingelheim GmbH internal report U09-2355-01, 2009
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Boehringer Ingelheim GmbH internal report U09-1908-01, 2009
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Boehringer Ingelheim GmbH Environmental Risk Assessment of Linagliptin, 2010 (U10-0020-01)
Miljöinformationen för metformin är framtagen av företaget Novartis för Eucreas®, Icandra, Zomarist
Miljörisk:
Användning av metformin har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning:
Metformin bryts ned långsamt i miljön.
Bioackumulering:
Metformin har låg potential att bioackumuleras.
Läs mer
Detaljerad miljöinformation
Disclaimer:
With the exception of the literature studies and the Novartis Core data sheet, all studies used in this Environmental Assessment are the property of Janssen. Novartis has been authorised by Janssen to use the study reports for the purpose of contributing to the Swedish www.fass.se database.
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 * 186664.64 * 100
PEC = 25.57 μg/L
Where:
A = 186664.64 kg metformin hydrochloride (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
Green algae (Pseudokirchneriella subspicata) (OECD201) (Springborn Smithers Study No. 13751.6179):
EC50 72 h (growth rate) > 99.0 mg/L
NOEC = 99.0 mg/L
Crustacean (Daphnia magna):
Acute toxicity
EC50 48 h (immobilisation) = 64.0 mg/L (EC Test Guideline 92/69/EEC C.2) (Cleuvers 2003)
EC50 48 h (immobilisation) > 110 mg/L (OECD 202) (Springborn Smithers Study No. 13751.6180)
Chronic toxicity
NOEC 21 days = 100.0 mg/L (OECD 211) (Smithers Viscient AG Study #1149.001.230)
Fish:
Acute toxicity (Danio rerio, zebrafish)
LC50 96 h (mortality) > 110.0 mg/L; no effect up to the highest concentration tested (OECD203) (Springborn Smithers Study No.13751.6181)
Chronic toxicity (Pimephales promelas, fathead minnow)
NOEC 32 days = 10.3 mg/L; no effect up to the highest concentration tested (OECD 210) (Smithers Viscient AG Study # 1149.001.122)
Other ecotoxicity data:
Bacterial respiration inhibition
EC50 3 h > 750 mg/L
NOEC = 1.5 mg/L (activated sludge respiration inhibition) (OECD209) (Smithers Viscient Study No. 13674.6228)
Sediment-dwelling organisms (Chironomus riparius, non-biting midge)
NOEC 28 days ≥ 100 mg/kg; no effect up to the highest concentration tested (OECD 218) (Smithers Viscient AG Study # 1149.001.173)
PNEC derivation:
PNEC = 1030 μg/L
PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used if three chronic toxicity studies from three trophic levels are available. The NOEC for chronic toxicity in fish has been used for this calculation.
Environmental risk classification (PEC/PNEC ratio)
PEC/PNEC = 25.57 μg/L / 1030 μg/L = 0.025, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of metformin has been considered to result in insignificant environmental risk."
Degradation
Biotic degradation
Ready degradability:
35.5 % degradation in 28 days, not readily biodegradable (OECD 301B). (Smithers Viscient Study No. 13674.6229)
Simulation studies:
DT50 (total system) = 43.0 – 53.0 days (OECD 308, 101 days). (Smithers Viscient Study No. 13674.6233)
At each sampling interval, the samples from each test system were separated into water and sediment fractions. The Day 0 and Day 3 sediment samples were extracted once with acetonitrile and once with acetonitrile:purified reagent water (80:20, v:v). The Day 3 samples were extracted two additional times with acetonitrile:purified reagent water:concentrated hydrochloric acid (80:20:0.1, v:v:v) for a total of four extractions. The Day 14 to Day 101 samples were extracted once with acetonitrile and twice with acetonitrile:purified reagent water:concentrated hydrochloric acid (80:20:0.1, v:v:v) for a total of three extractions.
Ultimate biodegradation was observed in the aerobic test systems. The cumulative amount of evolved 14CO2 was 18.0% of applied radioactivity (AR) and 2.2% AR for the two test systems at Day 101. Evidence of primary biodegradation was observed for [14C]metformin hydrochloride in the aerobic water/sediment test samples. Several minor regions of radioactivity were observed in some of the chromatograms for both aquatic sediment systems. In all cases, these peaks represented less than 10% of the applied radioactivity and were not considered further.
Justification of chosen degradation phrase:
According to the pass criteria for OECD308 studies, metformin can be classified as ‘Metformin is slowly degraded in the environment' (DT50 for total system ≤ 120 days).
Bioaccumulation
Partitioning coefficient:
Log P = -2.48 (OECD107) (Smithers Viscient Study No. 13674.6227)
Justification of chosen bioaccumulation phrase:
Since log P < 4, metformin has low potential for bioaccumulation.
Excretion (metabolism)
Intravenous single-dose studies in normal subjects demonstrate that metformin hydrochloride is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. (Eucreas®, Novartis Core data sheet, 2016)
PBT/vPvB assessment
Metformin cannot be considered a potential PBT substance, as it is neither persistent, nor has potential for bioaccumulation or toxicity in aquatic organisms.
References
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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
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Springborn Smithers Study No. 13751.6179. Final report: 07 January 2011. Metformin Hydrochloride – 72-Hour Acute Toxicity Test with Freshwater Green Alga, Pseudokirchneriella subcapitata, Following OECD Guideline #201 and the Official Journal of the European Communities L220/36, Method C.3
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Cleuvers, M. (2003), Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Tox. Letts. 2003, 142, pp.185-194.
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Springborn Smithers Study No. 13751.6180. Final report: 11 January 2011. Metformin Hydrochloride - Acute Toxicity to Water Fleas, (Daphnia magna) Under Static Conditions, Following OECD Guideline #202 and The Official Journal of the European Communities L142/456, Method C.2
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Smithers Viscient AG Study #1149.001.230. Final report: 14 December 2011. Metformin HCl: Chronic reproduction test with daphnids (Daphnia magna) under semi-static conditions
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Springborn Smithers Study No.13751.6181. Final report: 14 January 2011. Metformin Hydrochloride - Acute Toxicity to Zebra Fish (Brachydanio rerio) Under Static Conditions, Following OECD Guideline Number 203 and The Official Journal of the European Communities L 142/446, Method C.1
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Smithers Viscient AG Study # 1149.001.122. Final report: 15 December 2011. Metformin HCl: Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas) under Flow-through Conditions
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Smithers Viscient Study No. 13674.6228. Final report: 06 March 2012. Metformin Hydrochloride - Activated Sludge Respiration Inhibition Test Following OECD Guideline 209
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Smithers Viscient AG Study # 1149.001.173. 14C-Metformin HCl: Chronic toxicity test with midge larvae (Chironomus riparius) in a water/sediment system. Final report: 14 December 2011.
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Smithers Viscient Study No. 13674.6229. Final report: 03 November 2011. Metformin hydrochloride – Determination of the Biodegradability of a Test Substance Based on OECD Method 301B (CO2 Evolution Test)
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Smithers Viscient Study No. 13674.6233. Final report: 29 December 2011. [14C]Metformin Hydrochloride - Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308
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Smithers Viscient Study No.13674.6227. Final report: 3 November 2011. Metformin Hydrochloride - Determining the Partitioning Coefficient (n-Octanol/Water) by the Flask-Shaking Method Following OECD Guideline 107
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Eucreas® (vildagliptin metformin fixed combination), Novartis Core data sheet, Version 3.0, 28 November 2016.