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 = 0.00013 μg/L

Where:

A = 0.96 kg (total sold amount API in Sweden year 2022, data from IQVIA) (Ref I)

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 10 *10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Pseudokirchneriella subcapitata) (OECD 201) (Reference III) 

EC₅₀ 72h = 77 mg/L (growth rate)

NOEC 72h = 50 mg/L

Crustacean, water flea (Daphnia magna) (OECD 211) (Ref. III) 

Chronic toxicity

NOEC 21d = 2.14 mg/L

No effects noted for any endpoint (survival, reproduction, growth)

Fish, fathead minnow (Pimephales promelas) (OECD 210) (Ref. III)

Chronic toxicity

NOEC 32d = 1 mg/L

No effects noted for any endpoint (hatching, survival, growth)

PNEC = 100 μg/L (1 mg/L/ 10 based on the most sensitive NOEC for the fathead minnow and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00013/100 = 1.3E-06, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of ertugliflozin has been considered to result in insignificant environmental risk.

Degradation studies

Sludge Die-Away (OECD 314B) (Ref. III)

Ultimate biodegradation (CO₂ evolution) 40.8% in 28 days

25.3% remaining with solids at day 28

Loss of parent DT₅₀ 0.7 hours

Loss of parent DT₉₀ 2.31 hours

A 28-day sludge die-away study was conducted using radiolabelled test material, to determine the potential for ertugliflozin to undergo both primary and ultimate degradation during the wastewater treatment process. Measured ¹⁴CO₂ levels demonstrated removal of ertugliflozin by ultimate degradation or mineralization; cumulative ¹⁴CO₂ produced was 30.1% of the initial applied radioactivity (AR) at day 2, and 40.8% by test termination at day 28. In the biotic treatment, 94.2% AR was recovered at the 1 minute sampling interval, with 74.3% attributed to parent (ertugliflozin). Degradation of ertugliflozin continued, resulting in 1.5% AR and 0.2% AR attributed to parent at 8 hours and at test termination (day 28), respectively. Primary degradation of ertugliflozin resulted in the formation of 2 major transformation products. One relatively more polar transformation product reached a maximum of 35.2% of the initial AR at 5 hours, and declined to 2.2% by day 2. The second and relatively less polar transformation product, reached a maximum of 26.6% of AR by 1 hour, declining to 1.2% by 12 hours. The DT₅₀ for ertugliflozin was determined to be 0.7 hours. The DT₅₀ values for the two transformation products were determined to be 24.4 hours for the more polar product, and 1.59 hours for the less polar product.

Biodegradation in Surface Water (OECD 309) (Ref. III)

Ultimate biodegradation (CO₂ evolution) 36.7% in 28 days

24.5% remaining with solids at day 28

Parent - DT₅₀ 0.55 days, DT₉₀ 1.83 days

A 28-day study of the biodegradation of ertugliflozin in Brandywine Creek surface water containing approximately 8 g/L total suspended solids (TSS), was conducted. Disappearance of parent from the water-suspended solids system as a result of primary degradation, with 3.4% parent remaining by day 2, was reported. The formation of several minor transformation products (TPs), present at < 7% each, and 1 major, less polar TP, identified as TP5 was observed. TP5 reached a peak concentration of 56.8% by day 2 and decreased to 3% by day 21. Approximately 37% mineralization was observed by day 28. The DT₅₀ and DT₉₀ values for parent were 0.55 days and 1.83 days, respectively. The major transformation product DT₅₀ and DT₉₀ values were 4.66 days and 15.5 days, respectively.

Sediment Transformation (OECD 308) (Ref. III)

Mineralization 29.9% – 45.1% at 100 days

Aqueous Dissipation Rate 11.4 and 14.8 days (DT₅₀ water)

Total System Disappearance Rate 21.2 and 26.6 days (DT₅₀)

A 100-day study of the aerobic transformation of ertugliflozin was conducted in two aquatic-sediment systems, Brandywine Creek and Choptank River. Test systems were dosed with 129.9 μg of 14C-labeled ertugliflozin per test chamber. Test systems were incubated at approximately 20 ºC for up to 100 days. Aerobic conditions were maintained by gently bubbling a stream of air through the water layers in each test vessel. Effluent gases were passed through trap vials containing ethylene glycol to trap volatile organic compounds, and trap vials containing alkali solutions to trap evolved carbon dioxide. Duplicate test chambers of each type were sacrificed for transformation analyses immediately after test substance application and on days 7, 14, 28, 56, and 100. Overlying water layers, sediment extracts and sediment solids were analyzed separately for total radioactivity by liquid scintillation counting (LSC).

The mineralization or ultimate biodegradation observed in the Brandywine and Choptank water-sediment systems over 100 days was 29.9% and 45.1%, respectively. Water layers and sediment extracts were analyzed by HPLC/β-RAM for parent test substance and radio-labeled transformation products. Ertugliflozin rapidly dissipated from the water layer to the sediment layer resulting in aqueous dissipation DT₅₀ values of 11.4 and 14.8 days in the two systems tested. Maximum quantities of total transformation products in the water layers were detected on day 28, and accounted for 24.6% and 30.0% of AR. At test termination (day 100), total transformation products in the water layers accounted for 9.9% of AR in Choptank River and 2.2% of AR in Brandywine Creek.

Aqueous layer transformation product identification was performed on day 7 and day 28 water samples from the Choptank and Brandywine systems, respectively. TP5 was the predominant transformation product in the day 7 sample from the Choptank (Table 1). At day 28, the predominant transformation products detected in the water layer extracts from the Brandywine system were TP4 and TP5. Minor transformation products present at < 10% each were not identified.

Peak concentrations of ertugliflozin were detected on day 14 in the sediment extracts from the Choptank River (19.3%) and Brandywine Creek (32.4%). At test termination, the amount of ertugliflozin present in the sediments decreased to 3.8% (Choptank River) and 8.5% (Brandywine Creek). The sediment DT₅₀ values for ertugliflozin in the two systems tested were 7.0 and 26.1 days and the DT₉₀ values were 23.4 and 86.6 days. The fraction of non-extractable, irreversibly bound residues in the Choptank River and Brandywine Creek sediments at test termination were 30.5% and 51.5%, respectively. DT₅₀ and DT₉₀ values for ertugliflozin in the total water-sediment systems were determined to be 21.2 days and 70.2 days in Choptank River, and 26.6 days and 88.5 days in Brandywine Creek, respectively. The calculated DT₅₀ values for the disappearance of the primary, less polar transformation product (TP5) from the total test systems evaluated were 24.8 and 3.5 days.

Justification of chosen degradation phrase:

Since half-life < 32 days for total system, ertugliflozin is degraded in the environment.

Bioaccumulation

Partitioning coefficient (OECD 107) (Ref. III) 

Log D = 2.47 at pH 7

Justification of chosen bioaccumulation phrase:

Since log D < 4, ertugliflozin has low potential for bioaccumulation.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2023 (data 2022)”.

   
   

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

   http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

   
   

3. Pfizer, 2017. “Environmental Risk Assessment for Ertugliflozin”, 24 May 2017.

   
   

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

• 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

• 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                                 

• Cleuvers, M. (2003), Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Tox. Letts. 2003, 142, pp.185-194.                                                                                            

• 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     

• 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             

• 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                       

• 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                               

• Smithers Viscient Study No. 13674.6228. Final report: 06 March 2012. Metformin Hydrochloride - Activated Sludge Respiration Inhibition Test Following OECD Guideline 209

• 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.                                               

• 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)

• Smithers Viscient Study No. 13674.6233. Final report: 29 December 2011. [¹⁴C]Metformin Hydrochloride - Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308         

• 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                                        

• Eucreas^® (vildagliptin metformin fixed combination), Novartis Core data sheet, Version 3.0, 28 November 2016.