Detaljerad miljöinformation

PEC/PNEC = 23.4 µg/L / 100 µg/L = 0.23

PEC/PNEC ≤ 1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The PEC is based on the following data:

PEC (µg/L) = (A*10⁹*(100-R))/(365*P*V*D*100)

PEC (µg/L) = 1.5*10^-6*A*(100-R)

A (kg/year) =total sold amount API in Sweden year 2017, data from IQVIA (former IMS Health and Quintiles).

R (%) = 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 = 9 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Ref. 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. 1)

(Note: The factor 10⁹ converts the quantity used from kg to μg).

A = 155977.33 kg

R = 0 

PEC = 1.5 x 10^-6 x 155977.33 x (100-0) = 23.4 µg/L

Metabolism

Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans (Ref. 2).

Ecotoxicity data

_{Note 1 - Geometric average (GA) of 2 data points}

_{Note 2 - Geometric average (GA) of 4 data points}

_{Note 3 - Geometric average (GA) of 3 data points}

PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three tropic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on results from the assessment of water flea (Ceriodaphnia dubia) study, NOEC = 1 mg/L, and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 11).

PNEC = 1000 µg/L/10 = 100 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 23.4 / 100 µg/L = 0.23 µg/L, i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of metformin hydrochloride has been considered to result in low environmental risk.”.

In Swedish: ”Användning av metforminhydroklorid har bedömts medföra låg risk för miljöpåverkan.”.

Environmental Fate Data

Biodegradation

Results from the aerobic biodegradation test (Ref. 12), showed that metformin hydrochloride is not readily biodegradable.

Evidence from the OECD 308 study (Ref. 13) is that metfromin hydrochloride is likley to dissipate from the aqueous phase and partition into the sediment phase.

High organic matter (HOM) sediment system:

The average mass balance ranged from 93.3 – to 100.2% of applied radioactivity (AR) throughout the 102-day study. The AR declined rapidly in the water phase, by Day 14 26.3% and by Day 27 only 4.5% remained, with < 1% of the initial concentration remaining in the water phase by Day 102. At the end of the test, Day 102, 13.1% of the AR was associated with the sediment. Despite the investigation of a number of different extraction solvents (acetoniltrile: purified reagent water: concentrated hydrochloric acid), 12.8% remained non-extractable.

Metformin hydrochloride was extensively biodegraded, the cumulative amount of ¹⁴CO₂ evolved was 64% of AR by Day 27. The total system half-life was 6.59 days.

In the water and the sediment combined, two degradation products were present at >10% AR at Day 14. However, these were transient degradation products and neither was detected from Day 56 onwards. These were not considered further.

Low organic matter (LOM) sediment system:

The average mass balance ranged from 93.3 – to 103.9% of AR. Dissipation of the radioactivity from the water to the sediment was slower than that observed in the HOM test vessels, with 28.8% remaining in the water phase at Day 14, and 11.2% remaining at Day 102. Very little mineralisation was observed (3.2% at Day 102). The radioactivity in the test vessel remained associated with the sediment. At Day 14, 73.6% remained associated with the sediment, of which 30.7% of the AR was extractable. At Day 102, 81.5% of the AR was associated with the sediment in the low organic matter (LOM) vessels, however the extractable fraction had decreased to 14.0% of the AR.

Extractability of metformin hydrochloride was good. The proporotion of radioactivity associated with the non-extractable residues (NER) increased throughout the study, 68% AR at Day 102. The NER are considered non-bioavailable and therefore removed in the calculation of the LOM DT50 value. The total system half-life was 55 days.

Differences in the two systems can be explained by the fact that the degradation of metformin hydrochloride is believed to depend on the specific microorganisms in the HOM matrix at the time of dosing the can use metformin hydrochloride as a carbon source and subsequently biodegrade metformin hydrochloride, whereas the microorganisms in the LOM matrix do so to a lower extent. Additionally, the HOM sediment system had a higher microbial biomass which may also contribute to a higher amount of biodegradation in the HOM systems versus the LOM system.

Based on the data above, metformin hydrochloride is not predicted to be readily biodegraded during wastewater treatment. However, there is evidence that metformin hydrochloride will degrade within the aquatic environment, both in biotic and abiotic transformation (FDA 3.10 and OECD 308).

Based on the above, the phrase “Metformin hydrochloride is slowly degraded in the environment.” has been assigned.

In Swedish: “Metforminhydroklorid bryts ner långsamt i miljön.” under the heading “Nedbrytning”.

Bioaccumulation

Metformin hydrochloride has has no significant bioaccumulation potential, as indicated by the low Log Kow (Log Kow = -1.43). Therefore the statement “Metformin hydrochloride has low potential for bioaccumulation” has been assigned.
 

In Swedish: ”Metforminhydroklorid har låg potential att bioackumuleras.” under the heading ”Bioackumulering”.

Physical Chemistry Data

References

1. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (Version 3.0). February 2016.

   
   

2. Summary of Product Characteristics for Komboglyze Film-Coated Tablets. Accessed 21^st April 2016, and available at Link to document EMA

   
   

3. Hoberg, J., Metformin Hydrochloride - Acute Toxicity to the Freshwater Green Alga,Pseudokirchneriella subcapitata OECD 201, Springborn Smithers Laboratories, Inc.:Report No. 12534.6219, 2007.

   
   

4. Environmental Risk Assessment for metformin and its transformation product guanylurea in surface water. Caldwell.D, et al. SETAC Europe 24th Annual Meeting, Basle, Switzerland, May 11th–15th, 2014.

   
   

5. Hicks, S. L.; Acute Toxicity of Metformin HCl to Daphnia magna ABC Laboratories, Inc. Report No. 41778, Jul 14, 1994.

   
   

6. Putt, A., Metformin Hydrochloride - Full Life-Cycle Toxicity Test with Water Fleas Daphnia magna, Under Static-Renewal Conditions OECD 211, Springborn Smithers Laboratories, Inc.: Report No. 12534.6220, 2007.

   
   

7. Sword M. Static Acute Toxicity of Metformin HCl to Bluegill (Lepomis macrochirus) ABC Laboratories, Inc. Report number 41779, July 1994.

   
   

8. York, D., Metformin (BMS 207150) – Early Life-Stage Toxicity Test with Fathead Minnow, (Pimephales promelas), Following OECD Guideline 210. Smithers Viscient: Report No. 12534.6394, 2012.

   
   

9. Bradley, M., Metformin Hydrochloride – Toxicity Test with Sediment-Dwelling Midges (Chironomous riparius) Under Static Conditions, Following OECD Guideline 218. Smithers Viscient: Report No. 12534.6396, 2011.

   
   

10. Wood, J.; Microbial Growth Inhibition with Metformin HCl, ABC Laboratories, Inc. Report No. 41776, Jul 13, 1994.

    
    

11. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment. May 2008.

    
    

12. Bielefeld, T.A.; Aerobic Biodegradation of 14C-Metformin HCl in Water, ABC Laboratories, Inc. Report No. 41775, Aug 10, 1994.

    
    

13. McKnight, C. [¹⁴C]Metformin Hydrochloride [14C](BMS 201750) – Aerobic

    Transformation in Aquatic Sediments Following OECD Guideline 308. Smithers

    Viscient: Report No. 12534.6398, 2011.

    
    

14. Hallberg, C.; Hydrolysis of Metformin HCl as a function of pH, ABC Laboratories, Inc. Report No. 41774, Aug 10, 1994.

    
    

15. Putman, K.; Determination of the Aqueous Photodegradation of 14C-Metformin HCl, ABC Laboratories, Inc. Report No. 41950, Aug 11, 1994.

    
    

16. AstraZeneca Environmental Risk Assessment of Saxagliptin/Metformin Fixed Dose Combination [CV.000-594-251], June 2010.

    
    

17. Sorption / Desorption Springborn Smithers Laboratories FDA-3.08 12534.6221. July 2007.

Detaljerad miljöinformation

PEC/PNEC = 0.00034 µg/L / 950 µg/L

PEC/PNEC = 3.5 x10^-7

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The PEC is based on the following data:

PEC (µg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.5*10^-6*A*(100-R)

A (kg/year) = 2.2355 kg = total sold amount API (both saxagliptin and saxagliptin hydrochloride) in Sweden year 2018, data from IQVIA.

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). R = 0.

P = number of inhabitants in Sweden =9*10⁶

V (L/day) = volume of wastewater per capita and day = 200 L/day (Ref 1)

D = factor for dilution of waste water by surface water flow = 10 (Ref 1) (Note: The factor 10⁹ converts the quantity used from kg to μg)

PEC = 1.5 * 10^-6 *2.2355*(100-0) = 0.00034 µg/L

Metabolism and excretion

Saxagliptin is extensively metabolised in humans to numerous metabolites (Ref 2). Saxagliptin is excreted in urine and faeces together with the primary metabolite BMS-510849. This metabolite has approximately half of the pharmacological activity of saxagliptin in in vitro studies and is believed to contribute to the effects of saxagliptin in vivo (Ref 3). Overall, following oral administration (Ref 1) saxagliptin accounted for 34.1% of the excreted dose (urine + faeces) and BMS-510849 accounted for 36.6% of excreted dose (urine + faeces).

Ecotoxicity Data

EC50 50% Effect Concentration

LOEC Lowest Observed Effect Concentration

NOEC No Observed Effect Concentration

Predicted No Effect Concentration (PNEC)

Long-term tests have been undertaken for species from three trophic levels. Therefore, the PNEC is based on the lowest No Observed Effect Concentration (NOEC), 9.5 mg/L (Fish Early-Life Stage Toxicity with Pimephales promelas), and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref 9)

PNEC = 9.5 mg/L/10

= 950 µg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 0.00034 µg/L /950 µg/L

PEC/PNEC = 3.5 x10^-7

The PEC/PNEC ratio decides the wording of the aquatic environmental risk phrase. As the PEC:PNEC ≤0.1 the phrase ’Use of saxagliptin has been considered to result in insignificant environmental risk’ has been assigned.

In Swedish:Användning av saxagliptinhydroklorid har bedömts medföra försumbar risk för miljöpåverkan

Environmental Fate Data

Biodegradation

Saxagliptin cannot be classified as readily biodegradable (Ref 10) and, in domestic sewage, is unlikely to partition to the sludge solids during wastewater treatment (Ref 11).

The rate of aerobic and anaerobic transformation of [14C]Saxagliptin (Red 12) was studied in four sediments varying in pH, textural characteristics, organic matter content and microbial content (Goose River aerobic, Golden Lake aerobic, Goose River anaerobic and Golden Lake anaerobic sediments) with associated overlying waters for 102 Days.

The half-life (DT50) of saxagliptin in the water fraction ranged from 18.0 to 23.2 days in the aerobic and anaerobic test systems.

By Day 102 approximately 40-70% of the applied radioactivity was associated with the sediment, with 20-30% of the applied radioactivity extractable. Sediment samples were extracted twice using acetonitrile:water (80:20) and once with acetonitrile:water:concentrated hydrochloric acid (80:20:0.1). The half-life of saxagliptin in the total water/sediment test systems ranged from 20.0 to 31.5 days for the aerobic and anaerobic test systems.

Four major degradation products (>10% of the applied radioactivity) were observed at HPLC retention times of approximately 13, 18, 20 and 22 minutes for the aerobic and anaerobic test systems. Characterisation of these metabolites was performed by HPLC/MS/MS. The cumulative amount of evolved ¹⁴CO₂ was 2% of the applied radioactivity in each of the test systems. Less than 0.5% of the applied radioactivity was detected as volatile organics in the aerobic and anaerobic test systems and as ¹⁴CH₄ in the anaerobic test systems.

The total system half-life was ≤32 days; therefore the phrase ‘saxagliptin is degraded in the environment’ has been assigned.

In Swedish:saxagliptinhydroklorid bryts ned i miljön.

Bioaccumulation Data

Saxagliptin is ionisable (pKa 7.2), therefore the Log D_ow was determined across the environmentally relevant pH-range. The Log D_ow values are low; as such saxagliptin has no significant bioaccumulation potential and the phrase ‘Saxagliptin has low potential for bioaccumulation’ has been assigned.

In Swedish: saxagliptinhydroklorid har låg potential att bioackumuleras

Physical Chemistry Data

References

1. ECHA [European Chemicals Agency] 2016. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0). February 2016.

   http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

2. 930016961. Comparative Biotransformation of [14C]Saxagliptin after Oral Administration to Bile-Duct Cannulated Rats, Intact Rats, Dogs, Monkeys, and Humans. Bristol-Myers Squibb Company Internal Report 930016961, 2007.

   Doc ID-002356123

3. 930008287. In Vitro Potency and Specificity of BMS-477118 and Its Metabolite BMS-510849. Bristol-Myers Squibb Company Internal Report 930008287, 2004.

   Doc ID-002355026

4. 12534.6296. McLaughlin, S., Saxagliptin (BMS 477118-11) – Determination of Activated Sludge Respiration Inhibition. Report No. 12534.6296, 2007.

   Doc ID-002352373

5. 12534.6322. Saxagliptin (BMS 477118-11) – Acute Toxicity to Zebra Fish (Brachydanio rerio), Under Static Conditions Following OECD Guideline Number 203. Report No. 12534.6322, 2008.

   Doc ID-002352357

6. 12534.6297. Saxagliptin (BMS 477118-11) – Toxicity to the Freshwater Green Alga Pseudokirchneriella subcapitata. Report No. 12534.6297, 2007.

   Doc ID-002352369

7. 12534.6323. Saxagliptin (BMS 477118-11) – Full Life-Cycle Toxicity Test with Water Fleas, (Daphnia magna), Under Static Renewal Conditions, Following OECD Guideline #211. Report No. 12534.6323, 2008.

   Doc ID-002352365

8. 12534.6325. Saxagliptin (BMS 477118-11) – Early Life-Stage Toxicity Test with Fathead Minnow, (Pimephales promelas), Following OECD Guideline #210. Report No. 12534.6325, 2008.

   Doc ID-002352361

9. ECHA [European Chemicals Agency] 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment. May 2008

   http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

10. 12534.6295. Determination of the Biodegradability of Saxagliptin (BMS 477118-11) Based on the Draft OECD 310 Sealed Vessel CO₂ Evolution Biodegradation Test. Report No. 12534.6295, 2007.

    Doc ID-002352343

11. 12534.6320. [¹⁴C]Saxagliptin (BMS 477118-15) – Determining the Adsorption Coefficient (Koc) Following OECD Guideline 106. Report No. 12534.6320, 2007.

    Doc ID-002352347

12. 12534.6321. [¹⁴C]Saxagliptin (BMS 477118-14) – Aerobic and Anaerobic Transformation in Aquatic Sediments Following OECD Guideline 308. Report No. 12534.6321, 2008.

    Doc ID-002352352

13. 12534.6318. Saxagliptin – Determination of the n-Octanol/Water Partition Coefficient. Report No. 12534.6318, 2008.

    Doc ID-002352381

14. 12534.6319. [¹⁴C]Saxagliptin – Determination of the Abiotic Degradation of the Test Substance by Hydrolysis at Two Different pH Values Following OECD Guideline 111. Report No. 12534.6319, 2008.

    Doc ID-002352339