Detaljerad miljöinformation

PEC/PNEC = 0.0001488 µg/L / 950 µg/L = 1.83 x10-7

PEC/PNEC ≤ 0.1

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)      = 1.37*10^-6*A*(100-R)

PEC     = 1.37 * 10^-6 *1.2722*(100-0)

= 0.00017429 µg/L

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

= 1.2722kg

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

= 0 (default).

P          = number of inhabitants in Sweden =10*10⁶

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

= 200 L/day (ECHA default) (Ref 1)

D         = factor for dilution of wastewater by surface water flow

= 10 (ECHA default) (Ref 1)

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

Metabolism and excretion

Saxagliptin is extensively metabolised in humans to numerous metabolites. It is excreted in urine and faeces together with the primary metabolite, BMS-510849. This metabolite was indicated to be approximately half as potent as Saxagliptin in in vitro studies (Ref 15). Overall, following oral administration Saxagliptin accounted for 34.1% of the excreted dose (urine + faeces) and BMS-510849 accounted for 36.6% of excreted dose (urine + faeces) (Ref 2).

Ecotoxicity Data

Study	Method	Result	Ref
Activated sludge respiration inhibition test	OECD 209	3 hour NOEC (EC10) = 821 mg/L 3 hour EC50 >1000 mg/L	3
Acute Toxicity to Zebra Fish, Danio rerio	OECD 203	96 hour NOEC(mortality) = 45 mg/L 96 hour LC50(mortality) >91 mg/L	4
Toxicity to green algae, Pseudokirchneriella subcapitata	OECD 201	72 hour NOEC(growth rate) = 21 mg/L 72 hour EC50(growth rate) > 140 mg/L 72 hour NOEC(biomass) = 8.5 mg/L 72 hour EC50(biomass) = 91 mg/L	5
Chronic toxicity to Daphnia magna,	OECD 211	21 day NOEC(survival, reproduction and length) = 35 mg/L 21 day LOEC(survival, reproduction and length) = 94 mg/L	6
Fish Early-Life Stage Toxicity with Pimephales promelas	OECD 210	32 day NOEC(hatch, survival, weight and length) = 9.5 mg/L 32 day LOEC(hatch, survival, weight and length) > 9.5 mg/L	7
Toxicity to Chironomus riparius under Static Conditions	OECD 218	28 day NOEC = 6.4mg/kg dry weight 28 day LOEC = 16mg/kg dry weight 28 day EC50 > 100mg/kg dry weight	8

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 = 0.00017429 µg/L / 950 µg/L

PEC/PNEC = 1.83 x10^-7

As the PEC/PNEC ratio ≤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

Study	Method	Result	Ref
Aerobic biodegradation	OECD 310	The mean ultimate biodegradation value based on CO2 evolution peaked at 5.90% of theoretical at Day 28. Not readily biodegradable.	10
Adsorption/ desorption to soils and sludge	OECD 106	5 Soils Mean Kd (ads) = 13.7 ± 6.63 Mean Koc = 700 ± 327 Activated sewage sludge Mean Kd = 19.6 Mean Koc = 71.6	11
Aerobic transformation in aquatic sediment systems	OECD 308	The half-lives (DT50) in the water were 20 days [LOC] and 23.2 days [HOC] The half-lives (DT50) in the total system were 20 days [LOC] and 30 days [HOC] <15% of applied radioactivity remaining as parent compound at the end of the study	12

Biodegradation

Saxagliptin cannot be classified as readily biodegradable (Ref 10) and is unlikely to partition to the sludge solids during wastewater treatment based on finding from an OECD106 study (Ref 11).

The rate of aerobic and anaerobic transformation of [¹⁴C]Saxagliptin (Ref 12) was studied in two sediments (Goose River with a high organic carbon content of ~2.8% and Golden Lake with a low organic carbon content of ~1%) with associated overlying waters for 102 Days. Only the observations in under aerobic conditions are reported here.

The half-life (DT50) of Saxagliptin in the water fraction was 20 days and 23.2 days in the LOC and HOC systems, respectively.

Sediment samples were extracted twice using acetonitrile:water (80:20) and once with acetonitrile:water:concentrated hydrochloric acid (80:20:0.1). By Day 102 an average of 42.2% and 67.6% of the applied radioactivity was associated with the sediment in the LOC and HOC systems, respectively. Of this, an average of 21.9% and 26.4% were extractable in the LOC and HOC systems, respectively. The half-life of saxagliptin in the total systems was 20 days [LOC] and 30 days [HOC] in the LOC and HOC systems, respectively.

Two major degradation products (>10% of the applied radioactivity) were observed in each of the aerobic test systems. These metabolites were detected at HPLC retention times of approximately 13 and 18 minutes in the HOM system, and 18 and 20 minutes in LOM system.  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 0.1% of the applied radioactivity was detected as volatile organics.

At the end of the study, 3% and 7.3% of the applied radioactivity were identified as parent in the LOC and HOC systems, respectively.

As the total system half-life was ≤32 days, and less than 15% parent compound was remaining at the end of the study, the phrase ‘Saxagliptin is degraded in the environment’ has been assigned.

In Swedish: Saxagliptinhydroklorid bryts ned i miljön.

Bioaccumulation Data

Saxagliptin is ionisable, 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

Study	Method	Result	Ref
Octanol/water partition coefficient, OECD 107	OECD 107	Log Dow at pH 4 = -1.74 Log Dow at pH 8.2 = 0.114 Log Dow at pH 9 = 0.169	13
Hydrolysis, OECD 111	OECD 111	DT50 at pH 7, 20oC = 34.5 days DT50 at pH 9, 20oC = 41.0 days	14
Dissociation Constant	-	pKa = 7.3	15

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

   Doc ID-002352373

4. 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

5. 12534.6297. Saxagliptin (BMS 477118-11) – Toxicity to the Freshwater Green Alga Pseudokirchneriella subcapitata. Report No. 12534.6297, 2007.

   Doc ID-002352369

6. 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

7. 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

8. Saxagliptin (BMS-477118) - Full Life-Cycle Toxicity Test with Sediment-Dwelling Midges (Chironomus riparius) Under Static Conditions, Following OECD Guideline 218. Report 12534.6346, 2008. Doc ID-002352378

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. Determining 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, 2008. Doc ID-002352347

12. 12534.6321. [¹⁴C]Saxagliptin (BMS 477118-14) – Aerobic and Anaerobic Transformation in Aquatic Sediments Systems 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 (BMS 477118) – 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

15. Investigator Brochure BMS-477118 Saxagliptin. Version 7, 22-Jul-2009. Doc ID-002352235