Detaljerad miljöinformation

PEC/PNEC = 0.0440 /100 = 4.4x 10^-4

PEC/PNEC ≤ 0.1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is based on following data and calculated using the equation outlined in the fass.se guidance (Ref 1):

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*321.42*(100-R)

= 0.0440 µg/L

A (kg/year) = total sold amount API in Sweden year 2023, data from IQVIA/Lif        

= 321.42kg

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

= 0 (default)

P = number of inhabitants in Sweden

= 10 *10⁶

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

= 200 (default, Ref 1)

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

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

(Note: Whilst dapagliflozin is metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as parent dapagliflozin).

Metabolism

After oral administration, dapagliflozin is metabolised and excreted via faeces (approximately 21%) and to a larger extent via urine (approximately 75%) (Ref 2). The main part of the dose is excreted as metabolites, where the largest fraction is constituted by urinary glucuronide conjugates (60-70%) (Ref 3). Approximately 17% is excreted as parent; 15.6% via faeces and 1.2% via urine.

The only metabolite which is pharmacologically active is BMS-511926. The total renal and faecal excretion of BMS-511926 is <1% of dose (Ref 2). The glucuronide conjugates are not pharmacologically active, but it is not known if they are stable to enzymatic hydrolysis back to parent compound mediated by, for example, microflora.

Ecotoxicity data

Study Type	Method	Result	Ref
Activated sludge, respiration inhibition test	OECD209	3 h EC50 >200 mg/L 3 h NOEC = 200 mg/L	4
Toxicity to green algae, Pseudokirchneriella subcapitata, growth inhibition test	OECD201	72 hour NOECgrowth rate = 37 mg/L 72 hour LOECgrowth rate = 67 mg/L 72 hour EC50growth rate = 120 mg/L 72 hour NOECbiomass = 21 mg/L 72 hour LOECbiomass = 37 mg/L 72 hour EC50biomass = 48 mg/L	5
Acute toxicity to the giant water flea (crustacean) Daphnia magna	OECD202	48 hour EC50 >120 mg/L 48 hour NOEC = 120 mg/L	6
Fish early-life stage toxicity with fathead minnow, Pimephales promelas	OECD210	32 day NOEC = 1.0 mg/L 32 day LOEC > 1.0 mg/L based on hatch, survival, standard length, and dry weight	7
Long-term toxicity to Daphnia magna	OECD211	21 day NOAEC* = 10 mg/L	8
Long-term toxicity to the sediment dwelling midge, Chironomus riparius	OECD218	28 day NOEC = 150 mg/kg dry sediment 28 day LOEC > 150 mg/kg dry sediment, based on emergence, development rate and sex ratio	9

EC50 the concentration of the test substance that results in a 50% effect

NOEC no observed effect concentration

LOEC lowest observed effect concentration

NOAEC no observed adverse effect concentration

*A marginal positive effect on reproduction and length was statistically significant at 10 mg/L but considered to be non adverse for the purposes of ERA

PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the results from the chronic toxicity to fathead minnow (Pimephales promelas), the most sensitive species, and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 10).

PNEC = 1000/10 µg/L = 100 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC = 0.0440µg/L

PNEC = 100 µg/L

PEC/PNEC = 4.4x 10^-4

The PEC/PNEC ratio is < 0.1 which justifies the phrase: ‘Use of dapagliflozin has been considered to result in insignificant environmental risk’.

In Swedish: “Användning av dapagliflozin har bedömts medföra försumbar risk för miljöpåverkan” under the heading “Miljörisk”.

Environmental Fate Data

Study Type	Method	Result	Ref
Aerobic biodegradation	OECD301F	11% after 28 days. Not readily biodegradable	11
Adsorption/desorption to sludge	OPPTS guideline 835.1110	Kd(ads) = 51 L/Kg Koc = 138 L/Kg*	12
Aerobic transformation in aquatic sediment systems	OECD308	Mass balance 83-120% of applied radioactivity The half-lives (DT50) in the total system ranged from approx. 35.5 – 92.2 days Less than 10% parent in total system by day 8 Extensive mineralisation (14CO2 formation) was observed in both high and low organic matter vessels with 35 and 68% of the applied radioactivity after 99 days Kdsediment = 12 kg/L, based on measured partitioning at 8 days	13

Kd Distribution coefficient for adsorption

Koc Organic carbon normalized adsorption coefficient

*K_oc = Kd(ads)/ 0.37

Biotic degradation

The biodegradability of dapagliflozin was assessed in an OECD 301F study, where it was found to be not readily biodegradable (Ref 11).

The degradation of dapagliflozin in aquatic sediment systems was assessed according to the OECD 308 Test Guideline. In this test two different sediments were used, one with high organic matter (HOM) and one with low organic matter content (LOM). Radiolabelled test substance was dosed into the overlying water and the subsequent dissipation from the water phase, and partitioning and/or degradation in the sediment, was observed over a 99 day test period and test vessels were monitored for CO₂ evolution over 148 days.

The applied radiolabel dissipated rapidly from the water phase and partitioning into the sediment phase was observed. Concentrations of radiolabel in the sediment phase peaked around 8 days in both systems and thereafter declined. An average of 24% of applied radioactivity (AR) in the LOM system and an average of 44% AR in the HOM system remained as non-extractable residue (NER) by day 99.

Radiolabel associated with dapagloflozin parent declined to 6.3% AR and 1% AR by day 15 in the HOM and LOM systems, respectively. Transformation of dapagliflozin into a possible seven transient transformation products and associated extensive mineralisation were observed with 35% AR and 68% AR evolved as CO² after 99 days in HOM and LOM systems, respectively.

Conservative dissipation half-lives of 92.2 days (HOM) and 35.5 days (LOM) were derived by fitting total system values (extracted residue and NER in water and sediment) to a Single First-Order Rate Model. Although parent-specific DT50 values were not reported, the data demonstrate that dapagliflozin parent was rapidly lost from the water phase with no accompanying increase of parent found in sediment extracts. This, coupled with the evidence of extensive mineralisation and multiple transient metabolites, demonstrates that dapagliflozin was extensively degraded in both the high and low organic matter water-sediment systems.

Based on the results of both the OECD 301F and 308 studies, dapagliflozin has been assigned the risk phrase: ‘Dapagliflozin is slowly degraded in the environment.’

In Swedish: ‘Dapagliflozin bryts ned långsamt i miljön.’ under the heading “Nedbrytning”.

Bioaccumulation

As dapagliflozin is not ionisable within the environmentally relevant pH range (Ref 14) the octanol-water partition coefficient was measured at pH 7.4. Since Log P_ow < 4, dapagliflozin has low potential to bioaccumulate and the phrase ‘Dapagliflozin has low potential for bioaccumulation’ is assigned.

In Swedish: ‘Dapagliflozin har låg potential att bioackumuleras’ under the heading “Bioackumulering”.

Physical Chemistry Data

Study Type	Method	Result	Ref
Octanol-water distribution coefficient	OECD107	log Pow = 2.34 at pH 7	15
Water solubility	OECD105	pH 5 = 720 mg/L pH 7 = 538 mg/L pH 9 = 946 mg/L	16
Hydrolysis (preliminary study)	OECD111	<10% after 5 days at 50°C (pH 5 & 7) 11.5 % after 5 days at 50°C (pH 9) t½ at 25°C ≥ 1 year	17

References

1. Fass.se (2012).  Environmental classification of pharmaceuticals at www.fass.se: Guidance for pharmaceutical companies https://www.fass.se/pdf/Environmental_classification_of_pharmaceuticals-120816.pdf

2. Mass balance and metabolism of [¹⁴C]BMS-512148 in healthy male subjects. Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. Protocol Number MB102006. November 2006

3. Comparative Biotransformation of [14C]Dapagliflozin after Oral Administration to Intact Rats, Dogs, Mice, and Humans. Bristol-Myers Squibb Company. Research & Development Department of Preclinical Candidate Optimization. November 2008.

4. Dapagliflozin: Effect on the respiration rate of activated sludge. BL8577/B.  Brixham Environmental Laboratory, Brixham, UK. October 2008.

5. Dapagliflozin: Toxicity to the green alga Pseudokirchneriella subcapitata. BL8587/B.  Brixham Environmental Laboratory, Brixham, UK. November 2008.

6. Dapagliflozin: Acute toxicity to Daphnia magna. BL8590/B.  Brixham Environmental Laboratory, Brixham, UK. September 2008.

7. Dapagliflozin: Determination of effects on the Early-Life Stage of the fathead minnow (Pimephales promelas). BL8638/B.  Brixham Environmental Laboratory, Brixham, UK. December 2008.

8. Dapagliflozin: Chronic toxicity to Daphnia magna. BL8622/B.  Brixham Environmental Laboratory, Brixham, UK. March 2009.

9. [¹⁴C]Dapagliflozin: Effects in sediment on emergence of the midge, Chironomus riparius. BL8661/B.  Brixham Environmental Laboratory, Brixham, UK. March 2009.

10. ECHA (European Chemicals Agency) 2008. Guidance on information requirements and chemical safety assessment.  Chapter R.10: Characterisation of dose [concentration]-response for environment http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

11. Dapagliflozin: Determination of 28 day ready biodegradability. Report No. BL8586/B. Brixham Environmental Laboratory, Brixham, UK. July 2008.

12. Dapagliflozin: Activated sludge sorption isotherm. Report No. BL8614/B. Brixham Environmental Laboratory, Brixham, UK. August 2008.

13. Dapagliflozin: Aerobic transformation in aquatic sediment systems. BL8594/B. Brixham Environmental Laboratory, Brixham, UK. February 2009.

14. S.1.3 General Properties: Dapagliflozin Propanediol. VV-RIM-01656312. April 2016

15. Dapagliflozin: Determination of octanol/water partition coefficient. Report No. BL8585/B. Brixham Environmental Laboratory, Brixham, UK. June 2008.

16. Dapagliflozin: Determination of Water Solubility: Shake Flask Method. Report No. BLS3433/B. Brixham Environmental Laboratory, Brixham, UK. June 2008.

17. Dapagliflozin: Hydrolysis as a function of pH - preliminary study results summary.  BLS3434/B.  Brixham Environmental Laboratory, Brixham, UK. June 2008.