Detaljerad miljöinformation

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*A(100-R)

PEC = 0.0008 μg/L

Where:

A = 6 kg (total sold amount API in Sweden year 2021, 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 = 93 mg/L (growth rate)

NOEC 72h = 6.3 mg/L

Blue-Green Algae (Anabaena flos-aquae) (OECD 201) (Reference IV): 

EC₅₀ 72h = 110 mg/L (growth rate)

NOEC 72h = 6.5 mg/L

Crustacean, water flea (Daphnia magna) (OECD 211) (Ref V): 

Chronic toxicity

NOEC 21d = 5.9 mg/L (reproduction)

Fish, fathead minnow (Pimephales promelas) (OECD 210) (Ref VI): 

Chronic toxicity

NOEC 32d = 5.1 mg/L

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

PNEC = 510 μg/L (5.1 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 = 0.0008/510 = 1.6E-06, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of daptomycin has been considered to result in insignificant environmental risk.

Degradation studies

Biodegradation in Activated Sludge

71% to CO₂ in 28 days (OECD 301B) (Ref. VII)

The mean cumulative net percent CO₂ evolved (percent biodegradation) from the aqueous test medium fortified with daptomycin at 10 mg C/L was 10.48% on day 7 (start of 10-day window), 43.77% on day 19, and 71.27% on day 28.

Sediment Transformation (OECD 308) (Ref. VIII):

DT₅₀ (total system) = 15.3 to 16.4 days

The rate and route of transformation of [¹⁴C]daptomycin was studied in two US aquatic sediment systems: Taunton River and Weweantic River test systems. Test systems consisted of 50 g sediment (dry weight equivalent) aliquots, which were flooded with 150 mL of corresponding overlying water, connected to volatile trapping solutions, and incubated under aerobic conditions in the dark at 20 ± 2 °C. [¹⁴C]Daptomycin was applied to the water layer at a nominal concentration of 1.0 µg/mL.

Water/sediment samples were analyzed at 0, 3, 14, 28, 56, and 101 days of incubation. Sediment samples were extracted once with approximately 150 mL of 4/1 acetonitrile/0.1M hydrochloric acid in purified reagent water (v/v), transferred to a Nalgene bottle, placed on a shaker table at approximately 200 rpm for 10 minutes, and then centrifuged at 3500 rpm for 10 minutes. The sediment extracts were decanted, the volume recorded, transferred to a Nalgene bottle, and analyzed by LSC. The extraction procedure was repeated up to two more times for each sampling interval using 4/1 acetonitrile/0.1 M hydrochloric acid in purified reagent water (v/v) for a total of three extractions. The extracts were then combined and analyzed by liquid scintillation counting (LSC) and high-performance liquid chromatography with radiometric detection (HPLC-RAM) for determination and profiling of extracted residues. Following combustion analysis, representative post-extraction solids (PES) samples were further extracted by placing approximately 20 g of each PES sample into a Whatman cellulose thimble in a Soxhlet extraction apparatus and adding approximately 300 mL of 4/1 acetonitrile/0.1M hydrochloric acid in purified reagent water (v/v), following overnight heating, the sample was allowed to cool and the thimbles were rinsed with approximately 15 mL of 4/1 acetonitrile/0.1M hydrochloric acid in purified reagent water (v/v). The volume was measured and the extract was analyzed by LSC. The volatile trapping solutions were analyzed by LSC for determination of ¹⁴CO₂ and volatile organics. Non-extractable residues in representative PES samples were additionally characterized by Soxhlet extraction and organic matter fractionation. Representative volatile trapping solutions were additionally characterized by barium chloride precipitation to confirm the presence of ¹⁴CO₂.

Average material balance ranged from 89.3 to 108% applied radioactivity (AR) over the course of the study for both the Taunton River and Weweantic River test systems (see Protocol Deviation).

Significant ultimate biodegradation of [¹⁴C]daptomycin was observed with evolution of ¹⁴CO₂ reaching an average maximum at day 101 of 48.9% AR for the Taunton River test samples and 52.1% AR for the Weweantic River test samples. Negligible amounts of radioactivity were observed in the ethylene glycol trapping solutions for both test systems.

The rate of transformation of [14C]daptomycin was determined using non-linear kinetics following FOCUS Kinetics guidelines calculated using Computer Assisted Kinetic Evaluation (CAKE) software. The results of the single first-order (SFO) model for the experimental data at 20 °C are summarized in the table below.

No major transformation products of [14C]daptomycin (>10% AR or >5% AR in two consecutive intervals) were observed in either test system. Several minor transformation products were observed in both the aqueous layer and sediment extracts for both test systems, and were not investigated further.

Justification of chosen degradation phrase:

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

Bioaccumulation

Partitioning coefficient (OECD 107) (Ref. IX): 

Log K_ow < -2 at pH 7

Justification of chosen bioaccumulation phrase:

Since log K_ow < 4, daptomycin has low potential for bioaccumulation.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2022 (data 2021)”.

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. Smithers Viscient, 2018. "Daptomycin - 72-Hour Toxicity Test with the Freshwater Green Alga, Pseudokirchneriella subcapitata", Report No.359.7039, Smithers Viscient Labs, Wareham, MA, 24 August 2018.

   
   

4. Smithers Viscient, 2018. "Daptomycin - 72-Hour Toxicity Test with the Freshwater Cyanobacterium, Anabaena flos-aquae", Report No.359.7040, Smithers Viscient Labs, Wareham, MA, 31 August 2018.

   
   

5. Smithers Viscient, 2018. "Daptomycin - Full Life-Cycle Toxicity Test with Water Fleas (Daphnia magna) Under Static-Renewal Conditions", Report No.359.7070, Smithers Viscient Labs, Wareham, MA, 21 September 2018.

   
   

6. Smithers Viscient, 2018. "Daptomycin – Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas)", Report No.359.7069, Smithers Viscient Labs, Wareham, MA, 3 December 2018.

   
   

7. Smithers Viscient, 2018. "Daptomycin – Determination of the Biodegradability of a Test Substance Based on OECD Method 301B (CO2 Evolution Test)", Report No.359.7041, Smithers Viscient Labs, Wareham, MA, 29 January 2018.

   
   

8. Smithers Viscient, 2019. "14C Aerobic Transformation in Aquatic Sediment Systems", Report No.359.7068, Smithers Viscient Labs, Wareham, MA, 2 May 2019.

   
   

9. Smithers Viscient, 2019. "Daptomycin – Determining the Partitioning Coefficient (n-Octanol/Water) by the Shake-Flask Method Following OECD Guideline 107", Report No.359.7043, Smithers Viscient Labs, Wareham, MA, 16 January 2019.