Detaljerad miljöinformation

Avibactam is highly soluble at environmentally relevant pH and is not expected to bioaccumulate, volatilise or adsorb to soils and sediments. It was not readily biodegradable, however evidence from the water-sediment transformation test, in conjunction with the results of the definitive hydrolysis test, suggests that avibactam is not expected to be persistent in the aquatic environment.

Physical properties³

Solubility at pH 5: >1020 mg/L

Solubility at pH 7: >1040 mg/L

pKa: estimated using ACD Labs: strongest pKa(Base): -1.8 and strongest pKa(Acid): -4.9

Vapor pressure: estimated (Modified Grain method)  EPISuite: 7.69×10^-17 mmHg

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 = 0.000438 μg/L

Where:

A =	3.19406 kg (total sold amount API in Sweden year 2021)13
R =	0% removal rate (worst case scenario)
P =	number of inhabitants in Sweden = 10×106
V (L/day) =	wastewater volume per capita and day = 200 (ECHA default)1
D =	factor for waste water dilution by surface water flow = 10 (ECHA default)1

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Activated sludge microorgansims (guideline OECD 209)⁴

NOEC (respiration inhibition) = 1 000 000 µg/L

EC₅₀ (respiration inhibition) = > 1 000 000 µg/L

Green alga (Raphidocelis subcapitata) (guideline OECD 201)⁵

NOEC 72 h (growth rate, chronic toxicity) = 120 000 μg/L

LOEC 72 h (growth rate, chronic toxicity) = > 120 000 μg/L

Daphnids (Daphnia magna) (guideline OECD 211)⁶

NOEC 21 days (reproduction, chronic toxicity) = 100 000 μg/L

LOEC 21 days (reproduction, chronic toxicity) = > 100 000 μg/L

Fathead Minnow (Pimephales promelas) (guideline OECD 210)⁷

NOEC 32 days (reproduction, chronic toxicity) = 2 000 μg/L

LOEC 32 days (reproduction, chronic toxicity) = > 2 000 μg/L

Midge (Chironomus riparius) (guideline OECD 218)⁸

NOEC 28 days (emergence, chronic toxicity) = 300 000 μg/L

LOEC 28 days (emergence, chronic toxicity) = > 300 000 μg/L

Based on the lowest NOEC for the species Pimephales promelas and using the assessment factor² of 10, the PNEC is calculated to 2 000 / 10 = 200 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0. 000438 / 200 = 2.19×10^-6, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ‘Use of avibactam has been considered to result in insignificant environmental risk.’

Degradation

Biotic degradation

Ready degradability

Test results < 11% degradation in 28 days, i.e. the substance does not show properties of ready degradability (guideline OECD 301)⁹.

Simulation studies¹⁰

The degradation of [¹⁴C]avibactam in aquatic sediment systems was assessed according to the OECD 308 Test Guideline.  Mineralisation was substantial in both the high and low organic carbon test systems, reaching 72% and 73% (respectively) of the applied radioactivity by Day 100. Sediment samples were extracted sequentially using Reverse Osmosis (RO) water; 1:1 methanol:RO water; methanol and 0.1% formic acid in methanol. The extraction efficiencies of the radioactivity in the sediments were low, with a maximum of 4% of the total applied radioactivity being extracted. Day 21 sediment samples were subjected to a further extraction with acetonitrile, however little additional radioactivity was recovered. By Day 100, non-extractable residues measured in the high and low organic carbon sediments accounted for 35% and 27% of the applied radioactivity, respectively. Avibactam total system DT50 values in the high and low organic carbon sediment systems were 7 and 16 days, respectively, with no degradation products detected. At the end of the study, the active substance was no longer detectable. Therefore, the substance is degraded in the environment.

Abiotic degradation

Hydrolysis¹¹

Sterile freshwater hydrolysis half-life was measured according to guideline OECD 111.

Half-life (days)	pH	Temperature °C
42	5	25
16	5	40
8.1	5	50
36	7	25
8.6	7	40
3.7	7	50
4	9	25
0.82	9	40
0.31	9	50

Justification of chosen degradation phrase

Avibactam does not pass the test for readily degradable. The simulation study shows that the substance is degraded in the environment. Therefore, the phrase “Avibactam is degraded in the environment” is chosen.

Bioaccumulation

Partitioning coefficient (guideline OECD 107)¹²

Log D_ow = < -1.39 at pH 5

Log D_ow = < -1.36 at pH 7

Log D_ow = < -1.30 at pH 9

Justification of chosen bioaccumulation phrase

Since log D_ow < 4 at pH 7, the substance has low potential for bioaccumulation.

References

1. ECHA, European Chemicals Agency. 2016 Guidance on information requirements and chemical safety assessment chapter R16.

2. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment chapter R10.

3. Study report 10-0180/B: NXL104: Water Solubility (Shake Flask Method). April 2011. Brixham Environmental Laboratory, Brixham, UK. Report No BR0378/B

4. Study report 11409271A: Avibactam: Activated sludge respiration inhibition test. March 2014. Brixham Environmental Laboratory, Brixham, UK. Report No BR0923/B

5. Study report 10-0180/E: June 2011. Brixham Environmental Laboratory, Brixham, UK. Report No BR0443/B

6. Study report 10-0180/G: NXL104: Determination of chronic toxicity to Daphnia magna. November 2011. Brixham Environmental Laboratory, Brixham, UK. Report No BR0557/B

7. Study report 10-0180/H: NXL 104: Determination of the effect on the Early-life Stage of the Fathead minnow (Pimephales promelas). September 2011. Brixham Environmental Laboratory, Brixham, UK. Report No BR0493/B

8. Study report 11-0066/D: [¹⁴C] NXL104: Determination of the effects in a water-sediment system on the emergence of Chironomus riparius using spiked sediment. February 2012. Brixham Environmental Laboratory, Brixham, UK. Report No BR0541/B

9. Study report 11-0066/A: [¹⁴C]NXL 104: 28 day ready biodegradation, modified 301B. February 2012. Brixham Environmental Laboratory, Brixham, UK. Report No BR0545/B

10. Study report 11-0066/I: [¹⁴C]NXL104: Aerobic transformation in aquatic sediment systems. November 2013. Brixham Environmental Laboratory, Brixham, UK. Report No BR0658/B

11. Study report 10-0180/J: Hydrolysis as a function of pH test in support of the Environmental Risk Assessment of NXL104. February 2013. Brixham Environmental Laboratory, Brixham, UK. Report No BR0489

12. Study report 10-0180/C: NXL104: Determination of n-octanol-water partition coefficient (n-octanol/water): shake flask method. Report No. BR0396/B. Brixham Environmental Laboratory, Brixham, UK. April 2011.

13. IQVIA KG Consumption 2021 report.