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 = 0.0001 μg/L

Where:

A = 0.5 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

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

EC₅₀ 72h = 0.04 mg/L (growth rate)

NOEC 72h = 0.0018 mg/L (growth rate)

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

Chronic toxicity

NOEC 21d = 9.6 mg/L (reproduction, growth rate, survival)

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

Chronic toxicity

NOEC 32d = 10 mg/L

No effects noted for any endpoint

PNEC = 0.18 μg/L (1.8 ug/L/ 10 based on the most sensitive NOEC for the blue-green algae and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0001 /0.18 = 0.00038, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of ceftolozane has been considered to result in insignificant environmental risk.

Biotic degradation

Ready Biodegradation (OECD 301D) (Ref. VI):

0% Degradation in 28 days

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

22-55% to CO₂ in 99 days

DT₅₀ (total system) = 1.5 – 1.7 days

14C-labelled ceftolozane was incubated under aerobic conditions in the laboratory in two water/sediment systems (Swiss Lake [SL] and Schoonrewoerdsewiel [SW]) at 20 ± 2 °C in the dark for 99 days. The initial test substance concentration in the water layer of both test systems was 0.36 mg/L. The test systems were aerated continuously without disturbing the sediment. The outcoming air was passed subsequently through polyurethane foam (PUF), one trap containing ethylene glycol monoethyl ether (EGME) for trapping of organic volatiles and two traps containing 2M NaOH for trapping of CO2.

Samples were taken immediately after spiking (single samples) and after 3, 7, 14, 28, 60 and 99 days of incubation (duplicate samples). At each sampling point, radioactivity in the traps, the water layer and sediment extract was determined by LSC. Radioactivity remaining in the sediment layer after extraction was determined by combustion/LSC. The water layer was directly analysed by HPLC. The sediment was extracted with 80/20 (v/v) acetonitrile/water; the extract was analysed by HPLC after evaporation of acetonitrile. Additional extractions were performed to characterise the bound residues.

Upon addition of 14C-labelled ceftolozane to the water layer, ceftolozane degraded/dissipated from the water layer to less than 5% of applied radioactivity within 14 days of incubation in both the SL and SW system. Mineralisation was a major degradation pathway, with 55% (SL) or 22% (SW) of applied radioactivity recovered as CO2 at the end of the incubation period. Organic volatiles were not

detected <0.1%). Bound residues increased throughout the study, reaching a mean maximum of 35% of applied radioactivity after 7 days of incubation in the SL water/sediment system and 61% of applied radioactivity at the end of the incubation period of the SW water/sediment system. None of the substance was detected in the sediment layer.

One transformation product, which exceeded 10% of applied radioactivity, was detected in the water layer of both test systems. All other detected transformation products were less than 10%.

Justification of chosen biotic degradation phrase:

Since half-life < 32 days for total system and >15% remained as parent compound, ceftolozane is slowly degraded in the environment.

Bioaccumulation

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

Log Kow = - 0.21 at pH 7.4

Justification of chosen bioaccumulation phrase:

Since log Kow < 4, ceftolozane 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. IBACON, 2013. "CXA-101: A GLP Fresh Water Cyanobacteria Anabaena flosaquae Growth Inhibition Test", Report CX.101.TX.030; Institut für Biologische Analytik Project 77791210 und Consulting IBACON GmbHArheilger Weg 17 64380 Rossdorf Germany.

   
   

4. WIL Research, 2013. "CXA-101: A GLP DAPHNIA MAGNA, REPRODUCTION TEST (SEMI-STATIC)", Report CX.101.TX.023; WIL Research, Europe B.V.Hambakenwetering 7 5231 DD ‘s-Hertogenbosch, The Netherlands.

   
   

5. WIL Research, 2013. ""CXA-101: A GLP FATHEAD MINNOW EARLY-LIFE STAGE TOXICITY TEST (SEMI-STATIC)"", Report CX.101.TX.005; WIL Research, Europe B.V.Hambakenwetering 7 5231 DD ‘s-Hertogenbosch, The Netherlands."

   
   

6. WIL Research, 2013. "CXA-101: A GLP ASSESSMENT OF READY BIODEGRADABILITY USING A CLOSED BOTTLE TEST", Report CX.101.TX.006; WIL Research, Europe B.V.Hambakenwetering 7 5231 DD ‘s-Hertogenbosch, The Netherlands.

   
   

7. WIL Research, 2013. "CCXA-101: A GLP WATER/SEDIMENT STUDY", Report CX.101.TX.011; WIL Research, Europe B.V.Hambakenwetering 7 5231 DD ‘s-Hertogenbosch, The Netherlands.

   
   

8. Pion Labs, 2012. "logP/logD Determination", Report R122400-Rev00; Pion Inc. 10 Cook St., Billerica, MA, USA.

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 = 0.111 μg/l. μg/L

Where:

A = 810 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

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

NOEC (72 hours) (growth rate) = 440 ug/L

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

Chronic toxicity

NOEC (21 day) (growth rate, reproduction, survival) = 9600 ug/L 

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

Chronic toxicity

NOEC (32 day) (growth rate, survival, development) = 10600 ug/L

PNEC = 44 μg/L (440 ug/L/ 10 based on the most sensitive NOEC for the blue-green algae and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.011/44 = 0.0025, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of tazobactam has been considered to result in insignificant environmental risk.

Biotic degradation

Ready degradability (OECD 301D) (Ref. VI)

Not readily biodegradable (2 to 10% degradation in 28 days)

Sediment Transformation (OECD 308) (Ref. VII)

Half-life = 5 -12 days in total water-sediment systems

Half-life = 4.5 – 11. 3 days in water layers

Tazobactam degraded in the Swiss Lake (SL) and Schoonrewoerdsewiel (SW) systems with a degradation time for 90% degradation (DT₉₀) of 39.7 or 16.5 days, respectively. Tazobactam remained primarily in the water layer with no major amounts detected in the sediment layer. Tazobactam degraded to five transformation products that were found in the water layer at >10% of applied radioactivity in both test systems, with M-2 (confirmed to be Tazobactam M1) determined to be the major transformation product after 14 days in either system. No transformation products exceeded 10% of applied in the sediment layer.

14C-labelled Tazobactam Sodium was incubated under aerobic conditions in the laboratory in the SL and SW water/sediment systems at 20 ± 2 °C in the dark and aerated continuously without disturbing the sediment. The outcoming air was passed subsequently through polyurethane foam (PUF), one trap containing ethylene glycol monoethyl ether (EGME) for trapping of organic volatiles and two traps containing 2M NaOH for trapping of CO2. The SL system was incubated for 97 days and the SW system was incubated for 104 days. The initial 14C-labelled Tazobactam Sodium concentrations in the water layer were 0.30 and 0.31 mg/L for SL and SW system, respectively.

Samples were taken immediately after spiking (single samples) and after 3, 7, 14, 28, 57 (SL), 64 (SW), 97 (SL) and 104 (SW) days of incubation (duplicate samples). At each time point, radioactivity in the traps, the water layer and sediment extract was determined by LSC. Radioactivity remaining in the sediment layer after extraction was determined by combustion/LSC.

The water layer was directly analysed on HPLC. The sediment was extracted with 80/20 (v/v) acetonitrile/water. After evaporation of acetonitrile, the remaining aqueous residue was analysed on HPLC. A selection of samples was analysed by TLC.

Upon addition of 14C-labelled Tazobactam Sodium to the water layer, Tazobactam degraded in the water layer to less than 5% of applied radioactivity within 57 days of incubation in the SL system and to less than 5% of applied within 28 days of incubation in the SW system. No major amounts of Tazobactam Sodium were detected in the sediment layer: at maximum 7% of applied was detected in the sediment of the SL system after 3 to 7 days of incubation and 5% in the SW system after 3 days of incubation. Mineralisation to CO2 was not significant (≤ 2%) in both systems and no organic volatiles were detected (≤ 0.1%). Bound residues increased to 19% (SL) or 11% (SW) of applied at the end of the incubation period.

Five transformation products, each exceeding 10% of applied radioactivity were detected in both test systems. The majority of the activity of these transformation products was recovered in the water layer. The major transformation product was M-2 at 30% of applied (only detected in water layer) after 14 days of incubation in the SL system and at 53% of applied (only detected in water layer) after 14 days of incubation in the SW system. Upon subsequent analysis (using a sponsor supplied reference standard) M-2 was identified as Tazobactam M1. M-3 was detected at 15% of applied (only detected in water layer) after 57 days of incubation in the SL system and 28% of applied (26% in the water layer) after 104 days of incubation in the SW system. M-4 was detected at 20% of applied (18% in the water layer) after 28 days of incubation in the SL system and at 31% of applied (25% in the water layer) after 28 days of incubation in the SW system. M-5 was detected at 15% of applied (12% in the water layer) after 97 days of incubation in the SL system and at 37% of applied (31% in the water layer) after 104 days of incubation in the SW system. M-7 was detected at 11% of applied (9.5% in the water layer) after 97 days of incubation in the SL system and at 18% of applied (14% in the water layer) after 28 days of incubation in the SW system.

Justification of chosen biotic degradation phrase:

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

Bioaccumulation

Partitioning coefficient (OECD 107) (Ref. VIII)

Log K_ow = - 0.63 at pH 7.4

Justification of chosen bioaccumulation phrase:

Since log K_ow < 4, the substance 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. IBACON, 2013. "Tazobactam Sodium: A GLP Fresh Water Cyanobacteria to Anabaena flos-aquae Growth Inhibition Test", Report CX.101.TX.029; Institut für Biologische Analytik und Consulting( IBACON GmbH) Arheilger Weg 17 64380 Rossdorf Germany.

4. WIL Research, 2013. "TAZOBACTAM SODIUM: A GLP DAPHNIA MAGNA, REPRODUCTION TEST (SEMI-STATIC)", Report CX.101.TX.014; WIL Research, Europe B.V.Hambakenwetering 7 5231 DD ‘s-Hertogenbosch, The Netherlands.

5. WIL Research, 2013. "TAZOBACTAM SODIUM: A GLP FATHEAD MINNOW EARLY-LIFE STAGE TOXICITY TEST (SEMI-STATIC)", Report CX.101.TX.016; WIL Research, Europe B.V.Hambakenwetering 7 5231 DD ‘s-Hertogenbosch, The Netherlands.

6. WIL Research, 2013. "TAZOBACTAM SODIUM: A GLP ASSESSMENT OF READY BIODEGRADABILITY USING A CLOSED BOTTLE TEST", Report CX.101.TX.017; WIL Research, Europe B.V.Hambakenwetering 7 5231 DD ‘s-Hertogenbosch, The Netherlands.

7. WIL Research, 2013. "TAZOBACTAM SODIUM: A GLP WATER/SEDIMENT STUDY", Report CX.101.TX.022; WIL Research, Europe B.V.Hambakenwetering 7 5231 DD ‘s-Hertogenbosch, The Netherlands.

8. Prion, 2012. "log P/log D Determination" R122381-Rev03; Prion Inc, 10 Cook St, Billerica, MA, USA .