Detaljerad miljöinformation

Cilastatin

Environmental risk: Use of cilastatin has been considered to result in insignificant environmental risk.

Degradation: Cilastatin is degraded in the environment.

Bioaccumulation: Cilastatin has low potential for bioaccumulation.

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 = 0.0056 μg/L

Where:

A = 41 kg (total sold amount API in Sweden year 2022, 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) (Ref. III):

EC₅₀ 72 h (growth rate) > 99 mg/L

NOEC = 99 mg/L

No effects seen up to highest concentration tested

Green Algae (Pseudokirchneriella subcapitata) (OECD 201) (Ref. IV):

EC₅₀ 72 h (growth rate) > 99 mg/L

NOEC = 99 mg/L

No effects seen up to highest concentration tested

Crustacean, water flea (Daphnia magna):

Acute toxicity (OECD 202) (Ref. V)

EC₅₀ 48 hour (mobility) > 99 mg/L

NOEC = 99 mg/L

No effects seen up to highest concentration tested

Chronic toxicity (OECD 211) (Ref. VI)

EC₁₀ 21 day (mortality, growth, reproduction ) > 10 mg/L

No effects seen up to highest concentration tested

Fish, fathead minnow (Pimephales promelas):

Acute toxicity (OECD 203) (Ref. VII)

LC₅₀ 96 h (mortality) > 111 mg/L

NOEC = 111 mg/L

No effects seen up to highest concentration tested

Chronic toxicity (OECD 210) (Ref. VIII)

EC₁₀ 32 d (growth) > 9.9 mg/L

No effects seen up to highest concentration tested

PNEC = 990 μg/L (9900 μg/L / 10 based on the chronic EC₁₀ for the fathead minnow with an assessment factor (AF) of 10

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0056/990 = 6E-06, i.e. PEC/PNEC ≤ 1 which justifies the phrase

"Use of cilastatin has been considered to result in insignificant environmental risk.”

Biotic Degradation

Ready Biodegradation (OECD 301B) (Ref. IX)

The ready biodegradability of cilastatin was determined by the Carbon Dioxide Evolution Test Method (OECD Guideline 301B). The results indicated that the activated sludge inoculum was active, degrading the reference substance an average of 99.5% and that the test substance was not inhibitory to the inoculum at the concentration tested, as the toxicity control exceeded 25% degradation by Day 14 of the study. The average cumulative percent biodegradation for cilastatin was 27.7%, therefore it is not considered readily biodegradable.

Sediment Transformation (OECD 308) (Ref X)

This study was conducted to assess the transformation of cilastatin in two aerobic aquatic sediment systems. Test systems were dosed with 75 µg (12 µCi) of ¹⁴C-labeled Cilastatin per test chamber. Test systems were incubated in the dark at 20 ± 2 ºC for up to 100 days. Aerobic conditions were maintained by gently bubbling a stream of air through the water layers in each test vessel. Effluent gases were passed through vials containing ethylene glycol to trap volatile organic compounds and vials containing alkali solutions to trap evolved carbon dioxide. Duplicate test chambers were sacrificed for analyses immediately after test substance application and at 1, 3, 7, 14, 49, and 100 days after application. Overlying water layers, sediment extracts, sediment solids, potassium hydroxide (KOH) traps, and ethylene glycol (EG) traps were analyzed separately for total radioactivity by liquid scintillation counting (LSC).

Mean material balances (recoveries) ranged from 95.1% to 110.7% throughout the study. The mean cumulative amounts of mineralization observed on day 100 were 68.2% in Brandywine Creek and 94.0% in Choptank River test systems. Formation of ¹⁴CO₂ was the main route of transformation observed during the study. The mean amount of ¹⁴C in the sediment layers (i.e. sediment extracts + sediment solids) increased during the study to maximums of 41.9% in Brandywine Creek on day 14 and 21.0% in Choptank River on day 14. The fractions of radiolabeled residues that could not be extracted from the sediment layers (sediment solids + centrifuged solids) at the end of the test were 26.8% and 14.0%, respectively. A single supplemental extraction was done with each of four solvents, and each solvent extract removed ≤3% of the ¹⁴C from the solids. Sediment samples collected on days 1, 3, 7, 14, 49, and 100 were extracted on the days of collection. The weights of the sediment layers, after decanting the overlying waters, were determined. The entire sediment layers were transferred from the original test vessels into 250-mL high-density polyethylene (HDPE) bottles using 150 mL of extraction solvent. The extraction solvent was water + 0.5% NH4OH. The HDPE bottles were capped, shaken by hand to mix the sediment solids with the extraction solvent, placed in an ultrasonic bath for about 1 minute, placed on a gyratory shaker table set at
~250 revolutions per minute (rpm) for at least thirty minutes, and then centrifuged at 2500 rpm for ten minutes. The solvent extracts were decanted into glass bottles. Empty test vessels were rinsed with ~100 mL of extraction solvent, and the rinses were added to the sediment solids remaining in the HDPE bottles. The extraction process was repeated a second time, and the second extracts were combined with the first extracts. The extraction procedure was repeated two more times, and all four extracts were combined. The combined sediment extracts were poured into graduated cylinders, and the total volumes were recorded. The sediment extracts were returned to the glass bottles, and triplicate aliquots were removed for LSC analysis. The remaining sediment extracts were placed in a refrigerator for storage. The weights of the sediment solids remaining after extractions were determined, and the solids were placed in a refrigerator for storage.

Water layers and sediment extracts were analyzed by HPLC/β-RAM for parent test substance and radio-labeled transformation products.

The test substance disappeared from the water layers of both test systems primarily by transformation. Disappearance was best described using a simple first-order (SFO) model. The half-lives from Brandywine Creek and Choptank River water layers were 2.5 and 2.8 days, respectively. Partitioning of test substance from the water layers into the sediment layers and decline in the sediment layers were analyzed using a two-compartment model with data from both the water layers and sediment extracts. The amount of test substance measured in the sediment extracts never exceeded 1%, except for one Brandywine Creek sample collected on day 1 that had 3.5% cilastatin. The models did not provide acceptable results for sediment layers, so the half-lives were considered unreliable. The disappearance of test substance from total test systems (water layers + sediment extracts) was best described using a simple first-order (SFO) model. The half-lives from Brandywine Creek and Choptank River test systems were 2.5 and 2.8 days, respectively. The mean maximum amounts of transformation products in the water layers plus sediment extracts were 53.9% on day 7 in Brandywine Creek and 69.8% on day 7 in Choptank River. In addition to cilastatin, a single major transformation product peak (>10% of applied ¹⁴C) was observed with a retention time of approximately 11.6 minutes (TP3). This peak accounted for a maximum of 31.1% of the ¹⁴C in one of the Choptank River samples on day 7. Two other transformation product peaks were observed at approximately 12.7 and 13.3 minutes (TP4 and TP5) that accounted for >5% of the ¹⁴C on day 7 in both test systems.

Justification of chosen degradation phrase:

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

Bioaccumulation

Partitioning coefficient (OECD 107) (Ref. XI)

log Kow = -3.53 at pH 7

Justification of chosen bioaccumulation phrase:

The log K_ow < 4 justifies the phrase “Cilastatin has low potential for bioaccumulation.”

References

I. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2023 (data 2022)”.

II. ECHA, European Chemicals Agency. 2012 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

III. Wildlife International, 2016. "CILASTATIN: A 72-HOUR TOXICITY TEST WITH THE CYANOBACTERIA (Anabaena flos-aquae)," Project No. 105P-121, Easton, MD, USA, 29 June 2016.

IV. Wildlife International, 2016. "CILASTATIN: A 72-HOUR TOXICITY TEST WITH THE FRESHWATER ALGA (Pseudokirchneriella subcapitata)," Project No. 105P-120, Easton, MD, USA, 29 June 2016.

V. EAG (formerly Wildlife International), 2016. "CILASTATIN: A 48-HOUR STATIC ACUTE TOXICITY TEST WITH THE CLADOCERAN (Daphnia magna)," Project No. 105A-229, Easton, MD, USA, 18 November 2016.

VI. Eurofins EAG Agroscience, LLC., 2019. "CILASTATIN: A FLOW-THROUGH LIFE-CYCLE TOXICITY TEST WITH THE CLADOCERAN (Daphnia magna)" Project No. 105A-232C, Easton, MD, USA, 26 November 2019.

VII. EAG (formerly Wildlife International), 2016. "CILASTATIN: A 96-HOUR STATIC ACUTE TOXICITY TEST WITH THE FATHEAD MINNOW (Pimephales promelas)" Project No. 105A-230, Easton, MD, USA, 18 November 2016.

VIII. Eurofins EAG Agroscience, LLC., 2019. "CILASTATIN: AN EARLY LIFE-STAGE TOXICITY TEST WITH THE FATHEAD MINNOW (Pimephales promelas)" Project No. 105A-231, Easton, MD, USA, 09 April 2020.

IX. Wildlife International, 2016. "CILASTATIN: READY BIODEGRADABILITY BY THE CARBON DIOXIDE EVOLUTION TEST METHOD," Project No. 105P-181, Easton, MD, USA, 26 May 2016.

X. Eurofins EAG Agroscience, LLC., 2019. "CILASTATIN: AEROBIC TRANSFORMATION IN AQUATIC SEDIMENT SYSTEMS " Project No. 105E-186, Easton, MD, USA, 20 December 2019.

XI. EAG (formerly Wildlife International), 2016. "DETERMINATION OF THE n-OCTANOL/WATER PARTITION COEFFICIENT OF CILASTATIN BY THE SHAKE FLASK METHOD," Project No. 105C-1691, Easton, MD, USA, 5 August 2016.

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 = 0.0058 μg/L

Where:

A = 42 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 72 h (growth rate) = 4.6 ug/L

NOEC = 2 ug/L

Green Algae (Pseudokirchneriella subcapitata) (OECD 201 ) (Ref IV)

EC₅₀ 72 h (growth rate) > 74,000 ug/L

NOEC= 74,000 ug/L

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

Chronic toxicity

NOEC (21 day) (growth rate, reproduction, survival) > 11,000 ug/L 

Non-toxic up to highest concentration tested

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

Chronic toxicity

NOEC 32 days (mortality) = 9400 ug/L

Non-toxic up to highest concentration tested

PNEC =0.2 μg/L (2 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 = 0.006/0.2 = 0.029, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of imipenem has been considered to result in insignificant environmental risk.

Biotic degradation

Ready degradability (OECD 301B) (Ref. VII)

Ultimate biodegradation: 28.9% to CO2 in 28 days

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

54.3 – 57.9% to CO₂ in 100 days

DT₅₀ (total system) = 1.49 – 2 days

This study was conducted to assess the transformation potential of Imipenem in two aerobic aquatic sediment systems. Test systems were dosed with 229 μg (12 μCi) of ¹⁴C-labeled Imipenem per test vessel. Test systems were incubated in the dark at 18 ° to 21 ºC for up to 100 days. Aerobic conditions were maintained by gently bubbling a stream of air through the water layers in each test vessel. Effluent gases were passed through vials containing ethylene glycol to trap volatile ¹⁴C-labeled organic compounds and vials containing alkali solutions to trap evolved ¹⁴C-labeled carbon dioxide. Duplicate test vessels were sacrificed for analyses immediately after test substance application and at 3, 7, 14, 28, 56 and 100 days after application. Overlying water layers, sediment extracts, sediment solids, potassium hydroxide (KOH) traps, and ethylene glycol (EG) traps were analyzed separately for total radioactivity by liquid scintillation counting (LSC).

The sediment layers were extracted on the day of collection, except for Day 0 samples, which were not extracted, as recovery from the water layers was considered quantitative. The weights of the sediment layers, after decanting the overlying waters, were determined. The Day 0 sediment layers were air-dried and combusted to determine the total amount of radioactivity. The total radioactivity in the Day 0 sediments were assumed to be [14C]Imipenem. Sediment samples collected on Days 3, 7, 14, 28, 56 and 100 were extracted on the days of collection. The entire sediment layers were transferred from the original test vessels into 250-mL high-density polyethylene (HDPE) bottles using ~150 mL of extraction solvent. The extraction solvent was 0.5M phosphate buffer, pH ~7.4. The HDPE bottles were capped, shaken by hand to mix the sediment solids with the extraction solvent, placed on a gyrotory shaker table set at ~250 revolutions per minute (rpm) for at least thirty minutes, and then centrifuged at 2500 rpm for 15 minutes. The solvent extracts were decanted into glass bottles. Empty test vessels were rinsed with ~100 mL of extraction solvent, and the rinses were added to the sediment solids remaining in the HDPE bottles. The extraction process was repeated a second time, and the second extracts were combined with the first extracts. The extraction procedure was repeated two more times with ~100 mL of extraction solvent each time, and all four extracts were combined. The combined sediment extracts were poured into graduated cylinders, and the total volumes were recorded. The sediment extracts were returned to the glass bottles, and triplicate aliquots were removed for LSC analysis. The remaining sediment extracts were placed in a freezer for storage. The weights of the sediment solids remaining after extractions were determined, and the solids were placed in a refrigerator for storage, or were submitted immediately after extraction to begin processing for combustion.

Sediment solids not submitted directly for combustion processing were removed from refrigerated storage within 9 or 10 days for combustion analyses. The sediment solids were transferred to large watch glasses, and the total weights were recorded. The samples were placed in a fume hood to allow some of the solvent to evaporate. The total weights were recorded again, and weight losses due to solvent evaporation were calculated. Samples were ground and homogenized using a mortar and pestle and stainless steel spatulas. Five aliquots of each sample were weighed for combustion analysis using a Perkin-Elmer Model 307 Sample Oxidizer. The combustion samples were analyzed by LSC. The remaining sediment solids were transferred to glass bottles and returned to refrigerated storage. The total radioactivity in the sediment layers was calculated from the sum of the radioactivity in the sediment extracts plus sediment solids.

Supplemental extractions were performed on Day 100 samples to evaluate the potential to remove additional radiolabeled materials from the sediment solids remaining after extractions.  Extraction solvents were selected to represent a range of polarities from very polar (water) to very non-polar (hexane).  Aliquots (4-5 g) of the sediment solids were weighed into scintillation vials.  The aliquots were extracted with 10 mL of either water, methanol, or hexane.  The extraction procedure was as follows: solvents were added to the samples, vials were capped and shaken by hand for about 1 minute, vials were placed in an ultrasonic bath for at least five minutes, vials were placed on a gyrotory shaker table set at ~250 rpm for at least sixty minutes, vials were centrifuged at ~2000 rpm for ten minutes, extracts were decanted into graduated cylinders and volumes were recorded.  A portion of each water extract was further centrifuged at 10000 × G for five minutes. Triplicate aliquots of the extracts were removed for LSC analysis.  The remaining extracts and sediment solids were placed in refrigerated storage.

Mean material balances (recoveries) ranged from 92.8% to 104.8% AR throughout the study. The mean cumulative amounts of mineralization observed on Day 100 were 54.3% AR in Brandywine Creek and 57.9% in Choptank River test systems. Formation of ¹⁴CO2 was the main route of transformation observed during the study. The mean amount of ¹⁴C in the sediment layers (i.e. sediment extracts + sediment solids) increased during the study to maximums of 52.7% AR in Brandywine Creek and 35.6% AR in Choptank River, both on Day 14. The fractions of radiolabeled residues that could not be extracted from the sediment layers (sediment solids) at the end of the test were 35.7% AR and 27.8%, respectively. A single supplemental extraction was done with each of four solvents, and each solvent extract removed the equivalent of ≤1.6% of the ¹⁴C from the solids.

Water layers were analyzed by HPLC/β-RAM for parent test substance and radio-labeled transformation products.  The test substance disappeared from the water layers of both test systems primarily by transformation. The DT₅₀ values from Brandywine Creek and Choptank River water layers were 1.56 and 1.27 days, respectively. Poor extractability from sediment and unsuitable properties of the extraction solvent system precluded HPLC/β-RAM analyses of sediment extracts, and all radioactivity in sediment extracts was evaluated as parent Imipenem in order to provide conservative estimates of test substance behavior in sediments and total systems. Sediment data did not show a suitable pattern of decline for statistical analysis and was not modeled. The DT₅₀ for Imipenem in Brandywine Creek and Choptank River sediments are both reported as >100 days, the duration of the study. Sediment data was combined with water layer data to obtain estimates for total system disappearance. Total system data used for statistical analyses is shown in the table below as % AR:

There were no transformation products that could be definitively classified as accounting for >10% AR.

Justification of chosen biotic degradation phrase:

Since DT₅₀ < 32 days for the total system, the phrase “Imipenem is degraded in the environment” is thus chosen.

Bioaccumulation

Partitioning coefficient (OECD 107) (Ref. IX)

Log K_ow < - 1 at pH 7

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. EAG Eurofins, 2019. "Imipenem: A 96-Hour Toxicity Test with the Cyanobacteria (Anabaena flos-aquae)," Project No. 105P-124A, Easton, MD, USA, 20 December 2019.

4. EAG (formerly Wildlife International), 2016. "Imipenem: A 96-Hour Toxicity Test with the Freshwater Alga (Pseudokirchneriella subcapitata)," Project No. 105P-115, WIL, Easton, MD, USA, 2 November 2016.

5. EAG Eurofins, 2020. "Imipenem: A Flow-Through Life-Cycle Toxicity Test with the Cladoceran (Daphnia magna)," Project No. 105A-235A, Easton, MD, USA, 10 January 2020.

6. EAG Eurofins, 2020. "Imipenem: An Early Life-Stage Toxicity Test with the Fathead Minnow (Pimephales promelas)," Project No. 105A-234, Easton, MD, USA, 10 January 2020.

7. Wildlife International, 2016. "Imipenem: Ready Biodegradability by the Carbon Dioxide Evolution Test Method," Project No. 105E-176, WIL, Easton, MD, USA, 03 March 2016.

8. EAG Eurofins, 2020. "[¹⁴C]-Imipenem: A Prolonged Sediment Toxicity Test with the Midge (Chironomus Riparius) using Spiked Sediment", Project No. 105A-236, Eurofins EAG, Easton, MD, 4 Nov 2020.

9. EAG (formerly Wildlife International), 2016. "Imipenem: Estimation of n-octanol/water partition coefficient using high performance liquid chromatography (HPLC)," Project No.105C-165, WIL, Easton, MD, USA, 26 July 2016.

   
   

Detaljerad miljöinformation

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 = 0.00001 μg/L

Where:

A = 0.1 kg (total sold amount API in Sweden year 2022, 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) (Ref. III):

EC₅₀ 72h = 86 mg/L

NOEC 72h = 12 mg/L (growth)

Blue Green Algae (Anabaena flos-aquaea) (OECD 201) (Ref. IV):

EC₅₀ 72h > 11 mg/L

NOEC 72h = 11 mg/L

No effects noted for any endpoint (growth and yield)

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

Chronic toxicity

NOEC 21d = 2.7 mg/L (reproduction)

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

Chronic toxicity

NOEC 32d = 9.2 mg/L

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

PNEC = 270 μg/L (2.7 mg/ L/ 10 based on the most sensitive NOEC for the daphnia and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00001/270 = 1E-07, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of relebactam has been considered to result in insignificant environmental risk.

Biotic degradation

Biodegradation in Activated Sludge

11.3% to CO2 in 28 days (OECD 314B) (Ref VII)

DT₅₀ = 88 days

Not readily biodegradable

Water/Sediment Transformation (OECD 308) (Ref VIII)

Half-life (total system) 20-41 days

4-5% to CO2 after 100 days

No degradates > 10%

The rate and route of transformation of [¹⁴C]MK-7655 was studied in two US aquatic sediment systems. Test samples consisted of 50 g sediment (dry weight equivalent) aliquots, which were flooded with 150 mL of corresponding overlying water, connected to volatile traps, and incubated under aerobic conditions in the dark at 20 ± 2 °C. [¹⁴C]MK-7655 was applied at a nominal concentration of 1.0 µg/mL.

Water/sediment samples were analyzed at 0, 3, 14, 28, 55, and 101 days of incubation. Water/sediment samples were extracted according to the extraction method and analyzed by LSC and HPLC/RAM for determination and profiling of extractable residues. The post-extraction sediments were combusted and analyzed by LSC for determination of non-extractable residues. The volatile traps were analyzed by LSC for determination of ¹⁴CO₂ and volatile organics. Representative post-extraction soil samples were additionally characterized by harsh extraction and organic matter fractionation. Representative volatile traps were additionally characterized by barium chloride precipitation.

Average material balance ranged from 92.7 to 100% AR over the course of the 101‑day study for both the Taunton River and Weweantic River aerobic test systems.

The rate of degradation of [¹⁴C]MK-7655 was determined using linear kinetics in Excel. The results are summarized in the table below.

Evidence of primary biodegradation was observed for [¹⁴C]MK-7655 in the aerobic water/sediment test systems. Several minor peaks were observed in some of the chromatograms for the Taunton River and Weweantic River test samples. Minor peaks represented less than 10% AR in the water and sediment extracts and were not characterized further.

Justification of chosen biotic degradation phrase:

Since half-life for the total system was ≤120 days, the phrase “Relebactam is slowly degraded in the environment” is chosen.

Bioaccumulation

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

Log Kow = -2.0 at pH 7

Justification of chosen bioaccumulation phrase:

Since log Kow < 4, relebactam has low potential for bioaccumulation.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - 2023 (data 2022)”.

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, 2016. "MK-7655 − 72-Hour Toxicity Test with the Freshwater Green Alga, Pseudokirchneriella subcapitata Following OECD Guideline 201," Report No. 359.6992, SV, Wareham, MA, 04 February 2016.

4. Smithers Viscient, 2016. "Relebactam (MK-7655) - 72-Hour Toxicity Test with the  Freshwater Cyanobacterium, Anabaena flos-aquae, Following OECD Guideline 201," Report No. 359.6993, SV, Wareham, MA, 4 Oct. 2016.

5. Smithers Viscient, 2016. "MK-7655 – Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Flow-Through Conditions Following OECD Guideline 211," Report No. 359.6995, SV, Wareham, MA, 13 July 2016.

6. Smithers Viscient, 2016. "Relebactam (MK-7655) – Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas)," Report No. 359.6994, SV, Wareham, MA, 29 June 2016.

7. Smithers Viscient, 2016. "[14C]MK-7655 – Determination of the Biodegradability of a Test Substance in Activated Sludge Based on OECD Method 314B," Report No. 359.6999, SV, Wareham, MA, 4 January 2017.

8. Smithers Viscient, 2016. "[14C]MK-7655 – Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308," Report No. 359.6998, SV, Wareham, MA, 30 Nov 2016.

9. Smithers Viscient, 2012. "MK-7655 - Determining the Partitioning Coefficient (n-Octanol/Water) by the Shake Flask Method Following OECD Guideline 107," Report No. 359.6647, SV, Wareham, MA, 02 August 2012.