Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

Currently, moxifloxacin is marketed in Sweden as moxifloxacin hydrochloride. Moxifloxacin is the active pharmaceutical ingredient (API) and the marketed volume needs to be adjusted to this moiety for PEC calculation.

Moxifloxacin variety	Molecular weight	Conversion factor	Sale volume (2022)	API amount (2022)
Moxifloxacin	401.44 g/Mol	1.00	---	---
Moxifloxacin hydrochloride	437.9 g/Mol	0.92	395.21	363.60
Total sale volume API				363.60

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) = 0.05 μg/L

Where:

A = 363.60 kg (total sold amount API in Sweden year 2022, data from IQVIA / LIF)

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available

P = number of inhabitants in Sweden = 10 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Reference I)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies*

Algae (green algae, Desmodesmus subspicatus):

EC₁₀ 72 hours (growth rate) < 400 µg/L, E_rC₅₀ 72 hours (growth rate) > 25000 μg/L. Guideline OECD 201. (Reference II)

Algae (green algae, Anabaena flos-aquae):

EC₁₀ 72 hours (growth rate) = 3.16 μg/L, E_rC₅₀ 72 hours (growth rate) = 9.96 μg/L. Guideline OECD 201. (Reference III)

Crustacean (waterflea, Daphnia magna):

Acute toxicity

EC₅₀ 48 hours (immobilization) > 91000 μg/L. Guideline OECD 202. (Reference II)

Chronic toxicity

EC₁₀ 21 days (reproduction, mortality) = 5.5 μg/L. Guideline OECD 211. (Reference IV)

Fish (zebrafish, Danio rerio):

Acute toxicity

LC₅₀ 96 hours (survival) > 91600 μg/L. Guideline OECD 203. (Reference II)

Fish (fathead minnow, Pimephales promelas):

Chronic toxicity

NOEC 28 days (survival, growth) = 224 μg/L. Guideline OECD 210. (Reference V)

The PNEC was calculated by division of the lowest effect level (EC₁₀) of the most sensitive taxonomic group considering an appropriate assessment factor (AF). The most sensitive taxonomic group were algae and the lowest effect level was reported as EC₁₀ = 3.16 µg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish).

PNEC = 3.16 µg/L / 10 = 0.32 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.05 µg/L / 0.32 µg/L = 0.16.

Justification of chosen environmental risk phrase:

A risk quotient between 0.1 and 1 qualifies for the phrase “Use of moxifloxacin has been considered to result in low environmental risk.”.

Degradation

Biotic degradation

Ready degradability:

The study reported 0 % biodegradation of moxifloxacin in 28 days, i.e., the substance is not readily biodegradable. Guideline EC method C.4-C. (Reference VI)

Simulation studies:

Biodegradability of moxifloxacin was further assessed in a sediment-water transformation study. The ¹⁴C-labelled test item moxifloxacin was incubated in an aerated system, which contained intact lake sediment and overlaying water. Two types of sediments were used, one with higher organic carbon content and fine particle size (sediment-system 1, Nordhafen), the other with lower content of organic carbon and coarse grain size (sediment-system 2, Tegeler See), both in Berlin, Germany. The substance was incubated over a period of 100 days. A stock solution (total radioactivity: 5 MBq) was prepared in water and then added to the test vessels.

For the preparation of the test vessels 50 g of intact sediment and 150 g sample water were filled in each washing flask and 200 µL (equivalent to 0.1 MBq) of the stock solution were applied. In order to absorb evolving ¹⁴CO₂ and volatile compounds a trap of soda lime and silica wool saturated with paraffin oil was put on each washing flask except the flasks from the first time point (day 2). 18 test vessels were prepared for sediment-system 1 (Nordhafen) and 18 test vessels for sediment-system 2 (Tegeler See).

Samples for analysis were taken after 2, 8, 15, 43, 68 and 100 days. Three test vessels for each time point were removed for analysis. Radioactivity of [¹⁴C]-moxifloxacin in sediment was quantified by combustion analysis and radioassay. The water fraction was radioassayed by liquid scintillation counting (LSC). Hydrochloric acid was added to the soda lime fraction and evolving ¹⁴CO₂ was absorbed in a scintillation cocktail and radioassayed by LSC. The silica wool fraction was not further processed, since the mass balance did not indicate the production of a relevant volatile fraction.

The distribution of [¹⁴C] moxifloxacin to the sediment compartment and the disappearance from the water fraction was determined by plotting the radioactivity over time. The disappearance time (DT₅₀) was calculated by a kinetic modeling software (KIM, version 1.1). In one of the three replicates, oxygen content and pH value were determined at the beginning and the respective end.

The total mass balance ranged from 72 to 86 % of the total radioactivity (0.1 MBq) in sediment-system 1 and from 73 to 82 % of the total radioactivity (0.1 MBq) in sediment-system 2 without showing major differences between the sediment-systems.

[14C] Moxifloxacin remained only to about 0.6 and 5 % in the water phase of sediment location 1 and 2, respectively. After 0.3 and 0.6 days respectively, 50 % of the test item were removed from the water fraction. Ultimate biodegradation was low and accounted for 0.2 % of the radioactivity in sediment 1 and 2.

Thus, this study reported a half-life of substance moxifloxacin in water DT₅₀ = 0.3-0.6 days but no specific DT₅₀ in sediment/total system. Guideline OECD 308. (Reference VII)

Abiotic degradation

Hydrolysis:

Moxifloxacin was determined to be hydrolytically stable. Guideline EC, C7. (Reference VIII)

Justification of chosen degradation phrase:

Moxifloxacin established a DT₅₀ > 120 d for the total system and is resistant to hydrolysis, which qualifies for the phrase “Moxifloxacin is potentially persistent.”.

Bioaccumulation

Partitioning coefficient:

The log D_ow was reported as -0.36. Guideline OECD 117. (Reference IX)

Justification of chosen bioaccumulation phrase:

As the log D_ow was < 4 moxifloxacin is not considered bioaccumulative which qualifies for the phrase “Moxifloxacin has low potential for bioaccumulation.”.

Excretion (metabolism)

Moxifloxacin is excreted to 45-48 % as parent compound and to 14 % as acyl-glucuronide and 37-38 % sulfoconjugate metabolites. (Reference X)

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

2. Assessment on ecological behavior of BAY 12-8039. Institute for environmental analysis, Bayer AG, study no. 622 N/97 (1997) – Report in German.

3. BAY 12-8039 Alga, Growth Inhibition Test with Anabaena sp. (Anabaena flos-aquae), 72 hours. Bayer Pharma AG, study no. TOXT100101-3, report no. 120727BL (2012).

4. Reproduction study of Moxifloxacin (BAY 12-8039) in Daphnia magna. Bayer HealthCare, study no. TOXT2079961, report no. A45807 (2010).

5. Early-life-stage test with moxifloxacin (Bay 12-8039) on the fathead minnow (Pimephales promelas). Bayer HealthCare, study no. TOXT9080399, report no. A47404 (2010).

6. Biodegradation of [14C]BAY 12-8039. Bayer AG, study no. 71106108 (1997).

7. Aquatic-sediment study (aerobic) with moxifloxacin (BAY 12-8039). Bayer HealthCare AG, study no. TOXT3079926, report no. A44978 (2012).

8. Moxifloxacin HCl / BAY 12-8039 / Report on Physicochemical Properties / Rate of hydrolysis. Bayer Schering Pharma AG, study no. 09100279, report no. A49031.

9. Moxifloxacin HCl / BAY12-8039 / Report on physicochemical properties / N-Octanol/Water Partition Coefficient. Bayer Schering Pharma AG, study no. 09100284, report no. A49034.

10. Stass H, Kubitza D (1999). Pharmacokinetics and elimination of Moxifloxacin after oral andintravenous administration in man. J. Antimicrobial Chemotherapy 43, Suppl. B, 83-90.