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 = 0.0032 µg/L

Where:

A = 23.5788 kg (total sold amount API in Sweden year 2020, data from IQVIA)

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10*10⁶

V (L/day) = volume of wastewater per capita and day = 200 (Ref I)

D = factor of dilution of waste water by surface water flow = 10 (Ref I)

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of levofloxacin is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit of 0.01 μg/L.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green algae, Pseudokircheriella subcapitata:

Acute toxicity:

EC₅₀ 72 h (growth inhibition): 7 400 μg/L

Protocol: FDA 4.01

(Ref II)

Cyanobacteria, Anabaena flos-aquae

Acute toxicity:

EC₅₀ 72 h (growth rate): 308 µg/L

EC₁₀ 72 h (growth rate): 44 µg/L

NOEC 72 h (growth rate): 25.5 µg/L

Protocol: OCDE Test Guideline 201

(Ref VIII)

Water flea, Daphnia magna :

Acute toxicity:

NOEC 48 h (survival): > 45 500 μg/L

EC₅₀ 48 h (survival): > 100 000 µg/L

Protocol: OCDE Test Guideline 202

(Ref IX)

Fathead minnow, Pimephales promelas:

Acute toxicity:

NOEC 7 d (larval survival and growth): > 10 000 μg/L

EC₅₀ (not determined): < 8% mortality up to 10 mg/L.

Protocol: US EPA (Ref III)

(Ref II)

Zebrafish, Danio rerio

Acute toxicity: LC50 96 h (survival): > 100 mg/L

NOEC 96 h (survival): 9.4 mg/L

Protocol : OCDE Test Guideline 236

Ref (X)

Microorganisms:

Acute toxicity:

Adverse effect on activated sludge microorganisms (growth inhibition)

IC₅₀ 20 h: 1 000 μg/L

Protocol: OECD 209

(Ref IV)

Other ecotoxicity data:

PNEC = 4.4 ug/L

PNEC (μg/L) = lowest EC₁₀ 44/10, where 10 is the assessment factor used.

Following the EMA guideline, the EC₁₀ has been used despite the absence of chronic data for daphnia and fish since there is a presence of an antibacterial substance. Cyanobacteria, Anabaena flos-aquae and an assessment factor of 10 has been used for this calculation since it is known to be the most sensitive species when it comes to antibacterial substances.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC= 0.0032/4.4 = 0.00073

PEC/PNEC ≤ 0.1 which justifies the phrase “use of levofloxacin has been considered to result in insignificant environmental risk".

Degradation

Biotic degradation

No data available, which justifies for the degradation pharse: "the potential for persistence of levofloxacin cannot be excluded, due to lack of data".

Abiotic degradation

The substance is light sensitive. The photo-degradation half-life is estimated at 4-5 days (Ref V).

Bioaccumulation

The substance has low bioaccumulation potential, as indicated by a calculated log K_ow value of - 0.39. (Hansch and Leo method; Ref VI)

Excretion

Levofloxacin is mainly eliminated through urinary excretion (more than 85 % of the administered dose). The substance is eliminated slightly metabolized. The main metabolites, desmethylevofloxacin and the N-oxide, account for less than 5 % of the dose excreted and are pharmacologically inactive. (Ref VII)

References

1. 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

2. Robinson AA, Belden JB, Lydy MJ: Toxicity of fluoroquinolone antibiotics to aquatic organisms. Environmental Toxicology and Chemistry, 2005, 24,423-430.

3. U.S. Environmental Protection Agency. 1994. Short-term methods for estimating the chronic toxicity of effluents and receiving waters to freshwater organisms, 3rd ed. EPA/600/4-91/002. Office of Research and Development, Cincinnati, OH.

4. Kümmerer K., Alexy R., Hüttig J. and Schöll A.: Standardized tests fail to assess the effects of antibiotics on environmental bacteria, Water Research, 2004, 38, 2111-2116.

5. Lam MW, Cora JY, Brain RA, Johnson DJ, Hanson MA, Wilson CJ, Richards SM, Solomon KR, Mabury SA: Aquatic persistence of eight pharmaceuticals in a microcosm study. Environmental Toxicology and Chemistry, 2004, 23, 1431-1440.

6. Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995, p. 156.

7. Vidal, 2013, Vidal Product Monograph – Tavanic® 500 mg.

8. Sanofi, Internal report, Levofloxacin: Toxicity to Anabaena flos-aquae in an algal growth inhibition test, OECD 201. Study #140041218, November 2019.

9. Sanofi, Internal report, Levofloxacin : Acute Toxicity to Daphnia magna in a static 48-hour immobilization test, OECD 202. Study #140041220, November 2019.

10. Sanofi, Internal report, Levofloxacin : Acute Toxicity to Zebrafish (Danio rerio) Embryos in a 96-hour static Test, OECD 236. Study #140041238, November 2019.