Detaljerad miljöinformation

Predicted Environmental Concentration (PEC)

Calculation of PEC according to FASS guideline (2012), section 2.2.1 and Appendix 1:

PEC (µg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6*A (100-R)

PEC = xx µg /L

Where:

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

R = X % 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) (I)

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

A = In 2020, 109.40 kg was sold.

A = 109.40 kg

R = 0

PEC (µg/L) = (109.40 * 10⁹ (100-0) )/ (365 * 10* 10⁶ * 200 * 10 * 100 =

1.37 * 10^-6 * 109.40 * (100) = 0.015 µg/L

PEC (µg/L) = 0.015 µg/L

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Anabaena sp):

NOEC 72 h (biomass, growth) = 0.76 μg/L

(OECD 201) ^I

Crustacean (Daphnia magna):

Chronic toxicity

NOEC 21 days (parental survival) = 1.48 mg/L

NOEC 21 days (growth) = 0.072 mg/L

NOEC 21 days (time to first brood) = 4.63 mg/L

(OECD 211) ^I

Fish (Pimephales promelas):

Chronic toxicity

NOEC 32 days (hatching, success, fry survival, growth) = 6.97 mg/L

(OECD 210) ^I

The Predicted No Effect Concentration for Surface water is derived from the lowest NOEC from Tier A long-term toxicity tests (0.76 μg/L) by application of a default assessment factor of 10 due to data from long-term NOECs from three species representing three trophic levels.

PNEC = 0.76 μg/L /10= 0.076 μg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.015/0.076 = 0.20

PEC/PNEC ≤ 1 which justifies the phrase "Use of rifaximin has been considered to result in low environmental risk".

Degradation 

Biotic degradation

Ready degradability:

The mean cumulative carbon dioxide production by mixtures containing rifaximin was negligible (equivalent to 1% of the theoretical CO₂ production) at the end of the test on day 29. Degradation of the reference substance sodium benzoate was similar both in the presence and absence of rifaximin, which confirmed that the activity of the microbial inocula was not inhibited. Since the test mixtures are likely to have contained both rifaximin and its hydrolysis products, the result of this test indicates that rifaximin was neither readily biodegradable nor inhibitory to the activity of the bacterial inoculum^I.

Simulation studies:

The fate of rifaximin was studied under laboratory conditions in two natural aquatic

sediment systems (OECD 308)^III.  ¹⁴C-labelled Rifaximin was added to the two water-sediment systems to give a norminal concentration of 250 μg*L^-1. The test mixtures were incubated under aerobic conditions at approximately 20°C in darkness for 100 days and samples were taken for the analysis of total radioactivity by Liquid Scintillation Counting (LSC). The levels of rifaximin and its degradates were determined by High Performance Liquid Chromatography (HPLC) with UV and radiodetection.

The results of the study showed that rifaximin was readily hydrolysed in both water-sediment systems with DT₅₀ 0.12 and 0.22 days respectively in water and 0.13 and 0.24 days respectively in the whole system.

The first samples taken immediately after the addition of rifaximin to the systems on Day 0 showed the presence of eleven individual degradates and low levels of others. These degradates were consistently found in both the water and sediment phases of each system throughout the test. The highest level of extractable radioactivity (rifaximin and degradetes) in the aqueous phase was achieved one day after addition of rifaximin. Levels in sediments achieved maximum later in the test.

The levels of extractable degradates (total radioactivity – radioactivity attributable to rifaximin) in water and sediment were at the end of the test on Day 100, 11.1% and 23.9%, respectively, in one of the sediment systems, and 6.9% and 31.5% in the other system. The level of unextractable radioactivity at the end of the test were 56.3% of applied radioactivity in the first system and 52.9% in the other. Levels of total ¹⁴C-volatiles, which reflects the level of ultimate biodegradation and release of carbon dioxide, were low in both systems throughout (<5%).

However, assessment of the microbial content of the sediments conducted at the start and end of the test, confirmed that the number of organisms were similar indicating that exposure of rifaximin did not adversely affect their viability.

In conclusion, rifaximin and its degrates are likely to progressively partition to sewage solids and sediments where they are stable and predominantly unextractable.

Abiotic degradation

Hydrolysis:

Hydrolytic breakdown of rifaximin produced eleven discrete degrates and small quantities of unknown substances with progressively partitioned from aqueous to the sediment phase.

The effects of sediment-bound residues on aquatic invertebrates have not been assessed, but, the ready biodegradability test indicates that both rifaximin and its hydrolysis products, were not inhibitory to the activity of the bacterial inoculum.

Rifaximin is readily adsorbed onto sewage solids which indicates that in a sewage treatment plant, assuming that no abiotic degradation takes place, levels in the aqueous liquid would be reduced to approximately 1% of the initial concentration^I.

Justification of chosen degradation phrase:

Substance rifaximin does not pass the ready degradability test. The phrase "Rifaximin is potentially persistens" is thus chosen.

Bioaccumulation

Partitioning coefficient:

LogK_ow = 2.76 at pH 7 (OECD 117)^III

Justification of chosen bioaccumulation phrase:

LogK_ow of rifaximin is below the trigger level that is considered to indicate a potential to bioaccumulate, i.e. the substance has low potential for bioaccumulation.

Excretion (metabolism)

Substance rifaximin is excreted to 97% as parent compound in the faeces and only a small proportion of the dose is excreted in the urine^III. Only one metabolite, 25-desacetyl rifaximin has been found and identified.

PBT/vPvB assessment

According to the established EU criteria, the compound should not be regarded as a

PBT/vPvB substance.

References

1. ECHA 2016. Guidance on information requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment. Version 3.0, February 2016. https://echa.europa.eu/documents/10162/.../information_requirements_r16_en.pdf

2. Rifaximin Environmental Risk Assessment for its combined use in the treatment of gastrointestinal disorders and Hepatic Encephalopathy – Phase I and Phase II (Tiers A and B). 2011. HLS Study No BQG0011.

3. Rifaximin. Environmental Risk Assessment Phase I and Phase II (Tiers A and B). 2010 HLS Study No. AFW0050.