Environmental Risk Assessment Data Roflumilast
Roflumilast is an anti-inflammatory medicine called phosphodiesterase-4 inhibitor. Roflumilast reduces the activity of phosphodiesterase-4, a protein occurring naturally in body cells. When the activity of this protein is reduced, there is less inflammation in the lungs. This helps to stop narrowing of airways occurring in chronic obstructive pulmonary disease (COPD), thus easing breathing problems.
Roflumilast is an active pharmaceutical ingredient used in the following AstraZeneca product: Daxas.
In a human pharmacokinetics study with radiolabelled roflumilast, total recovery of radioactivity amounted to 90 % of the dose, 70 % being excreted in urine and about 20 % in faeces. Roflumilast itself is not detectable in urine, and its active metabolite roflumilast N-oxide is detected only in small amounts (1%). Instead, 4 inactive metabolites, each about 10 – 15 % were found in urine. The origin of radioactivity in faeces was not investigated.
Roflumilast is not readily biodegradable, nor is it expected to bioaccumulate in aquatic organisms.
The Predicted Environmental Concentration (PEC) / Predicted No Effect Concentration (PNEC) ratio is 1.6 x 10-2, which means use of roflumilast is predicted to present a low risk to the environment.
Predicted Environmental Concentration (PEC) The PEC is based on the following data:
PEC (µg/L) = (A*109*(100-R))/(365*P*V*D*100)
A (kg/year) = total patient consumption of roflumilast in the European country with the highest per capita use in 2016 (Source: IMS Health1) R (%) = % removal during wastewater (sewage) treatment (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). It is assumed that R = 0 as a worst case. P = number of inhabitants in the country with the highest per capita use (Source: EuroStat2). A/P = 9.5 x 10-8 kg/inhabitant V (L/day) = volume of wastewater per capita and day = 200 (European Medicines Agency (EMA) default value (Ref. 1)) D = factor for dilution of waste water by surface water flow = 10 (EMA default value) (Note: The factor 109 in the equation above converts the quantity used from kg to μg)
PEC = 0.00013 µg/L
(Note: Whilst
Predicted No Effect Concentration (PNEC) Short-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the lowest EC50 value
1 IMS Health, MIDAS International Data for 2016, available for 19 European markets 2 The number of persons having their usual residence in a country on 1 January 2016. Available from http://ec.europa.eu/eurostat/web/population-demography-migration-projections/population-data/main-tables Accessed: 20/4/17 0.084 mg/L (equivalent to 84 µg/L) which was reported for the green alga, Desmodesmus subspicatus, and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref. 2).
PNEC = 84 µg/L /1000 = 0.084 µg/L
PEC/PNEC PEC = 0.00013 µg/L PNEC = 0.084 µg/L
PEC/PNEC = 1.6 x 10-2
The PEC/PNEC ratio of 1.6 x 10-2 corresponds to the phrase ‘Use of the substance has been considered to result in low environmental risk’ in the www.fass.se scheme (Ref 3).
Environmental Fate Summary Roflumilast is not readily biodegradable. It is a weak acid with a pKa of 8.74, as such aqueous solubility increases from about 0.8 mg/L under neutral conditions to about 35.8 mg/L at pH 10. Based on the octanol-water partition coefficient, Roflumilast is not expected to bioaccumulate in aquatic organisms.
Aquatic Toxicity Data for Roflumilast Study Type Method Result Reference Toxicity to green algae, OECD201 72 hour NOEC (growth rate) =0.024 mg/l 4 Desmodesmus subspicatus, 72 hour LOEC (growth rate) =0.043 mg/l growth inhibition test 72 hour EC50 (growth rate) = 0.084 mg/l (Note 1) 72 hour NOEC (biomass) =0.024 mg/l 72 hour LOEC (biomass) =0.043 mg/l 72 hour EC50 (biomass) =0.043 mg/l Acute toxicity to Daphnia OECD202 48 hour EC50 (immobility) > 0.430 mg/L 5 magna (Note 1) 48 hour NOEC (immobility) = 0.430 mg/L Acute toxicity to Zebra fish, OECD203 96 hour LC50 (mortality) > 0.295 6 Brachydanio rerio (Note 1) 96 hour NOEC (mortality) = 0.295 NOEC No Observed Effect Concentration LOEC Lowest Observed Effect Concentration EC50 the concentration of the test substance that results in a 50% effect LC50 the concentration of the test substance that results in a 50% mortality
Environmental Fate Data for Roflumilast Study Type Method Result Reference Determination of ready OECD 301D Degradation after 21 days <11.6% 7 biodegradability Not readily biodegradable
Kd Distribution coefficient for adsorption Koc Organic carbon normalized adsorption coefficient # Calculated Koc = Kd(ads) / 0.37
Physical Chemistry Data for Roflumilast Study Type Method Result Reference Disassociation constant Not stated pKa = 8.74. 8 Solubility Not stated Water (21 – 22°C) 0.52 – 0.56 mg/L 8 Octanol-water partition Not stated logP at pH 7.4 = 3.99. 8 coefficient
Note 1: Concentrations were confirmed by analysis, and results expressed as measured concentrations.
References 1. Committee for Medicinal Products for Human Use (CHMP); Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006, EMEA/CPMP/SWP/4447/00 corr2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/W C500003978.pdf 2. ECHA (European Chemicals Agency) 2008. Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterisation of dose [concentration]- response for environment http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.h tm 3. Fass.se (2012). Environmental classification of pharmaceuticals at www.fass.se: Guidance for pharmaceutical companies https://www.fass.se/pdf/Environmental_classification_of_pharmaceuticals-120816.pdf 4. 204/2007 Algae growth inhibition test with Roflumilast on Desmodesmus subspicatus. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007 5. 211/2007 Acute toxicity of Roflumilast to Daphnia magna. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007 6. 214/2007 Acute toxicity of Roflumilast to the zebra-fish, Brachydanio rerio. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007 7. 116/2007 Determination of ready biodegradability of Roflumilast “Closed bottle test”. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007 8. Internal Report, 3.2.S.1.3 General Properties (Roflumilast), 2009