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Environmental Risk Assessment Data Enalapril Maleate Enalapril maleate is used in the AstraZeneca drug product Lexxel for the treatment of hypertension. It is a fixed-dose combination of the ACE inhibitor enalapril maleate and the highly vascular selective calcium antagonist felodipine. Enalapril maleate is a pro-drug which is hydrolysed to the active compound enalaprilat, the main active converting enzyme inhibitor. Excretion of enalaprilat and enalapril is primarily renal. Approximately 94% of the dose is recovered in the urine and faeces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat. Since both enalapril and enalaprilat are excreted from the human body, both compounds were aimed to be taken into account in the PEC evaluation. However, very limited ecotoxicity data are available for enalapril or enalaprilat. Therefore, the Predicted Environmental Concentration (PEC) / Predicted No Effect Concentration (PNEC) has not been determined. No information is available concerning the biodegradability, however enalapril is not predicted to bioaccumulate in aquatic organisms. 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 enalapril (active moiety) in the European country with the highest per capita use in 2010 (Source: IMS Health) R (%) = % removal during wastewater (sewage) treatment (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). For enalapril, it is assumed that R = 0 as a worst case. P = number of inhabitants in the European country with the highest per capita use of enalapril in 2010 (Source: IMS Health). A/P = 2.8 x 10-4 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 = 3.8 x 10-1 µg/L (Note: Whilst enalapril is metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as parent enalapril) Predicted No Effect Concentration (PNEC) Short-term testing is available for the crustacean Thamnocephalus platyrus.. However, species from three trophic levels are normally used to calculate a PNEC in accordance with the ECHA guideline (Ref. 2); therefore a PNEC has not been determined. PEC/PNEC PEC = 3.8 x 10-1 µg/L PNEC = Not determined February 2012 As the PNEC is not calculated, the PEC/PNEC has not been determined. 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, Ref EMEA/CPMP/SWP/4447/00. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/1 0/WC500003978.pdf 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 Aquatic Toxicity Data - Enalapril Endpoint Species LC50 Thamnocephalus platyurus Common Name Beaver-tail Fairy Shrimp Method Time Result Thamnotoxkit 24 h 184 mg/L Note 1,2,3 Physical Chemistry Data - Enalapril Endpoint Solubility Water Method Potentiometric Method Test Conditions pH 1, 25oC pH 5, 25oC pH 6.8, 25oC pH 7.4, 25oC Result 3300 g/L 24 g/L 430 g/L 1700 g/L Note 3,4 Partition Coefficient Octanol Water Dissociation Constant - o 25 C Log P = 0.16 Note 3,4 - 25oC pKa(1) = 2.97 pKa(2) = 5.35 Note 3,5 Note 1: Results are expressed as nominal concentrations Note 2: Data from Nalecz-Jawecki G., Persoone G.; Toxicity of Selected Pharmaceuticals to the Anostracan Crustacean Thamnocephalus platyurus. Environ. Sci. Pollut. Res. 2006, 13, 22-27. Note 3: This study pre-dates current ERA regulatory requirements and may not have been undertaken to standardised test guidelines. Note 4: Data from Avdeef A., Berger C.M.; pH-Metric Solubility. 3. Dissolution Titration Template Method for Solubility Determination. Eur. J. Pharm. Sci. 2001, 14, 281-291. Note 5: These data are taken from Ip D.P., Brenner G.S.; Enalapril Maleate. Anal. Profiles Drug Subst. 1987, 16, 207-243.