Environmental Risk Assessment Data

Metoprolol

Metoprolol is a cardioselective beta-blocker for the treatment of hypertension, angina pectoris,

heart failure, disturbances of cardiac rhythm including supraventricular tachycardia. It is also used to
prevent further heart problems following myocardial infarction, functional heart disorders with
palpitations and for the prevention of migraines.

Metoprolol is used in two forms, metoprolol tartrate and metoprolol succinate. Metoprolol
succinate is an extended-release version of metoprolol, so it remains in the bloodstream for longer
than metoprolol tartrate.

Metoprolol succinate is the active pharmaceutical ingredient used in the following AstraZeneca
products: Seloken ZOK, Toprol-XL and Betaloc ZOK, and Metoprolol tartrate is used in Seloken and
Betaloc. Metoprolol is also used in Logimax, the fixed-dose combination metoprolol/felodipine.

Metoprolol is extensively metabolised in the body, with only a minor fraction (approximately 5%)
excreted as the parent drug. The main route for excretion is via the urine.

Metoprolol is not readily biodegradable and is not predicted to bioaccumulate in aquatic organisms.
The Predicted Environmental Concentration (PEC) / Predicted No Effect Concentration (PNEC) ratio is
0.34, which means use of metoprolol 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 metoprolol (active moiety) 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). For metoprolol, it is assumed that R = 0 as
a worst case.
P = number of inhabitants in the European country with the highest per capita use in 2016 (Source:
Eurostat2).
A/P = 1.8 x 10-3 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, Ref 1)
(Note: The factor 109 in the equation above converts the quantity used from kg to μg)

PEC = 2.5 µg/L

(Note: Whilst metoprolol is metabolised in the body, little is known about the ecotoxicity of the
metabolites. Hence, as a worst case, for this calculation, it is assumed that 100% of excreted
metabolites have the same ecotoxicity as metoprolol).

Predicted No Effect Concentration (PNEC)

1
IMS Health, MIDAS International Data for 2016, available for 22 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
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 7.3 mg/L
(equivalent to 7300 µg/L) which was reported for the acute toxicity to green alga (Desmodemus
subspicatus) and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref. 2).

PNEC = 7300 µg/L /1000 = 7.3 µg/L

PEC/PNEC
PEC = 2.5 µg/L
PNEC = 7.3 µg/L

PEC/PNEC = 0.34

The PEC/PNEC ratio of 0.34 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

The potential for the rapid aerobic biodegradation of metoprolol was determined in accordance with
ISO 7827-1984 (E), using the OECD guidelines’ criteria for ready biodegradation; the results show
that metoprolol is not readily biodegradable. The octanol-water partition coefficient study shows
that the risk of bioaccumulation in aquatic organisms is low.

Aquatic Toxicity Data for Metoprolol Succinate

Study Type Method Result Reference
Toxicity to green algae, 92/69/EEC 72 hour ErC50 (Average Specific 4
Desmodesmus subspicatus, growth Annex V C.3 Growth Rate) 7.3 mg/L
inhibition test (Note 1)
Toxicity to green algae, 72 hour NOEC (growth rate) = 5
Pseudokirchinella subcapitata, 7.5 mg/L
growth inhibition test (Note 1) 72 hour LOEC (growth rate) =
15 mg/L
72 hour EC50 (growth rate) =
58.3 mg/L
OECD 201

72 hour NOEC (Area Under the

Activated sludge, respiration
inhibition test (Note 2)
Growth Curve) = 7.5 mg/L
72 hour LOEC (Area Under the
Growth Curve) = 15 mg/L
72 hour EC50 (Area Under the
Growth Curve) = 22.8 mg/L
OECD 209 3 hour NOEC = 100 mg/L 6
3 hour EC50 >100 mg/L

Acute toxicity to Daphnia magna OECD 202 48 hour EC50 (immobility) >120 7
(Note 1) mg/L
Acute toxicity to Ceriodaphnia dubia EPA 600/4 48 hour EC50 (immobility) 8
(Note 1) 90/027 = 45.3 mg/L
Study Type Method Result Reference
Acute toxicity to Rainbow Trout, OECD 203 96 hour LC50 (mortality) 9
Oncorhynchus mykiss (Note 1) = 130 mg/L

Acute toxicity to zebra fish Danio OECD 203 96 hour LC50 (mortality) 10
rerio (Note 1) = 167 mg/L

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 Metoprolol Succinate

Study Type Method Result Reference
Aerobic biodegradation ISO 7827-1984 % dissolved organic carbon 10
(E) after 28 days = 14 %
Not readily biodegradable

Physical Chemistry Data for Metoprolol Succinate

Study Type Method Result Reference
Partition Coefficient Octanol OECD 107 Log P = -0.06 @ pH 5 11
Water Log P = -0.90 @ pH 7
Solubility Water Estimated 1.69 x 104 mg/L (at 25 °C) 12

Note 1: Concentrations were confirmed by analysis, and results expressed as nominal.

Note 2: Results are expressed nominal 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. Aquatic Ecotoxicity of Pharmaceuticals Including the Assessment of Combination Effects.
Cleuvers M. Toxicology Letters 2003 v142 n3 p185 – 194.
5. Metoprolol Succinate: Toxicity to the green alga Selenastrum capricornutum. Brixham
Environmental Laboratory, AstraZeneca, UK, Report BL7587. October 2003.
6. Metoprolol Succinate: Effect on the respiration rate of activated sludge. Brixham
Environmental Laboratory, AstraZeneca, UK, Report BL7772. December 2003.
7. Metoprolol Succinate: Acute toxicity to Daphnia magna. Brixham Environmental Laboratory,
AstraZeneca, UK, Report BL7588. October 2003.
8. Prediction and Experimental Validation of Acute Toxicity of Beta Blockers in Ceriodaphnia
dubia. Fraysse B et al. Environ. Toxicol. Chem 2005 v24 n10 p2470 – 2476.
9. Metoprolol Succinate: Acute toxicity to rainbow trout (Oncorhynchus mykiss). Brixham
Environmental Laboratory, AstraZeneca, UK, Report BL7589. October 2003.
10. Environmental assessment of the pharmaceutical agent "A004" from AB Astra. Report No:
4/92, Toxicon. April 1992
11. Metoprolol Succinate: Determination of n-octanol-water partition coefficient. Brixham
Environmental Laboratory, AstraZeneca, UK, Report BL7827. September 2004.
12. McFarland, J. W., A. Avdeef, C. M. Berger & O. A. Raevsky: Estimating the water solubilities
of crystalline compounds from their chemical structures alone. J. Chem. Inform. Computer
Sci. 2001, 41, 1355–1359