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AstraZeneca

Filmdragerad tablett 10 mg
(rosa-färgad, skåra, 6,5 mm)

ß-receptorblockerare

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  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Propranolol

Miljörisk: Användning av propranolol har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Propranolol bryts ned i miljön.
Bioackumulering: Propranolol har låg potential att bioackumuleras.


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Detaljerad miljöinformation

PEC/PNEC = 0.018 μg/L /0.23 μg/L = 0.078 → PEC/PNEC ≤ 0.1


Environmental Risk Classification


Predicted Environmental Concentration (PEC)


PEC is based on following data:


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


PEC (µg/L) = 1.5*10-6*A*(100-R)


A (kg/year) = total actual API sales (active moiety) in Sweden 2014. 

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

hydrolysis or biodegradation).

P = number of inhabitants in Sweden = 9 *106

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default)

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

(Note: The factor 109 converts the quantity used from kg to μg).


A = 902.920 kg. This figure is based on sales figures from IMS for 2014 for propranolol hydrochloride.


R = 87%. The removal during sewage treatment (86.5%) is estimated using the EUSES model (which contains Simple Treat) described in the ECHA Technical Guidance Document (Ref 1) where following assumptions have been made: propranolol is readily biodegradable, with vapor pressure (VP) <5*10-6 Pa, water solubility 97.9 g/L (Ref 26) and Kd sludge = 480 L/kg (Ref 28). Propranolol is an involatile solid with negligible VP at ambient conditions, a measured VP is not available and therefore the nominal value used in this calculation assumes no losses to the atmosphere.


PEC = 1.5 * 10-6 * 902.920 * (100 - 87) = 0.018μg/L


Metabolism and excretion

Propranolol hydrochloride is extensively metabolized in the body, and excreted mainly via the urine, less than 5% of the given dose via faeces (Ref 2). Only a little part is excreted as the parent compound however, approximately 17% of the given dose is excreted as a conjugated propranolol which could potentially de-conjugate to parent propranolol during sewage treatment (Ref 3).


Ecotoxicity Data


Propranolol Hydrochloride


Endpoint

Species

Common name

Time

Result (mg/L)

Method

Reference

NOEC Growth

Synechococcus leopoliensis

Cyano-bacterium

96 h

0.35

Growth inhibition test

4

NOEC Growth

Cyclotella meneghiniana

Diatom

96 h

0.094

Growth inhibition test

4

EC10 Growth rate

Phaeodactylum tricornutum

Diatom

72 h

0.09

Growth inhibition test

5

NOEC Growth

Pseudokirchneriella subcapitata

Green algae

96 h

5.0

Growth inhibition test

4

NOEC Growth

0.11


6

NOEC Biomass

72 h

<0.78

OECD 201 (microplate fluoresence method)

7

NOEC Growth

Lemna minor

Common duckweed

7 d

>100

DIN AK 2000

8

NOEC Reproduction

Brachionus calyciflorus

Rotifer

48 h

1

ISO/DIN 20666

7

0.18

AFNOR T90-377

4

NOEC Fecundity

Daphnia magna

Giant water flea

9 d

0.055

Modified USEPA 1994

9

NOEC Growth

0.22



NOEC Fecundity

21 d

<0.05

Adapted OECD 211

10

NOEC Immobilisation

0.20


NOEC Fecundity

Ceriodaphnia dubia

Water flea

7 d

0.009

US EPA Method 1002.0

4

NOEC Egg production and Hatchability

Pimephales promelas

Fathead minnow

21 d

0.11

Non-standard adult reproduction

11

NOEC Growth

Oncorhynchus mykiss

Rainbow trout

10 d

1.0

OECD 215

12

NOEC Growth

Danio rerio

Zebra FIsh

10 d

2

ISO 12890

4

NOEC Hatching rate



96h

4

Based on OECD 236

13

NOEC Growth

Pimephales promelas

Fathead minnow

7 d

<0.128

US EPA Method 1000.0

9

Propranolol Base

Endpoint

Species

Common name

Time

Result (mg/L)

Method

Reference

NOEC Reproduction

Ceriodaphnia dubia

Water flea

7 d

0.125

US EPA 1991

14

NOEC

Larval Length

Paracentrotus lividus

Sea urchin

48 h

0.005

Non standard Embryogenisis note1

15

NOEC

Larval Abnormality




0.002



NOEC

Mortality & Hatching rate

Danio rerio

Zebra fish

80 hpfa

1.25

OECD 212

15

a hpf = hours post fertilization


Note 1: further detail of the study design and endpoints are given in Appendix 1


Predicted No Effect Concentration (PNEC)


Reliable long-term ecotoxicity data for propranolol hydrochloride is available for representatives from three trophic levels (algae, invertebrates and fish) and for propranolol base for representatives from two trophic levels (invertebrates and fish). The lowest NOEC is 0.002 mg/L, since the effect concentration was derived for propranolol base (molecular weight 259.343 g/mol) and the assessment is for the hydrochloride salt (molecular weight 295.808 g/mol) the NOEC is adjusted, by a factor of 1.14, based on the molecular weight and an assessment factor of 10 is applied to derive the PNEC, in accordance with the guidance.


PNEC = (2.0 μg/L x 1.14) /10 = 0.23 μg/L


Environmental risk classification (PEC/PNEC ratio)


PEC/PNEC = 0.018 μg/L /0.23 μg/L = 0.078

PEC/PNEC ≤ 0.1


The PEC/PNEC ratio decides the wording of the aquatic environmental risk phrase, and the risk phrase for PEC/PNEC ≤ 0.1 reads as follows:

“Use of propranolol has been considered to result in insignificant environmental risk”

In Swedish: ”Användning av propranolol har bedömts medföra försumbar risk för miljöpåverkan” under the heading ”Miljörisk”.


Environmental Fate Data


Propranolol Base

Endpoint

Method

Test Substance Concentration

Time

Result

Reference

Biodegradation

Based on OECD 301B @ sludge conc. 30 mg/L

0.01 and 0.1 mg L-1 

10d

> 60%

Readily biodegradable

16


Based on OECD 301B @ sludge conc. 3000 mg/L

0.01 and 0.1, 100 mg L-1




Percentage Mineralisation

Modified OECD 301B & OECD 302B

low sludge; 0.1, 1, 10 & 100 mg/L

80d

15.9 - 30.9%

17

high sludge; 0.1, 1, 10 mg/L


20.5 - 30.8%

high sludge; 100 mg/L


70.6%

Biodegradation Half life

OECD 301A – DOC die-away

100 µg/L

28 d

DT50: 120 h

18

DT50: 620 h

Biodegradation

OECD 301A and OECD 310

0.1 and 1.0 mg/L

28d

≥60% biodegradation

19

Transformation Half life

OECD 309 study, degradation in freshwater

1.0 and 0.1 mg/L in two River Waters

60d

Water at 20°C

DT50: 52.1 d

DT50: 54.6 d

DT50: 16.2 d

DT50: 24.2 d

20

similar to OECD 308

5 µg/vessel at 22°C

Burgen sediment (TOC 0.74%, clay/silt 10%)

Dausenau Sediment (TOC 4.36%, clay/silt 47%)


Total system

DT50: 33 d

DT50: 9.9 d

21

Bioconcentrat-ion Factor (Whole Body)

Mytilus edulis trossulus (Baltic Sea Blue Mussels)

Method unknown

0.001 - 10 mg/L

8 d

BCF = ca 160

22

Partition Coefficient Octanol Water

OECD 107

pH 4, 20oC

pH 5, 20oC

pH 6, 20oC

pH 7, 20oC

pH 8, 20oC

pH 9, 20oC


Log P = 1.6

Log P = 1.4

Log P = -0.12

Log P = 0.72

Log P = 1.6

Log P = 2.6

23

pH Metric Method

Neutral form


Log P = 3.48

24

Propranolol Hydrochloride

Endpoint

Method

Test Substance Concentration

Time

Result

Reference

Partition Coefficient Octanol Water

OECD 107

pH 5

pH 6

pH 9

-

Log P = 1.42

Log P = 0.018

Log P = 2.82

25

pH 5

pH 7

pH 9


Log P = 1.39

Log P = 0.722

Log P = 2.63

23

Degradation

Under conditions of the OECD301B test, propranolol hydrochloride fulfilled the criteria for ready biodegradability at 0.1 mg/L, more than 60% mineralization was achieved. In the highest concentration of propranolol hydrochloride (100 mg/L) with the lowest concentration of sludge (30 mg/L), propranolol could not be classified as readily biodegradable. However, at higher sludge concentration (3000 mg/L), comparable to those of most sewage treatment works, propranolol was found to be readily biodegradable at 100 mg/L.


Based on this information, propranolol has been assigned the risk phrase: ‘Propranolol is degraded in the environment’.


In Swedish: “Propranolol bryts ner i miljön” under the heading “Nedbrytning”.


For estimating PEC, the removal during sewage treatment (R) is estimated using the ECHA Technical Guidance Document (Ref 1) where following assumptions have been made: propranolol is readily biodegradable, with vapor pressure <5*10-6 Pa, water solubility 97.9 g/L (Ref 26) and Kd sludge = 480 L/kg (Ref 28), ending up in R = 86.5%.


Bioaccumulation


Since BCF < 500, and Log P < 4 at pH intervals 4-9, propranolol has low potential to bioaccumulate and the phrase ‘Propranolol has low potential for bioaccumulation’ is assigned.


In Swedish: ”Propranolol har låg potential att bioackumuleras” under the heading ”Bioackumulering”.


Physical Chemistry Data


Propranolol Hydrochloride

Endpoint

Method

Test Conditions

Result

Reference

Solubility Water

UV Spectrophotometry

25oC

97.9 g/L

26

Dissociation Constant

Unknown

-

9.53

27

Sludge Adsorption Coefficient

OPPTS 835.110

0.1 mg/L, 20oC

Kd =

390- 420

28

Adsorption characteristics

OECD 106

Low Organic Carbon, High Clay Soil, pH 6.8

Kd = 16.3

Koc = 4405

27

High Organic Carbon, Low Clay Soil, pH 4.3

Kd = 199

Koc = 2803

Propranolol Base

Endpoint

Method

Test Conditions

Result

Reference

Solubility Water

Unknown

-

609.4 mg L

4

Dissociation Constant

Unknown

-

9.53

24

Sediment Adsorption Coefficient

OECD 106

River Burgen Sediment, Clay/Silt 10 %, pH 6.6

Log Koc = 2.66

29

River Dausenau River Sediment, Clay/Silt 47%, pH 6.5

Log Koc = 2.43

Adsorption characteristics

Akui River Sedimen, pH 6.7

Kd = 2.2

Koc = 2900

18

Tamiya River Sediment, pH 6.6

Kd = 100

Koc = 10000

Tatara River Sediment, pH 5.7

Kd = 160

Koc = 9400

Elliot Silt Loam Soil, pH 6.6

Kd = 1100

Koc = 50000


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. Dollery C. Propranolol (hydrochloride). Therapeutic drugs. 2nd edition. 259-265. Edinburgh. Edinburgh: Churchill Livingstone, Harcourt Brace & Company Ltd. (1999)

  3. Holm G., Murray-smith R. AstraZeneca Existing Products Review: Propranolol Brixham Environmental Laboratory, UK. Report No. BL7441/B (2007)

  4. Ferrari B.; Mons R.; Vollat B.; Fraysse B.; Paxeus N.; Giudice R.L.; Pollio A.; Garric J. Environmental Risk Assessment of Six Human Pharmaceuticals: Are the Current Environmental Risk Assessment Procedures Sufficient for the Protection of the Aquatic Environment?  Environ. Toxicol. Chem. 2004, 23, 5, 1344-1354

  5. Claessens M, Vanhaecke L, Wille K, Janssen CR. 2013. Emerging contaminants in Belgian marine waters: Single toxicant and mixture risks of pharmaceuticals. Marine Pollution Bulletin, 71: 41–50.

  6. Yamamoto H.; Nakamura Y.; Nakamura Y.; Kitani C.; Imari T.; Sekizawa J.; Takao Y.; Yamshita N.; Hirai N.; Oda S.; Tatarazako N. Initial Ecological Risk Assessment of Eight Selected Human Pharmaceuticals in Japan. Environ. Sci. 2007 14, 4, 177-193

  7. Liu Q.T.; Williams T.D.; Cumming R.I.; Holm G.; Hetheridge M.J.; Murray-Smith R. Comparative Aquatic Toxicity of Propranolol and its Photodegraded Mixtures: Algae and Rotifer Screening. Environ. Toxicol. Chem. 2009, 28, 12, 2622-2631

  8. Maszkowska J, Stolte S, Kumirska J, Łukaszewicz P, Mioduszewska K, Puckowski A, Caban M, Wagil M, Stepnowski P, Białk-Bielińska A. 2014. Beta-blockers in the environment: Part II. Ecotoxicity study. Science of the Total Environment 493: 1122–1126

  9. Dzialowski E.M.; Turner P.K.; Brooks B.W. Physiological and Reproductive Effects of Beta Andregenic Receptor Antagonists in Daphnia magna. Arch. Environ. Contam. Toxicol. 2006, 50, 4, 503-510

  10. Stanley J.K.; Ramirez A.J.; Mottaleb M.; Chambliss C. K.; Brooks B.W. Enantiospecific Toxicity of the β-blocker Propranolol to Daphnia magna & Pimephales promelas. Environ. Toxicol. Chem.2006, 25, 7, 1780–1786

  11. Giltrow E.; Eccles P.D.; Winter M.J.; McCormack P.J.; Rand-Weaver M.; Hutchinson T.H.; Sumpter J.P. Chronic Effects Assessment and Plasma Concentrations of the beta-Blocker Propranolol in Fathead Minnows (Pimephales promelas). Aquat. Toxicol. 2009, 95, 3, 195-202

  12. Owen S.F.; Huggett D.B.; Hutchinson T.H.; Hetheridge M.J.; Kinter L.B.; Ericson J.F.; Sumpter J.P. Uptake of Propranolol, a Cadiovascular Pharmaceutical, from Water into Fish Plasma and its Effects on Growth and Organ Biometry. Aquat. Toxicol. 2009, 93, 217-224

  13. Sun L, Xin L, Peng Z, Jin R, Jin Y, Qian H, Fu Z. 2014. Toxicity and Enantiospecific Differences of Two b-blockers, Propranolol and Metoprolol, in the Embryos and Larvae of Zebrafish (Danio rerio). Environmental Toxicology, 29: 1367-1378

  14. Huggett D.B.; Brooks B.W.; Peterson B.; Foran C.M. Schlenk D. Toxicity of Select Beta Adrenergic Receptor-Blocking Pharmaceuticals (β-Blockers) on Aquatic Organisms. Arch. Environ. Contam. Toxicol. 2002, 43, 2, 229-235

  15. Ribeiro S, Torres T, Martins R, Santos MM. 2015. Toxicity screening of Diclofenac, Propranolol, Sertraline and Simvastatin using Danio rerio and Paracentrotus lividus embryo bioassays. Ecotoxicology and Environmental Safety, 114: 67-74.

  16. Daniel M., Gillings E., Roberts G.C. Propranolol hydrochloride: Biodegradation in a modified OECD 301B (Ready biodegradability) and a modified 302B (Inherent biodegradability) test. Brixham Environmental Laboratory, UK. Report No BL8033 (2006).

  17. Good J., Gillings E. Roberts G.C. Propranolol hydrochloride: The effect of biomass and test substance concentration on the observed biodegradation. Brixham Environmental Laboratory, UK. Report No BL7808. (2006).

  18. Yakamoto H.; Nakamura Y.; Moriguchi S.; Nakamura Y.; Honda Y.; Tamura I.; Hirata Y.; Hayashi A.; Sekizawa J. Persistence and Partitioning of Eight Selected Pharmaceuticals in the Aquatic Environment: Laboratory Photolysis, Biodegradation, and Sorption Experiments. Water Research 2009, 43, 2, 351-36

  19. Roberts G, Daniel M, Campbell A. 2012. Influence of inoculum source on the biodegradability of propranolol and atenolol. Poster presentation number WE 179. SETAC Gothenburg.

  20. Oliver R., Bilyk M. Atenolol and Propranolol River die Away. Brixham Environmental Laboratory, UK. Report No BR0028. (2011).

  21. Ramil M.; El A.T; Fink G.; Scheurer M.; Ternes T.A. Fate of beta Blockers in Aquatic-Sediment Systems: Sorption and Biotransformation. Environ. Sci. Technol. 2010, 44, 3, 962-70

  22. Ericson H.; Thorsen G.; Kumblad L. Physiological Effects of Diclofenac, Ibuprofen and Propranolol on Baltic Sea Blue Mussels. Aquat. Toxicol. 2010, 99, 2, 223-31

  23. Bamforth J.E. Propranolol hydrochloride: determination of n-octanol,-water partition coefficient at extended pH range. Brixham Environmental Laboratory, UK. Report No BL7942. (2005).

  24. Avdeef A.; Box K.J.; Comer J.E.A.; Hibbert C.; Tam K.Y. pH-Metric Log P.10. Determination of Liposomal Membrane-Water Partition Coefficient of Ionisable Drugs. Pharm. Res. 1998, 15, 209-218

  25. Bowles, A. J. Propranolol Hydrochloride: Determination of n-octanol-water partition coefficient. Brixham Environmental Laboratory, UK. Report No BL7543. (2005).

  26. Thomas E.; Rubino J. Solubility, Melting Point and Salting-out Relationships in a Group of Secondary Amine Hydrochloride Salts. Int. J. Pharm. 1996, 130, 179-185

  27. Drillia P.; Stamatelatou K.; Lyberatos G. Fate and Mobility of Pharmaceuticals in Solid Matrices. Chemosphere 2005, 60, 1034–1044

  28. MacLean S.A., Roberts G. Propranolol hydrochloride: Adsorption and desorption to sewage sludge. Brixham Environmental Laboratory, UK. Report No BL8001 ( 2006)

  29. Ramil M.; El A.T; Fink G.; Scheurer M.; Ternes T.A. Fate of beta Blockers in Aquatic-Sediment Systems: Sorption and Biotransformation. Environ. Sci. Technol. 2010, 44, 3, 962-70



Appendix 1


Experiments involving the fertilisation and development of sea urchin eggs and embryos have been accepted internationally as appropriate for toxicity tests (U.S. EPA, 1995; Environment Canada, 1997; CETESB, 1999). Direct measurement of growth and development are considered relevant for PNEC derivation. A summary of the experimental design reported in Ribero et al 2015 (Ref 15) is presented below, based on the criteria of Klimisch et al 1997, reliability category 2 is assigned.


Organisms: sea urchins were collected in Portugal (N41° 2’26, 18”, W -8° 39’2, 24”), eggs and sperm were extracted and toxicity tests were performed when fertilisation rate was >97%.


Media: Artificial seawater; Potassium chloride (0.67 g/L),Calcium chloride(1.36 g/L),Magnesium chloride hexahydrate (4.66 g/L), Magnesium sulphate (2.04 g/L), Sodium chloride (24.6 g/L) and Sodium bicarbonate (0.39 g/L).


Test Vessels: 24-well plates containing 3 ml solution (20 eggs/mL), 8 well replicates per treatment.


Test concentrations: Prepared by serial dilution, stock solutions prepared Dimethylsulfoxide (DMSO), experimental solutions obtained via dilution with artificial sea water, final DMSO concentration 0.01%.


Experimental design: Control and solvent control (grouped for statistical analysis) seven test concentrations; 0.8, 2.0, 5.0, 12.5, 125, 1250, 12500 µg/L.


48 hour exposure, at 20°C in the dark.


At the end of the exposure embryos were fixed by adding three drops of 37% formaldehyde and directly observed under an inverted microscope. Assessment criteria for development are described within the paper. End points; larval length (n = 240 for controls; n = 120 for exposed groups), Percentage total abnormalities (n = 320 for controls; n =160 for exposed groups). The number of analyzed individuals for the two criteria was based on Saco-Álvarez et al (2010).


Results: All data were tested for normality and homogeneity of variances prior to testing for significance analysis using appropriate parametric/non-parametric tests as required. Statistically significant reductions (P < 0.05) in larval length at ≥ 12.5 ug/L. Statistically significant increase in the percentage of abnormal organisms at ≥ 5 ug/L.

48 hour larval length NOEC = 5 µg/L

48 hour larval abnormality NOEC = 2 µg/L


Appendix 1 References:


CETESB. – 1999. Método de ensaio: Água do mar - Teste de toxicidade crônica de curta duração com Lytechinus variegatus, Lamarck,1816 (Echinodermata: Echinoidea). L5.250. Cia. De Tecnologia de Saneamento Ambiental do Estado de São Paulo, Brasil., 22 pp.


Environment Canada. – 1992. Biological test method: Fertilization assay using echinoids (sea urchins and sand dollars), amended November 1997. EPS 1/RM/27. North Vancouver, BC., 97 pp


U.S. Environmental Protection Agency. – 1995. Short-term methods for estimating the chronic toxicity of effluents and receiving waters to west coast marine and estuarine organisms. EPA/ 600/ R-95-136. Cincinnati, Ohio.


Saco-Álvarez,L.,Beiras,R.,Durán,I.,Lorenzo,J.I.,2010.Methodologicalbasisforthe optimization of marine sea-urchin embryo test (SET) for the ecological assessment of coastal water quality. Ecotoxicol. Environ. Saf. 73,491–499.