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Inderal®

AstraZeneca

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

ß-receptorblockerare

Aktiv substans:
ATC-kod: C07AA05
Läkemedel från AstraZeneca omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

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 = 0.016 μg/L /0.23 μg/L = 0.070

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 sold amount API in Sweden year 2017, data from IQVIA (former IMS Health and Quintiles).

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) (Ref. 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. 1)

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


A = 819.85 kg propanolol hydroklorid


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. 2), 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 * 819.85 * (100 - 87) = 0.016μg/L


Metabolism and excretion

Propranolol hydrochloride is extensively metabolized in the body and excreted mainly via the urine with less than 5% of the given dose via faeces (Ref. 3). Minimal amounts are excreted as the parent compound; however, approximately 17% of the given dose is excreted as a conjugated propranolol which could potentially de-conjugate back to the parent propranolol during sewage treatment (Ref. 4).


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

5

NOEC Growth

Cyclotella meneghiniana

Diatom

96 h

0.094

Growth inhibition test

5

EC10 Growth rate

Phaeodactylum tricornutum

Diatom

72 h

0.09

Growth inhibition test

6

NOEC Growth

Pseudokirchneriella subcapitata

Green algae

96 h

5.0

Growth inhibition test

5

NOEC Growth

0.11


7

NOEC Biomass

72 h

<0.78

OECD 201 (microplate fluoresence method)

8

NOEC Growth

Lemna minor

Common duckweed

7 d

>100

DIN AK 2000

9

NOEC Reproduction

Brachionus calyciflorus

Rotifer

48 h

1

ISO/DIN 20666

8

0.18

AFNOR T90-377

5

NOEC Fecundity

Daphnia magna

Giant water flea

9 d

0.055

Modified USEPA 1994

10

NOEC Growth

0.22



NOEC Fecundity

21 d

<0.05

Adapted OECD 211

11

NOEC Immobilisation

0.20


NOEC Fecundity

Ceriodaphnia dubia

Water flea

7 d

0.009

US EPA Method 1002.0

5

NOEC Egg production and Hatchability

Pimephales promelas

Fathead minnow

21 d

0.11

Non-standard adult reproduction

12

NOEC Growth

Oncorhynchus mykiss

Rainbow trout

10 d

1.0

OECD 215

13

NOEC Growth

Danio rerio

Zebra FIsh

10 d

2

ISO 12890

5

NOEC Hatching rate



96h

4

Based on OECD 236

14

NOEC Growth

Pimephales promelas

Fathead minnow

7 d

<0.128

US EPA Method 1000.0

10

Propranolol (as free base)

Endpoint

Species

Common name

Time

Result (mg/L)

Method

Reference

NOEC Reproduction

Ceriodaphnia dubia

Water flea

7 d

0.125

US EPA 1991 note 1

15

NOEC

Larval Length



Paracentrotus lividus

Sea urchin

48 h

0.005

Non-standard embryo development note 2

16

NOEC

Larval Abnormality

0.002

NOEC

Mortality & Hatching rate

Danio rerio

Zebra fish

80 hours post fertilization

1.25

OECD 212

16

Note 1: Other species were tested within this study, however the testing methodology and/or reporting for these species’ tests were assessed according to Klimisch et. al. 1997 (Ref. 31) to be Category 3 or 4 and therefore not suitable for this assessment.


Note 2: Non-standard literature study assessed according to Klimisch et. al. 1997 (Ref. 31) to be a category 2 study -reliable with restrictions (non-standard, non-GLP study, without analysis of test concentrations).


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 (as free base) from two trophic levels (invertebrates and fish). The lowest NOEC is 0.002 mg/L, since the effect concentration was derived for propranolol free 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 ECHA guidance (Ref. 2).


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


Environmental risk classification (PEC/PNEC ratio)


PEC/PNEC = 0.016 μg/L /0.23 μg/L = 0.070

i.e., PEC/PNEC ≤ 0.1 which justifies the phrase “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 (as free base)

Endpoint

Method

Test Substance Concentration

Time

Result

Reference

Biodegradation

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

0.01 and 0.1 mg/L

10 d

> 60%

Readily biodegradable

17

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

0.01 and 0.1, 100 mg/L

Percentage Mineralisation

Modified OECD 301B and OECD 302B

low sludge; 0.1, 1, 10 and 100 mg/L

80 d

15.9 - 30.9%

18

high sludge; 0.1, 1 and 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

19

DT50: 620 h

Biodegradation

OECD 301A and OECD 310

0.1 and 1.0 mg/L

28 d

≥ 60% biodegradation

20

Transformation Half life

OECD 309 study, degradation in freshwater

1.0 and 0.1 mg/L in two River Waters

60 d

Water at 20°C

DT50: 52.1 d

DT50: 54.6 d

DT50: 16.2 d

DT50: 24.2 d

21

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

22

Bioconcentrat-ion Factor (Whole Body)

Mytilus edulis trossulus (Baltic Sea Blue Mussels)

Method unknown

0.001 - 10 mg/L

8 d

BCF = 160

23

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

24

pH Metric Method

Neutral form


Log P = 3.48

25

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

26

pH 5

pH 7

pH 9


Log P = 1.39

Log P = 0.722

Log P = 2.63

24

Degradation

Under conditions of the OECD301B test, propranolol fulfilled the criteria for ready biodegradability at 0.1 mg/L, more than 60% mineralization was achieved. In the highest concentration of propranolol (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”.


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

27

Dissociation Constant

Unknown

-

9.53

28

Sludge Adsorption Coefficient

OPPTS 835.110

0.1 mg/L, 20oC

Kd =

390- 420

29

Adsorption characteristics

OECD 106

Low Organic Carbon, High Clay Soil, pH 6.8

Kd = 16.3

Koc = 4405

28

High Organic Carbon, Low Clay Soil, pH 4.3

Kd = 199

Koc = 2803

Propranolol (as free base)

Endpoint

Method

Test Conditions

Result

Reference

Solubility Water

Unknown

-

609.4 mg/L

5

Dissociation Constant

Unknown

-

9.53

25

Sediment Adsorption Coefficient

OECD 106

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

Log Koc = 2.66

30

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

Log Koc = 2.43

Adsorption characteristics

Akui River Sediment, pH 6.7

Kd = 2.2

Koc = 2900

19

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


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  2. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment. May 2008.

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  14. 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.

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