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Enalapril comp ratiopharm

Teva

Tablett 20 mg/12,5 mg
(rund, vit, platt, med delskåra på ena sidan och fasad kant, diameter 8 mm)

ACE-hämmare + diuretikum

ATC-kod: C09BA02
Läkemedel från Teva omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Miljöinformationen för enalapril är framtagen av företaget MSD för Renitec Rapitab, Renitec®, Renitec® comp., Synerpril®

Miljörisk: Risk för miljöpåverkan av enalapril kan inte uteslutas då det inte finns tillräckliga ekotoxikologiska data.
Nedbrytning: Det kan inte uteslutas att enalapril är persistent, då data saknas.
Bioackumulering: Enalapril har låg potential att bioackumuleras.


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Detaljerad miljöinformation


Environmental Risk Classification


Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*109*(100-R))/(365*P*V*D*100) = 1.5*10-6*A(100-R)

PEC = 0.33 μg/L


Where:

A = 2213 kg (total sold amount API in Sweden year 2015, data from IMS Health).

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 9 *106

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

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


Predicted No Effect Concentration (PNEC)


Ecotoxicological studies

Crustacean, water flea (Daphnia magna):

Acute toxicity

EC50 48 h (mortality) = 346 mg/L (OECD 202) (Ref. II)


Fish, Fathead minnow (Pimephales promelas)

Acute toxicity

LC50 96 h (mortality) >1000 mg/L (FDA 4.11) (Ref.III)


Environmental risk classification (PEC/PNEC ratio)

As data are not available for three trophic levels, an environmental risk classification is not possible.


Degradation


Justification of chosen degradation phrase:

As no degradation studies are available, the phrase, “The potential for persistence of enalapril cannot be excluded”, is thus chosen.


Bioaccumulation


Partitioning coefficient:

Log Kow = 0.59 (method not provided). (Ref.IV)


Justification of chosen bioaccumulation phrase:

Since log Kow < 4, the substance has low potential for bioaccumulation.



References

I. 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


II. ICI Brixham Laboratory. "ENALAPRIL MALEATE: Determination of the acute toxicity to Daphnia magna," Study No. BL/B/3595, ICI, UK, 19 May 1989.


III. Merck, 1994. "Enalapril maleate (MK-0421) Ecotoxicological Characterization," 20 May 1994.


IV. Cheregi, M. et al, 2013. “Greener bioanalytical approach for LC/MS-MS assay of enalapril and enalaprilat in human plasma with total replacement of acetonitrile throughout all analytical stages”, J. Chromatogr. B 927 (2013) 124-132.

Miljöinformationen för hydroklortiazid är framtagen av företaget AstraZeneca för Atacand Plus, Atacand® Plus, Zestoretic

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


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Detaljerad miljöinformation


PEC/PNEC = 0.41 μg/L /1000 μg/L

PEC/PNEC = 0.00041


Environmental Risk Classification

Predicted Environmental Concentration (PEC)


The PEC is based on the 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) = 0 if no data is available.

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 = 2729.7 kg.

R = 0


PEC = 1.5 * 10-6 * 2729.7 * (100-0) = 0.41 μg/L


Metabolism and excretion

Hydrochlorothiazide is a diuretic used to treat hypertension. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of an oral dose is eliminated unchanged within 24 hours (ref 2).


Ecotoxicity data

Endpoint

Species

Common Name

Method

Time

Result

Ref.

EC50 - Based on Growth Rate & Yield

Pseudokirchneriella subcapitata (formerly known as Selenastrum capric-ornutum)

Green Alga

OECD 201,

ISO 8692

72 h

>100 mg/L

Note 1

3

NOEC - Based on Growth Rate & Yield

100 mg/L

Note 1

LC50

Daphnia magna

Giant Water Flea

OECD 211,

ISO 10706:2000

21 d

>100 mg/L

Note 1

4

NOEC - Based on Overall Endpoints

Note 2

100 mg/L

Note 1

LOEC - Based on Overall Endpoints

Note 2

>100 mg/L

Note 1

LOEC - Based on Overall Endpoints

Chironomus riparius

Midge

OECD 218

28 d

>10 mg/kg

Note 1

5

NOEC - Based on Overall Endpoints

10 mg/kg

Note 1

NOEC - Based on Overall Endpoints

Note 3

Pimephales promelas

Fathead Minnow

OECD 210,

OPPTS 850.1400 (Draft)

30 d

10 mg/L

Note 1

6

EC50 - Based on Activated Sludge Respiration Inhibition

-

Activated Sludge

OECD 209

3 h

>100 mg/L

7

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

Note 2: The endpoints measured were reproduction, survival and length.

Note 3: The endpoints were hatchability, survival, length and weight.


PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three tropic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on results from the assessment of reproduction to fathead minnow (Pimephales promelas) study, NOEC = 10 mg/L, and an assessment factor of 10 is applied, in accordance with ECHA guidance (ref. 8).


PNEC = 10000 μg/L/10 = 1000 μg/L


Environmental risk classification (PEC/PNEC ratio)


PEC/PNEC = 0.41 μg/L /1000 μg/L = 0.00041 i.e. the PEC/PNEC ≤ 0.1 which justifies the phrase “Use of hydrochlorothiazide has been considered to result in insignificant environmental risk”.


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


Environmental Fate Data

Endpoint

Method

Test Substance Concentration

Time

Result

Ref

Percentage Mineralisation

OECD 301B

1.0 mg/L

Note 4

28 d

36 %

9

Percentage Compound Removal

57 %

Half-Life

OECD 308

0.1 mg/L

In High Organic Matter Sediment

Note 4

99 d

Total System DT50 = 37.3 days (23.0 in Overlying Water, and 42.8 days in Sediment)

58% mineralisation

10

0.1 mg/L

In Low Organic Matter Sediment

Note 4

Total System DT50 = 34.7 days (23.2 in Overlying Water, and 55.5 days in Sediment)

70% mineralisation

Note 4: Results are expressed as nominal concentrations.


Biodegradation

Overall, the evidence from the OECD 308 study suggests that hydrochlorothiazide will not be persistent in the aquatic environment.


Aerobic transformation in aquatic sediments showed that in both the high and low organic matter test vessels, dissipation from and degradation of hydrochlorothiazide in the overlying water occurred. Radioactivity associated with the sediment was extracted using separate methanol and ethanol extractions. Radio-Thin Layer Chromatography and mass spectrometry analysis confirmed the presence of hydrochlorothiazide in the extracts as well as the degradation of hydrochlorothiazide, predominantly in the water phase, 4-amino-6-chlorobenzene-1,3-disulfonamide which was present at approximately 10% of the total applied radioactivity (combined overlying water and sediment extracts).


A significant amount of mineralisation occurred throughout the study, accounting for 58% and 70% of the applied radioactivity, in the high and low organic matter vessels respectively. Due to the position of the radio-label in the molecule it is possible that only partial mineralisation of [14C] hydrochlorothiazide occurred.


The evidence from studies above (not readily biodegradable, total system DT50 ≤ 120d) suggests that hydrochlorothiazide is slowly degraded. Therefore, the phrase “Hydrochlorothiazide is slowly degraded in the environment” has been assigned.


In Swedish:Hydroklortiazid bryts ned långsamt i miljön” under the heading “Nedbrytning”.


Physical Chemistry Data

Endpoint

Method

Test Conditions

Result

Ref.

Partition Coefficient Octanol/Water

OECD 107,

EC 440/2008 Part A

-

Log P= 0.09 @ pH 7


11

Solubility Water

Note 5

25°C, pH 6.2

609 mg/L

12

Adsorption/desorption to sludge

OECD 106

EMEA Guideline 2006

Tiburg Sewage Sludge, pH 6.2,

1 mg/L

Note 4

Kd(ads) = 11.9

13

Koc(ads)  = 28.9

Adsorption/desorption to sludge

Maaskant Sewage Sludge, pH 5.2,

1 mg/L

Note 4

Kd(ads)  = 14.2

Koc(ads)  = 33.0

Note 4: Results are expressed as nominal concentrations.

Note 5: This study predates current ERA regulatory requirements and may not have been undertaken to standardized test guidelines.



Bioaccumulation


Since Log Pow < 4, hydrochlorothiazide has no significant bioaccumulation potential, therefore the phrase “Hydrochlorothiazide has low potential for bioaccumulation” has been assigned.


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

 

References

 

  1. ECHA, European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0). February 2016.


  2. Hydrochlorothiazide. www.rxlist.com (Feb 2015).


  3. Fresh Water Algal Inhibition Test with HCTZ DS. NOTOX Project 490915. NOTOX B.V. Brixham Environmental Laboratory, UK, AstraZeneca Report BD4131, October 2009. 


  4. Daphnia Magna Reproduction Test Inhibition with HCTZ DS (Semi-static). NOTOX Project 485927. NOTOX B.V. Brixham Environmental Laboratory, UK, AstraZeneca Report BD4133, November 2007.


  5. [14C] hydrochlorothiazide: Determination of the effects in a water-sediment system on the emergence of Chironomus riparius using spiked sediment. Hayfield A.J. Brixham Environmental Laboratory, UK, AstraZeneca Report BR0137. March 2010


  6. Fish-Early-Life Stage (ELS) Toxicity Test with HCTZ DS (Semi-static). NOTOX Project No. 485928. NOTOX B.V. Brixham Environmental Laboratory, UK, AstraZeneca Report BD4132, January 2008.


  7. Report on the Test for Activated Sludge Inhibition of PBS000397.1 NOTOX Project 948033. Weinstock M. NOTOX Project B.V. Brixham Environmental Laboratory, UK, AstraZeneca Report BD4186. October 1994


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


  9. [14C]Hydrochlorothiazide: 28 day ready biodegradation. Commander R.F. Brixham Environmental Laboratory, UK, AstraZeneca Report BR0030, October 2009.


  10. Hydrochlorothiazide: Aerobic transformation in aquatic sediment systems. Oliver R. Brixham Environmental Laboratory, UK, AstraZeneca Report BR0040 
    February 2010.


  11. Determination of the Partition Coefficient (n-Octanol-Water) of HCTZ DS. NOTOX Project 490916. NOTOX B.V. Brixham Environmental Laboratory, UK, AstraZeneca Report BD4130, July 2009.


  12. Hydrochlorothiazide. Deppeler H.P. Anal. Profiles Drug Subst. 1981 v10 p405-441


  13. Adsorption/Desoprtion of HCTZ on Two Sludges. NOTOX Project 490914. Brixham Environmental Laboratory, UK, AstraZeneca Report BD4187, October 2009.