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Atacand® Plus

AstraZeneca

Tablett 16 mg/12,5 mg
(persikofärgade, ovala, bikonvexa, 4,5×9,5 mm tabletter med en skåra på båda sidor och märkta A/CS på den ena sidan)

Angiotensin II-receptorantagonist och diuretikum

ATC-kod: C09DA06
Läkemedel från AstraZeneca omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Hydroklortiazid

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.


Läs mer

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.

Kandesartan

Miljörisk: Användning av kandesartan har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Kandesartan är potentiellt persistent.
Bioackumulering: Kandesartan har låg potential att bioackumuleras.


Läs mer

Detaljerad miljöinformation

PEC/PNEC = 0.145 μg/L /100 μg/L = 0.00145

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 solid amount API in Sweden year 2016, data from IMS Health. 

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 = 967.94. Since candesartan cilexetil is a prodrug, mainly excreted as candesartan, conversion is made to equivalent amount of candesartan by 1341.97*(440.46/610.66) (molecular weights for candesartan and candesartan cilexetil, respectively). 1341.97 kg is based on sales figures from IMS for 2016 for candesartan cilexetil.


R = 0


PEC = 1.5 * 10-6 * 967.94 * (100-0) = 0.145 μg/L


Metabolism and excretion

Candesartan cilexetil is a prodrug. After ingestion it is completely converted to the active drug candesartan, which then constitutes approximately 87% of the excreted metabolites. Approximately 33% of the given dose is excreted via the urine and approximately 65% is excreted in the faeces. No prodrug is excreted after use of candesartan cilexetil (ref. 2).


Ecotoxicity data


Candesartan

Endpoint

Species

Common

Name

Method

Time

Result

Reference

NOEC - Based on

Growth

Pseudokirchneriella

subcapitata (formerly known as Selenastrumcapri- cornutum)

Green Alga

OECD 201

72 h

32 mg/L

Note 1a

3

LOEC- Based on

Growth

56 mg/L

Note 1a

ErC50 - Based on

Growth

>56 mg/L

Note 1a

EC50 - Based on

Immobilisation

Daphnia magna

Giant Water

Flea

OECD 202

48 h

>120 mg/L

Note 1a

4

NOEC - Based on

Immobilisation

120 mg/L

Note 1a

NOEC - Based on

Reproduction, Survival or Length

OECD 211

21 d

10 mg/L

Note 1a

5

NOEC - Based on

Hatch, Survival, Length and Dry Weight

Pimephales promelas

Fathead

Minnow

OECD 210

32 d

1.0 mg/L

Note 1a

6

EC50 - Based on

Activated Sludge Respiration Inhibition

-

-

OECD 209

3 h

>100 mg/L

Note 2

7

NOEC - Based on

Activated Sludge Respiration Inhibition

100 mg/L

Note 2

Although there is no environmental exposure to the prodrug, candesartan cilexetil, results for studies are available and have been included for completeness. The results indicate no toxicity in any tested species at the limit of solubility in the test media.


Candesartan Cilexetil

Endpoint

Species

Common

Name

Method

Time

Result

Reference

EbC50 - Based on Area Under Growth Curve

Pseudokirchneriella subcapitata (formerly

known as

S capricornutum)


Green Alga


OECD 201


72 h


>0.012 mg/L

Note 1b

8


ErC50 - Based on Average Specific Growth Rate

>0.012 mg/L

Note 1b

NOEC - Based on

Area Under the

Growth Curve

0.012 mg/L

Note 1b

NOEC - Based on

Average Specific

Growth Rate

0.012 mg/L

Note 1b

LOEC - Overall



>0.012 mg/L

EC50 - Based on

Immobilisation

Daphnia magna


Giant Water

Flea


OECD 202

Part 1


48 h


>0.016 mg/L

Note 1b

9


NOEC - Based on

Immobilisation

0.016 mg/L

Note 1b

LOEC - Overall

>0.016 mg/L

LC50

Oncorhynchus mykiss


Rainbow

Trout


OECD 203


96 h


>0.0172 mg/L

Note 1b

10


NOEC - Based on

Mortality

0.0172 mg/L

Note 1b

LOEC - Overall

>0.0172 mg/L

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

Note 1b: Results are expressed as mean measured concentrations.

Note 2: Results are expressed as nominal concentrations.


PNEC (Predicted No Effect Concentration)


The use of candesartan cilexetil will mainly result in the active drug candesartan entering the environment, and therefore the assessment is based on candesartan.


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 early life stage toxicity test with fathead minnow (Pimephales promelas) and an assessment factor of 10 is applied, in accordance with ECHA guidance (ref. 1).


PNEC = 1000 μg/L/10 = 100 μg/L


Environmental risk classification (PEC/PNEC ratio)


PEC/PNEC = 0.145 µg/L/100 µg/L= 0.00145

i.e. 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 candesartan has been considered to result in insignificant environmental risk”


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


Environmental Fate Data


Candesartan

Endpoint

Method

Test Substance

Concentration

Time

Result

Reference

Percentage Aerobic

Biodegradation

OECD 301F

100 mg/L

Note 3

28 d

<5%

11

BOD

<0.05 g O2/g

COD

-

-

1.74 g O2/g

Dissipation Half-life

OECD 308

0.1 mg/L in Overlying

Water with High Organic Matter Sediment

Note 3

-

T1/2 = 222 d

12

0.1 mg/L in Overlying

Water with Low Organic Matter

-

T1/2 = 97 d

There was no significant degradation of candesartan under the test conditions. Degradation half lives for the total system could not be calculated.

Degradation Half-life

OECD 309

(Preliminary

Study)

0.2 mg/L in High

Organic Matter

River Water

Note 3

30 d

T1/2 = 12 d

13

0.2 mg/L in High

Organic Matter Suspended Sediment Note 3

T1/2 = 12 d

0.2 mg/L in Low

Organic Matter

River Water

Note 3

T1/2 = 7 d

0.2 mg/L in Low

Organic Matter Suspended Sediment Note 3

T1/2 = 8 d

Percentage

Mineralisation

OECD 309

(Preliminary

Study)

0.2 mg/L in High or

Low Organic Matter

Suspended Sediment

& Overlying Water

Note 3

30 d

<1 %

13

Percentage

Hydrolysis

OECD 111

10 mg/L

Note 3

5 d

12 % @ pH 5, 50oC

<10 % @ pH 7 & 9, 50oC

14

Hydrolysis Half-life

OECD 111

10 mg/L

Note 3

 

T1/2 ≥1 yr @ 25oC

14

Distribution

Coefficient Octanol

Water

OECD 107

50 & 100 mg/L

-

Log D = 2.11 @ pH 5, 20oC

Log D = - 0.68 @ pH 7, 20oC

15

Partition Coefficient

Octanol Water

Shake flask, OECD107


-

-

log Dow = 2.11 at pH 5

log Dow = -0.675 at pH 7 log Dow = -0.902 at pH 9

17

Note 3: Results are expressed as nominal concentrations.


Candesartan Cilexetil

Endpoint

Method

Test Substance

Concentration

Time

Result

Reference

Percentage

Biodegradation

OECD 301B

15 mg/L Organic

Carbon

Note 3

28 d

<9 % ThCO2

16

Note 3: Results are expressed as nominal concentrations.


Biodegradation

The degradation of candesartan in aquatic sediment systems (Ref 12) was assessed according to the OECD 308 Test Guideline. Only partial dissipation of the radioactivity from the water phase was observed at Day 99, 86% and 57% of the radioactivity remained in the aqueous phase and in the high (HOC) and low (LOC) organic carbon test systems, respectively. The dissipation half lives in the supernatants were calculated as 222 days and 95 days for the high and low organic matter vessels, respectively (simple first order (SFO) half lives). No significant mineralization or formation of volatile organic transformation products was observed and, at the end of the test, 22 and 45% the radioactivity was associated with the sediment phase and in the HOC and LOC, respectively.


The solvent used for the primary sediment extraction was ethanol. Non-extracted radioactivity remaining with the sediment was investigated using extraction solvents differing in polarity (methanol, hexane, acetone, 50:50 methanol:dichloromethane, acetonitrile and acidified methanol).


At the end of the study, 87-90% of the radioactivity associated with water phase, and 76-81% of the radioactivity extracted from the sediment phase, was identified as candesartan using thin layer liquid chromatography. Two minor degradation products were observed but neither represented >10% of the applied radioactivity.

candesartan is not readily biodegradable.


Based on the data above the phrase ‘Candesartan is potentially persistent” is chosen.


In Swedish: “Kandesartan är potentiellt persistent” under the heading “Nedbrytning”.


Bioaccumulation

Since Log P < 4 the phrase ‘Candesartan has low potential for bioaccumulation’ is assigned.


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


Physical Chemistry Data


Physical Chemistry Data - Candesartan

Endpoint

Method

Test Conditions

Result

Reference

Solubility Water

Note 4

-

<100 mg/L

18

Dissociation

Constant

UV Adsorption

Note 4

-

pKa = 3.8

(Carboxylic acid and tetrazole ring)

18

-

pKa = 2.1

(Benzimidazole ring)

Adsorption

Coefficient

OPPTS 835.1110

0.26 mg/L in

Sewage Sludge

Kd = 17

19

Note 4: This study pre‑dates current ERA regulatory requirements and may not have been undertaken to standardised test guidelines.


Physical Chemistry Data - Candesartan Cilexetil

Endpoint

Method

Test Conditions

Result

Reference

Solubility Water

High

Performance Liquid Chromatography Note 5

25ºC

<0.05 mg/L

20

Dissociation

Constant

UV Adsorption

Note 5

pH 6.9, 20ºC

pKa(1) = 2.1

(Benzimidazole

Ring)

20

pKa(2) = 4.6 (Tetrazole Ring)

Note 5: This study pre-dates current ERA regulatory requirements and may not have been undertaken to standardised test guidelines.


References

  1. ECHA, European Chemicals Agency, 2008 Guidance on information requirements and chemical safety assessment. 


  2. Excretion balance and absolute bioavailability study with 14C-labelled candesartan cilexetil after a single oral and intravenous dose in healthy male volunteers. Report No. SH-ACH-0001. Astra Hässle AB (1996).


  3. Candesartan: Toxicity to the green alga Pseudokirchnerilla subcapitata. Smyth D.V. AstraZeneca Brixham Environmental Laboratory 2007. Report BL8486.


  4. Candesartan: Acute Toxicity to Daphnia Magna. Bowles A.J. AstraZeneca Brixham Environmental Laboratory 2004. Report BL7774.


  5. Candesartan: Chronic Toxicity to Daphnia Magna. Caunter J.E. Brixham AstraZeneca Environmental Laboratory 2008. Report BL8516.


  6. Candesartan: Determination of effects on the early-life stage of the fathead minnow (Pimephales promelas). Caunter J.E. AstraZeneca Brixham Environmental Laboratory 2007. Report BL8494.


  7. Candesartan: Effect on the Respiration Rate of Activated Sludge. Daniel M. AstraZeneca Brixham Environmental Laboratory 2007. Report BL8471.


  8. Inhibition of Growth to the Alga Selenastrum capricornutum. S.D. Mattock. Covance Laboratories Ltd 1997. Report BD3824.


  9. Acute Toxicity to Daphnia magna. S.D. Mattock. Covance Laboratories Ltd 1997. Report BD3825.


  10. Acute Toxicity to Oncorhynchus mykiss. S.D. Mattock. Covance Laboratories Ltd 1997. Report BD3826.


  11. Determination of 28 day ready biodegradability. Bowles A.J.; Daniel M. AstraZeneca Brixham Environmental Laboratory 2004. Report BL7773.


  12. Candesartan: Aerobic transformation in aquatic sediment systems. MacLean S.A. AstraZeneca Brixham Environmental Laboratory 2008. Report BL8479.


  13. Candesartan: Aerobic transformation in aquatic systems screen. Noble H. AstraZeneca Brixham Environmental Laboratory 2009. Report BR0051.


  14. Candesartan: Hydrolysis as a function of pH - Preliminary study. Trollope H. AstraZeneca Brixham Environmental Laboratory 2007. Report BL8449.


  15. CANDESARTAN: Determination of n-octanol/water distribution coefficient. Trollope H. AstraZeneca Brixham Environmental Laboratory 2007. Report BL8450.


  16. Assessment of ready biodegradability of carbon dioxide evolution; Candesartan cilexitil. Mattock S.D. Covance Report 1997. Report BD3974.


  17. Candesartan: Determination of n-octanol/water distribution coefficient. Report No. BL 8450/B. AstraZeneca Brixham Environmental Laboratory, Brihxam, UK. November 2007.


  18. Physical and Chemical Characteristics of CV-11974 (Candesartan). Takeda Chemical Industries Ltd. Report BD4180.


  19. Candesartan: Adsorption and desorption to sewage sludge. MacClean S.A. AstraZeneca Brixham Environmental Laboratory 2007. Report BL8467.


  20. Marketing S1.03 General Properties for Candesartan Cilexitil (TCV-116). Naoki Kaida; Takeda Chemical Industries Ltd 2010. Report BD4181.