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Madopark®

Roche

Tablett 100 mg/25 mg
(rosa, med krysskåra)

Medel vid parkinsonism

Aktiva substanser:
ATC-kod: N04BA02
Läkemedel från Roche omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Benserazid

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


Läs mer

Detaljerad miljöinformation

Identification and characterisation

CAS number 14919-77-8 [1]

Molecular weight 293.705 [1]

Remark -

Brand name Madopark, Madopark Depot, Madopark Quick, Madopark Quick mite [1]


Physico-chemical properties

Aqueous solubility 335000 mg/l (20 °C) [1]

Dissociation constant, pKa pKb ~ 6.9, several other species QSAR Benzerazide

Melting point 145–148 °C

Vapour pressure 3.83E-11 Pa (25 °C) QSAR Benserazide

Boiling point ND

KH 9.42E–26 Pa*m3/mol QSAR Benserazide

QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris)


Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (μg/L) = (A x 1'000'000'000 x (100-R)) / (365 x P x V x D x 100) = 1.5 x 10-6 x A x (100 - R) = 0.064 μg/L

Where:

A Sold quantity in 2019 = 905,8885kg (total sold amount API in Sweden year 2019, data from IQVIA)

R Removal rate = 53 % calculated with Simple Treat 4.0 [8]

P Population of Sweden = 9000000

V Volume of Wastewater = 200 l/day [2]

D Factor for Dilution = 10 [2]


Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Desmodesmus subspicatus): [4]

ErC50 72 h (growth rate) = 2.66 mg/l (OECD 201)

ErC10 72 h (growth rate) = 0.883 mg/l (OECD 201)

NOErC 72 h (growth rate) = 0.299 mg/l (OECD 201)


Water-flea (Daphnia magna): [5]

EC50 48 h (immobilisation) = 18.8 mg/l (OECD 202)

NOEC 48 h (immobilisation) = 6.25 mg/l (OECD 202)


Rainbow trout (Oncorhynchus mykiss): [6]

LC50 96 h (mortality) = 316 mg/l (OECD 203)

NOEC 96 h (mortality) = 200 mg/l (OECD 203)


Micro-organisms: [7]

NOEC (toxicity control) 28 d (endpoint) = 50 mg/l (OECD 301 F)


PNEC Derivation

The PNEC is based on the following data:

PNEC (mg/l) = lowest EC50/1000, where 1000 is the assessment factor used. An ErC50 of 2660 μg/l for algae has been used for this calculation.

PNEC = 2660 / 1000 = 2.66 μg/l


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.064 μg/L

PNEC Predicted No Effect Concentration = 2.66 μg/L

Ratio PEC/PNEC = 0.024


PEC/PNEC =0.064/2.66 = 0.024 for Benserazide hydrochloride which justifies the phrase 'Use of Benserazide hydrochloride has been considered to result in insignificant environmental risk.'


Degradation

Biotic Degradation

Ready biodegradability: [7]

2% after 28 days of incubation BOD/ThOD (OECD 301 F)

48% after 28 days of incubation DOC/TOC (OECD 301 F)

100% after 28 days of incubation Parent (OECD 301 F)


Inherent biodegradability: [6]

84% after 7 days of incubation DOC (OECD 302 B)

93% after 14 days of incubation DOC (OECD 302 B)

93% after 28 days of incubation DOC (OECD 302 B)


Other degradation information: ND


Abiotic Degradation

Photodegradation: 58% (120 h, 22 °C, light) [7]

Hydrolysis: 52% (120 h, 22 °C, in the dark) [7]


Benserazide is not readily degradable, but inherently biodegradable according to OECD 302 B. This justifies the phrase 'Benserazide hydrochloride is slowly degraded in the environment.'


Bioaccumulation/Adsorption

logKOW ≤0.5 QSAR Benzerazide

(consensus of various QSARs, 8 QSAR values, avg = -2.23 ± 0.65)

KOC 1.39 L/kg QSAR Benzerazide

BCF <10 QSAR Benzerazide

Benserazide hydrochloride has low potential for bioaccumulation (log Kow <4).


Excretion/metabolism

Benserazide is co-administered with Levodopa in Madopark. Benserazide is well absorbed and extensively metabolised in the gut epithelium and liver to trihydroxybenzylhydrazine, a potent aromatic aminocarboxylase inhibitor that prevents peripheral Levodopa metabolism. The metabolites of benserazide are mainly excreted by urinary pathway. [3]


PBT/vPvB Assessment

P: Freshwater half-life <40 d, based on hydrolysis [7]

Sediment half-life ND

Persistence criteria fulfilled? not P


B: BCF (experimental)

alternatively, logDOW(p H 7) ≤0.5 , log Pow

Bioaccumulation criteria fulfilled? no data on potential bioaccumulation


T: chronic NOEC < 0.01 mg/l? n not T

CMR substance? n not CMR [1]

Endocrine-disrupting effects? n not ED

T criteria fulfilled? not T


PBT Assessment: not PBT


References

1. F. Hoffmann-La Roche Ltd (2016): Safety Data Sheet for Benserazide hydrochloride, 24.06.2016;https://www.roche.com/sustainability/what_we_do/for_communities_and_

environment/ environment/safety_data_sheetsrow.htm

2. 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

3. Schweizerisches Azneimittelkompendium (2007): Monograph for Madopar/Benserazide. http://www.kompendium.ch/MonographieTxt.aspx?lang=de&MonType=fi

4. Study Report: BMG Project no. 1228/a.2-07: Benserazid-HCl, fresh water algal growth inhibition test withD esmodesmus subspicatus , January 2008.

5. Study Report: BMG Project no. 1228/b-07: Benserazid-HCl, 48-hour acute toxicity toD aphnia magna, January 2008.

6. Study Report: Roche Project no. E-39/85: Oekotoxikologische Beurteilung BWL, July 1985.

7. Study Report: BMG Project no. 1228/c-07: Benserazid-HCl, ready biodegradability - evaluation of the aerobic biodegradability in an aqueous medium: manometric respirometry test, January 2008.

8. Struijs (2014). SimpleTreat 4.0: a model to predict fate and emission of chemicals in wastewater treatment plants. RIVM report 601353005/2014. Model downloaded from RIVM



ND = Not Defined















Levodopa

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


Läs mer

Detaljerad miljöinformation

Identification and characterisation

CAS number 59-92-7 [1]

Molecular weight 197.19 [1]

Remark - [1]

Brand name Madopark, Madopark Depot, Madopark Quick, Madopark Quick mite [1]


Physico-chemical properties

Aqueous solubility 5000, >2700 mg/l [1]

Dissociation constant, pKa 2.3; 8.7; 9.7; 13.4 QSAR

Melting point 275 °C [1]

Vapour pressure 3.41E-08 Pa (25 °C) QSAR

Boiling point ND

KH 2.103E-11 Pa*m3/mol QSAR.

QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris)


Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (μg/L) = (A x 1'000'000'000 x (100 - R)) / (365 x P x V x D x 100) = 1.5 x 10-6 x A x (100 - R) = 0.052 μg/L

Where:

A = Sold quantity in 2017 = 4317.5859 kg/y (total sold amount API in Sweden year 2017, data from IQVIA)

R = Removal rate = 92 % calculated with Simple Treat 4.0 [9]

P = Population of Sweden = 9000000

V = Volume of Wastewater = 200 l/day [2]

D = Factor for Dilution = 10 [2]


Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Pseudokirchneriella subcapitata): [5]

EbC50 72 h (biomass) = 1.5 mg/l (OECD 201)

NOEC 72 h (biomass) = 0.32 mg/l (OECD 201)


Water-flea (Daphnia magna): [6]

EC50 48 h (immobilisation) > 100 mg/l (OECD 202)

NOEC 48 h (immobilisation) = 100 mg/l (OECD 202)


Rainbow trout (Oncorhynchus mykiss): [7]

LC50 96 h (mortality) > 100 mg/l (OECD 203)

NOEC 96 h (mortality) = 100 mg/l (OECD 203)


Micro-organisms: [3]

NOEC (toxicity control) 28 d (endpoint) = 100 mg/l (OECD 301 F)


PNEC Derivation

The PNEC is based on the following data:

PNEC (mg/l) = lowest EC50/1000, or acute NOEC/1000, where 1000 is the assessment factor used.

An EbC50 of 1500 μg/l for algae has been used for this calculation

PNEC = 1500 / 1000 = 1.5 μg/l


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.052 μg/L

PNEC Predicted No Effect Concentration = 1.50 μg/L

Ratio PEC/PNEC = 0.035


PEC/PNEC =0.052/1.50 = 0.035 for Levodopa which justifies the phrase 'Use of Levodopa has been considered to result in insignificant environmental risk.'


Degradation

Biotic Degradation

Ready biodegradability:

72-73% after 28 days of incubation BOD/ThOD (OECD 301 F) [3, 4]

67-70% at the end of the 10-d window BOD/ThOD (OECD 301 F) [3, 4]

98% after 28 days of incubation DOC/TOC (OECD 301 F) [3, 4]


Inherent biodegradability: ND

Other degradation information: ND


Abiotic Degradation

Photodegradation: ND

Hydrolysis: ND


Levodopa is readily biodegradable which justifies the phrase 'Levodopa is degraded in the environment.'


Bioaccumulation/Adsorption

logPOW: -2.39 EpiSuite experimental database match [8]

KOC: 1; 161 QSAR

BCF: <10 QSAR


Levodopa has low potential for bioaccumulation (log KOW <4).


Excretion/metabolism

Levodopa is rapidly absorbed after oral administration and widely distributed. Extensive metabolisaton is mainly by decarboxylation to dopamine and also by methylation to 3-O-methyldopa. Most of a dose is decarboxylated by the gastric mucosa before entering the systemic circulation, this decarboxylase activity is inhibited by co-administered benserazide. Dopamine is further metabolised to noradrenaline, 3-methoxytyramine and two major excretory metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA). About 70 to 80% of a dose is excreted by urinary pathway in 24 h, about 50% as DOPAC and HVA, 10% as dopamine, up to 30% as -O-methyldopa and less than 1% as unchanged drug. Less than 1% of a dose is eliminated in the faeces. [1, 8]


PBT/vPvB Assessment

P: Freshwater half-life <40 d, based on ready biodhydrolysis [3, 4]

Sediment half-life ND

Persistence criteria fulfilled? not P


B: BCF (experimental)

alternatively, base or acid?

alternatively, logDOW(p H 7) -2.39 , logDow < 3 [8]

Bioaccumulation criteria fulfilled? no significant bioaccumulation potential


T: chronic NOEC < 0.01 mg/l? n not T

CMR substance? n not CMR [1]

Endocrine-disrupting effects? n not ED

T criteria fulfilled? not T


PBT Assessment: confirmed not PBT


References

1. F. Hoffmann-La Roche Ltd (2016): Safety Data Sheet for Levodopa, 24.06.2016; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/

environment/safety_data_sheetsrow.htm.

2. 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.

3. Study Report: Roche Project no. B-166335. Ready Biodegradability: Manometric Respirometry Test for Levodopa, October 1996.

4. Study Report: BMG Project no. A09-02230. Levodopa – Ready Biodegradability – Evaluation of the Aerobic Biodegradability in an Aqueous Medium: Manometric Respirometry Test, March 2010.

5. Study Report: NOTOX Project no. 180102. Fresh Water Algal Growth Inhibition Test with Levodopa, December 1996.

6. Study Report: NOTOX Project no. 180023. Acute Toxicity Study in Daphnia magna with Levodopa, December 1996.

7. Study Report: Roche Project no. B-166336. 96-Hour Acute Toxicity Test with Levodopa in Rainbow Trout, November 1996.

8. US EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11. United States Environmental Protection Agency, Washington, DC, USA.

9. Struijs (2014). SimpleTreat 4.0: a model to predict fate and emission of chemicals in wastewater treatment plants. RIVM report 601353005/2014. Model downloaded from RIVM.


ND = Not Defined