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.
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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