Detaljerad miljöinformation

Identification and characterisation

CAS number 14919-77-8 [1]

Molecular weight 293.705 [1]

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

Physico-chemical properties

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

Dissociation constant, pK_a 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

K_H 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) = 1.37 x 10^-6 x A x (100 - R) = 0.052 μg/L

Where:

A Sold quantity = 799,8151 kg/y sales data from IQVIA / LIF - kg consumption 2021

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

P Population of Sweden = 10 000 000

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

D Factor for Dilution = 10 Default [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 (μg/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. [1]

PNEC = 2660 μg/l / 1000 = 2.66 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.052 μg/L

PNEC Predicted No Effect Concentration = 2.66 μg/L

Ratio PEC/PNEC = 0.019

PEC/PNEC = 0.052/2.66 = 0.019 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

logK_OW ≤0.5 QSAR Benzerazide

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

K_OC 1.39 L/kg QSAR Benzerazide

BCF <10 QSAR Benzerazide

Benserazide hydrochloride has low potential for bioaccumulation (log K_ow <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]

References

1. F. Hoffmann-La Roche Ltd (2021): Environmental Risk Assessment Summary for Benserazide hydrochloride. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm.

2. European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2.

3. electronic Medicines Compendium (eMC). https://www.medicines.org.uk/emc/.

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

Detaljerad miljöinformation

Identification and characterisation

CAS number 59-92-7 [1]

Molecular weight 197.19 [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

K_H 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) = 1.37 x 10^-6 x A x (100 - R) = 0.047 μg/L

Where:

A = Sold quantity = 4270.994 kg/y sales data from IQVIA / LIF - kg consumption 2021

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

P = Population of Sweden = 10 000 000

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]

ErC50 72 h (growth rate) = 3.2 - 5.6 mg/l (OECD 201)

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

In the concentration range of the ErC50, the colour of the test solutions contributed significantly to the effect on algal growth by absorbing wave lengths necessary for algal growth. The ErC50 is, therefore, an approximate value.

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 (μg/l) = lowest EC50/1000, or acute NOEC/1000, where 1000 is the assessment factor used. The lower range of the ErC50 for algae, i.e. 3.2 mg/l, has been used for this calculation. [1]

PNEC = 3200 μg/l / 1000 = 3.20 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.047 μg/l

PNEC Predicted No Effect Concentration = 3.20 µg/l

Ratio PEC/PNEC = 0.015

PEC/PNEC = 0.047/3.20 = 0.015 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

logP_OW: -2.39 EpiSuite experimental database match [8]

K_OC: 1; 161 QSAR

BCF: <10 QSAR

Levodopa has low potential for bioaccumulation (log K_OW <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]

References

1. F. Hoffmann-La Roche Ltd (2021): Environmental Risk Assessment Summary for Levodopa. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm.

2. European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2.

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