Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula: (Ref.1)

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

Where:

A (kg/yr)	409,98 kg	Total karbidopa sold (kg) in Sweden in 2021 from IQVIA (Ref. 2)
R	0 %	Removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation); use 0 if no data is available. (Ref.1)
P	10*106	Number of inhabitants in Sweden (Ref. 1)
V (L/day)	200	Volume of wastewater per capita and day (200 L/day is the default value) (Ref. 1,3)
D	10	Factor for dilution of wastewater by surface water flow (10 is the default value) (Ref. 1,3).

Note:  The factor 10⁹ converts the quantity distressed from kg to mcg.

PEC (μg/L) = (409,98*10⁹*(100-0))/(365*10*10⁶*200*10*100)

PEC = 0,056 μg/L

Ecotoxicological Studies with Karbidopa

Activated Sludge, Respiration Inhibition Test (OECD 209)

The activated sludge, respiration inhibition test (ASRIT) was completed to assess the effects of karbidopa on activated sludge microorganisms in accordance with OECD Guideline 209. (Ref. 4)

The EC₅₀ was not achieved within the studied concentration range from 0 to 1000 mg/L.  Additionally, based on the data obtained from the study, a NOEC could not be determined.

Freshwater Alga Growth Inhibition Test (OECD 201)

The toxicity of karbidopa to the freshwater alga, Raphidocelis subcapitata, was determined in accordance with OECD Guideline 201.  Percent inhibition values relative to the negative (EC_x) values for cell density, growth rate, and yield, as well as the NOEC and LOEC values were calculated at 72 hours of exposure and summarized in the table below. (Ref. 5)

Endpoint	Time Weighted Mean Karbidopa Concentration
Cell Density:
72-hour EC50a	0,63 mg/L
72-hour EC20a	0,44 mg/L
72-hour EC10a	0,37 mg/L
Yield:
72-hour EyC50a	0,64 mg/L
72-hour EyC20a	0,45 mg/L
72-hour EyC10a	0,37 mg/L
Growth Rate:
72-hour ErC50a	1,1 mg/L
72-hour ErC20a	0,88 mg/L
72-hour ErC10a	0,79 mg/L
Cell Density, Yield, and Growth Rate:
72- our NOECb	0,13 mg/L
72-hour LOECb	0,24 mg/L

a. EC_x, E_yC_x, and E_rC_x values were estimated, when possible, using non-linear regression with replicate data and time‑weighted mean, measured karbidopa concentrations.

b. NOEC and LOEC values were based on statistical comparisons (Dunnett's test; p ≤ 0,05) between treatment and negative control data.

The NOEC for all endpoints was 0,13 mg/L.

Daphnia magna Reproduction Test (OECD 211)

The effects of karbidopa on survival, growth, reproductive output the crustacean Daphnia magna were studied in a 21-day static-renewal chronic toxicity test following the OECD Guideline 211. The results are below. (Ref. 6) 

Parameter	EC Value (95% Confidence Interval) (mg/L)		NOEC (mg/L)	LOEC (mg/L)
Adult Survival	EC10	NDa	1,7	> 1,7
	EC50	> 1,7 (NC)b,c
Live Young Produced Per Surviving Parental Animal	EC10	> 1,7 (NC)b,c
	EC50	> 1,7 (NC)b,c
Live Young Produced Per Parent Daphniad	EC10	> 1,7 (NC)b,c
	EC50	> 1,7 (NC)b,c
Total Length	EC10	NDa
	EC50	NDa
Dry Weight	EC10	NDa
	EC50	NDa

a. ND = Not determined in the study.

b. NC = Not calculable, since the calculated EC_x value was extrapolated beyond the data range used in the calculation and/or the 95% confidence intervals were overly wide.

c. Empirically estimated to be greater than the highest test concentration, since there was less than a 10% decrease in any treatment group in comparison to the pooled control.

d. Live young produced per parent Daphnia at the start of the test excluding parental accidental and/or inadvertent mortality.

The NOEC was 1,7 mg/L for all survival, reproduction, and growth endpoints.

Fish Early-Life Stage Toxicity Test (OECD 210)

The chronic effects of karbidopa on the time to hatch, hatching success, survival, and growth of fathead minnows, Pimephales promelas, was evaluated under semi-static conditions for 33 days following the OECD 210 guidance. The results, based on time-weighted mean measured karbidopa concentrations, are below. (Ref. 7) 

Biological Parameter	LC/EC10 (95% CI) (mg/L)		LC/EC20 (95% CI) (mg/L)		NOEC (mg/L)	LOEC (mg/L)
Time to Hatch	NDa		NDa		1,5	> 1,5
Hatching Success	LC10	> 1,5 (NC)b,c	LC20	> 1,5 (NC)b,c
Post-Hatch Larval Survival	LC10	> 1,5 (NC)b,c	LC20	> 1,5 (NC)b,c
Overall Survival	EC10	> 1,5 (NC)b,c	EC20	> 1,5 (NC)b,c
Total Length	EC10	> 1,5 (NC)b,c	EC20	> 1,5 (NC)b,c
Wet Weight	EC10	> 1,5 (NC)b,c	EC20	> 1,5 (NC)b,c
Dry Weight	EC10	> 1,5 (NC)b,c	EC20	> 1,5 (NC)b,c

CI = Confidence Interval

a. Not determined in the study.

b. NC = Not calculable, since the calculated LC/EC_x value was extrapolated beyond the data range used in the calculation and/or the 95% confidence interval contained a zero or was overly wide.

c. Empirically estimated to be greater than the highest karbidopa concentration, since there was less than a 10% decrease in the highest treatment group in comparison to the negative control.

The NOEC was determined to be 1,5 mg/L for all survival, hatch, and growth endpoints.

Predicted No Effect Concentration (PNEC)

PNEC (μg/L) = NOEC/AF

AF = Assessment Factor = 10

Organism	NOEC
Freshwater Algae (Raphidocelis subcapitata)	0,13 mg/L
Daphnia magna	1,7 mg/L (all endpoints)
Fathead Minnow (Lepomis macrochirus)	1,5 mg/L (all endpoints)

The PNEC was determined in accordance with ECHA guidance. (Ref. 8) 

The chronic aquatic effects of karbidopa were assessed in green algae, fish, and Daphnia.  Freshwater algae (Raphidocelis subcapitata) was determined to be the most sensitive species tested (NOEC of 0,13 mg/L).  Therefore, the PNEC_SURFACEWATER was calculated using the NOEC for freshwater algae. 

NOEC = 0,13 mg/L

Assessment Factor = 10

PNEC = 0,13/10

PNEC = 0,013 mg/L

PNEC = 13 μg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC Ratio:

PEC = 0,06 μg/L

PNEC = 13 μg/L

PEC/PNEC = 0,06/13

PEC/PNEC = 0,00432

Justification of environmental risk classification:

Since PEC/PNEC ≤ 0,1, the use of karbidopa has been considered to result in insignificant environmental risk.

Degradation

Aerobic Transformation in Aquatic Sediment Systems (OECD 308)

The biotransformation of [¹⁴C]karbidopa was investigated according to OECD Guideline 308 in two water-sediment systems (Brandywine Creek and Choptank River) under aerobic conditions. (Ref. 9)

Test systems were dosed with 52,0 μg (12,0 μCi) of [¹⁴C]karbidopa per test vessel. Test vessels were incubated in the dark at 20 ± 2 ºC for up to 100 days. Aerobic conditions were maintained by gently bubbling a stream of air through the water layers in each test vessel. Effluent gases were passed through vials containing potassium hydroxide to trap evolved carbon dioxide. Duplicate test vessels were sacrificed for analyses immediately after test substance application and at 1, 3, 7, 15, 30, 51, 75, and 100 days after application. Water layers were decanted and analyzed separately. The sediment was extracted three times, first with a phosphate buffer (0,5 M), followed by acetonitrile, and then with tetrahydrofuran. The remaining sediment solids were combusted to provide a material balance. The potassium hydroxide traps (¹⁴CO₂), overlying water layers, sediment extracts, and sediment solids were analyzed separately for total radioactivity by liquid scintillation counting (LSC).

Mean material balances (recoveries) ranged from 82,2 to 99,2% in Brandywine Creek water-sediment system and 84,9 to 108,5% in the Choptank River water-sediment systems.

The mean cumulative amount of mineralization after 100 days of incubation was 41,8% and 39,6% in the Brandywine Creek and Choptank River water-sediment systems, respectively, demonstrating that karbidopa and its biotransformation products would degrade to CO₂ in an aquatic sediment environment.

The mean amount of extractable ¹⁴C from the sediment was low ranging 2,5 to 16,2% AR throughout the study and for both water-sediment systems. The extraction scheme used was considered exhaustive given the range of solvents used during preliminary testing and the selection of three different solvents of varying polarity for the definitive test.

The amount of radioactivity remaining on the sediment solids after extraction, or non-extractable residues (NER), wavered throughout the study rather than showing a steady increase over time. These results coincided with material balance values, which also fluctuated, suggesting that volatile losses, e.g. dissolved carbonates or low molecular weight amines or alcohols, were being lost during processing steps prior to combustion.

Biotransformation of karbidopa was rapid in the water layer of both water-sediment systems with essentially all of the applied karbidopa being degraded within 3 days of dosing. Biotransformation products consisted of multiple polar compounds that were poorly resolved and eluted near the solvent front. One biotransformation product, tentatively identified as MRT23 reached a mean maximum in the total system of 14,2 and 23,8% AR at Day 7 and then declined to 1,3 and 3,5% AR by study termination (Day 100) in the Brandywine Creek and Choptank water-sediment systems, respectively.

Although karbidopa rapidly degraded, kinetic data was able to be calculated for the water layer only. The test substance, [¹⁴C]karbidopa, disappeared from the water layers of both test systems primarily by hydrolysis. Disappearance was best described using Single First Order kinetic (SFO) calculated using the software CAKE (version 3.4 release, Tessella, Ltd.). The DT₅₀ and DT₉₀ values for karbidopa from the Brandywine Creek and Choptank River are presented in the table below. The DT₅₀ at 12°C values were calculated based on the FOCUS guidance (Generic Guidance for Estimating Persistence and Degradation Kinetics from Environmental Fate Studies on Pesticides in EU Registration. Version 1.1, 2014).

The disappearance of karbidopa from water layers in the aerobic sediment systems was determined to be:

Sediment Systema	DT50 (20°C)	DT90 (20°C)	DT50 (12°C)
Brandywine	0,67 days	2,2 days	1,4 days
Choptank	0,79 days	2,6 days	1,7 days

a. Sediment layers were not analyzed at Day 0, 1, and 3 and were not included in the calculation.

As is shown, the DT₅₀ values for the total system in the Brandywine and Choptank Rivers were 0,67 and 0,79 days, respectively.

Justification of chosen degradation phrase:

DT₅₀< 120d for the total system; therefore, karbidopa is slowly degraded in the environment. 

Bioaccumulation

Partition Coefficient (n-octanol/water): Shake Flask Method (OECD 107)

Log P_ow was determined by the OECD 107 shake flask method partition coefficient (n octanol/water) at pH 4, 7, and 9 and 20°C. (Ref. 10)

Endpoint	pH	Result
Log Pow	4	-1,99 ± 0,07
	7	-2,18 ± 0,05
	9	-2,60 ± 0,01a

a. The Pow for pH 9 is calculated with the LOQ value (0,599 µg/mL) as the octanol concentration to determine a less than value.

Justification of chosen bioaccumulation phrase:

Log D_ow at pH 7< -2,18; therefore, karbidopa has low potential for bioaccumulation.

References

1. FASS.se.  Environmental classification of pharmaceuticals at www.fass.se.  Guidance for pharmaceutical companies. 2012 V 2.0.  2021.

2. IQVIA. 2021. IQVIA / LIF - kg consumption/2021.

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

4. Eurofins EAG Agroscience, LLC. R&D/20/0621. Carbidopa (A-39432.0): An Activated Sludge, Respiration Inhibition Test. AbbVie Study TX19-063. 2021.

5. Eurofins EAG Agroscience, LLC. R&D/20/0931. Carbidopa (A-39432.0): A 72 Hour Toxicity Test with the Freshwater Alga (Raphidocelis subcapitata). AbbVie Study TX19-067. 2021.

6. Eurofins EAG Agroscience, LLC. R&D/19/1323. Carbidopa (A-39432.0): A Semi Static Life-Cycle Toxicity Test with the Cladoceran (Daphnia magna). AbbVie Study TX19-068. 2021.

7. Eurofins EAG Agroscience, LLC. R&D/19/1324. Carbidopa (A-39432.0): An Early Life-Stage Toxicity Test with the Fathead Minnow (Pimephales promelas). AbbVie Study TX19-069. 2021

8. European Chemicals Agency (ECHA). Guidance on information requirements and chemical safety assessment Chapter R.10: Characterisation of dose [concentration]-response for environment. 2008.

9. Eurofins EAG Agroscience, LLC. R&D/20/0930. Carbidopa (A-39432.0): Aerobic Transformation in Aquatic Sediment Systems. AbbVie Study TX19-065. 2021.

10. Eurofins EAG Agroscience, LLC. R&D/19/1322. Carbidopa (A-39432.0): Determination of n-Octanol/Water Partition Coefficient (Shake Flask Method). AbbVie Study TX19-061. 2020.

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