Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

Etoposid variety	Molecular weight (g/mol)	Tonnage conversion factor
Etoposid	588,6	1
Etoposid phosphate	668,5	1,14

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6*A(100-R)

PEC = 0,000745 μg/L

Where:

A = 5,44 kg etoposide as the total of 0,7128 kg etoposide phosphate all normalized to etoposid molecular weight (total sold amount API in Sweden year 2021, data from IQVIA). Reduction of A may be justified based on metabolism data.

R = 0 - 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 = 10 *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)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (guideline OECD 201) (Ref. 2):

EC₅₀ 72 h (growth inhibition) = 12569,2 μg/L

EC₁₀ or NOEC = 5621,6 μg/L

Crustacean (D. magna):

Acute toxicity

EC₅₀ 48 h (immobilization) = 30000 μg/L (guideline OECD 202) (Ref. 3)

Chronic toxicity

EC₁₀ 21 days (reproduction inhibition) = 98 μg/L (guideline OECD 211) (Ref. 3)

Crustacean (Ceriodaphnia dubia):

Acute toxicity

LC₅₀ 24 h (mortality) = 19200 μg/L (guideline EPA-600-4-90, US EPA,1993) (Ref. 3)

Chronic toxicity

EC₁₀ 7 days (reproduction inhibition) = 96 μg/L (guideline ISO 20665, 2008) (Ref. 3)

Zebrafish (Danio rerio) (guideline OECD 203) (Ref. 7):

Acute toxicity

LC₅₀ 96 h (mortality) = 70800 µg/L

LC₅₀ 96 h (fertilization) = 118000 µg/L

The PNEC is based on the lowest EC50 / 1000, where 1000 is the assessment factor used if acute data for 3 trophic levels is available. The EC50 for growth inhibition in the algae Pseudokirchneriella subcapitata has been used for this calculation since it is

the most sensitive of the tested species.

PNEC 12,5 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0,000745 / 12,57 = 5,92* 10^-5, PEC/PNEC ≤ 0,1 which justifies the phrase Use of etoposide has been considered to result in insignificant environmental risk.

Degradation

Biotic degradation

Ready degradability:

Test results 40 % degradation in 7 days (Ref. 6)

not readily biodegradable (BIOWIN QSARs) (Ref. 4)

Justification of chosen degradation phrase: Etoposide does not fulfil the criteria for ready degradability. The phrase “Etoposide is potentially persistent” is thus chosen.

Bioaccumulation

LogP = 0,60 (Ref 5)

Since log P < 4 at pH 7, the substance has low potential for bioaccumulation.

References:

1. 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

2. T. Elersek, S. Milavec, M. Korošec, P. Brezovsek, N. Negreira, B. Zonja, M. López de Alda, D. Barceló, E. Heath, J. Ščančar, M. Filipič; Toxicity of the mixture of selected antineoplastic drugs against aquatic primary producers; Environ Sci Pollut Res (2016) 23:14780–14790.

3. A. Parrella, M. Lavorgna, E. Criscuolo, C. Russo, V. Fiumano, M. Isidori; Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans; Chemosphere 115 (2014) 59–66.

4. C. Moermond B. Venhuis M. vanElk A. Oostlander P. vanVlaardingen M. Marinković J. Vandijk; Cytostatics in Dutch surface water Use, presence and risks to the aquatic environment, RIVM Letter report 2018-0067.

5. PubChem 2022-01-22, https://pubchem.ncbi.nlm.nih.gov/compound/36462

6. T. Kosjek, N. Negreira, E. Heath, M. López de Alda and D. Barceló; Biodegradability of the anticancer drug etoposide and identification of the transformation products; Environ Sci Pollut Res (2016) 23:14706–14717.

7. R. Kovács, K. Bakos, B. Urbányi, J. Kóvesi, G. Gazsi, A. Csepeli, A. János Appl, D. Bencsik, Z. Csenki, A. Horváth; Acute and sub-chronic toxicity of four cytostatic drugs in zebrafish; Environ Sci Pollut Res (2016) 23:14718–14729