Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

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 = 5.5012 *10^-3  μg/L

Where:

A = 40.1548 kg (total sold amount API in Sweden year 2021, data from IQVIA).

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. I)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus) (EN ISO8692:1989, DIN 1993) (Reference II):

EC₅₀ 72 h (growth rate) = 45 000 μg/L

LOEC 72 h (growth rate) = 10 000 μg/L

Crustacean (Daphnia magna) (Reference II):

Acute toxicity

EC₅₀ 48 h (immobilization) = 110 000 μg/L (EN ISO 6341:1996)

EC₅₀ 21 d (reproduction) = > 1 000 μg/L (OECD1998)

Chronic toxicity

LOEC 48 h (immobilization) = 50 000 μg/L (EN ISO 6341:1996)

LOEC 21 days (reproduction) = >1 000 μg/L (OECD1998)

Other ecotoxicity data: PNEC = 20 μg/L

PNEC (μg/L) = lowest LOEC/50, where 50 is the assessment factor used for two long-term ecotoxicity data endpoints representing two trophic levels. LOEC for Daphnia magna has been used for this calculation since it is the most sensitive of the two tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0055/20 =0.0003, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ‘Use of gemcitabine has been considered to result in insignificant environmental risk.’

Also, according to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of gemcitabine is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 µg/L.

Degradation

Biotic degradation

Ready degradability:

Test results in 45 % degradation in 40 days (OECD 301D). (Reference III)

Inherent degradability:

Test results in 50 % degradation in 40 days (OECD 302B). (Reference III)

Justification of chosen degradation phrase:

Gemcitabine does not pass the ready degradation test and is not inherently degradable. The phrase “Gemcitabine is potentially persistent.” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log P_ow = -1,5 at pH 7 (predicted value by ChemAxon). (Reference IV)

Justification of chosen bioaccumulation phrase: 

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

Excretion (metabolism)

Gemcitabine is excreted to less than 10 % as parent compound in the urine. During the week following administration, 92 to 98% of the dose of gemcitabine administered is recovered, 99% in the urine, mainly in the form of 2’-deoxy-2’, 2’-difluorouridine (dFdU) and 1% is excreted in faeces.

Gemcitabine is rapidly metabolised by cytidine deaminase in the liver, kidneys, blood and other tissues. Intracellular metabolism of gemcitabine produces the gemcitabine mono, di and triphosphates (dFdCMP, dFdCDP and dFdCTP) of which dFdCDP and dFdCTP are considered active. These intracellular metabolites have not been detected in plasma or urine. The primary metabolite, dFdU, is not active and is found in plasma and urine (Reference V)

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. Zounkova R et al. Ecotoxicity and genotoxicity assessment of cytotoxic antineoplastic drugsand their metabolites. Chemosphere 2014;81:253-260. doi: 10.1016/j.chemosphere.2010.06.029.

3. Booker V et al. Prioritising anticancer drugs for environmental monitoring and risk assessment purposes. Sci Total Environ. 2014;473-474:159-170. doi: 10.1016/j.scitotenv.2013.11.145.

4. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037. Available at https://go.drugbank.com/drugs/DB00441[2023-05-11]

5. SmPC Gemcitabine Accord (2022-10-24) Available at https://www.fass.se/LIF/product?userType=0&nplId=20101209000151&docType=6&scrollPosition=613.2000732421875  [2023-05-11]