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Gemzar®

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Lilly

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Cytostatikum

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ATC-kod: L01BC05
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Miljöpåverkan (Läs mer om miljöpåverkan)

Gemcitabin

Miljörisk: Användning av gemcitabin har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Gemcitabin är potentiellt persistent.
Bioackumulering: Gemcitabin har låg potential att bioackumuleras.


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Detaljerad miljöinformation


Environmental Risk Classification


Predicted Environmental Concentration (PEC)

PEC (µg/L) = (A x 1000000000 x (100 – R)) ÷ (365 x P x V x D x 100)

= 0,0000015 x A x (100 – 0)

= 0,0000015 x 37,6057 x 100

= 0,006 µg/L

Where:

A = 37,6057 kg (total amount sold in Sweden in 2015 as gemcitabine, data from IMS Health). This number is not adjusted for metabolism.


API form

Sales in 2014 kg

gemcitabine hydrochloride

42,8151

gemcitabine

37,6057*

*calculated by multiplying the kg of gemcitabine hydrochloride sold by the molecular weight ratio of gemcitabine free base:gemcitabine hydrochloride salt (263.2:299.66)

.

R = Assumed 0% removal rate in a sewage treatment plant

P = 9000000 population of Sweden

V = 200 L of wastewater per capita per day (ECHA, 2016)

D = 10, dilution of wastewater by surface water flow (ECHA, 2016)


Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Algae (Pseudokirchneriella subcapitata) (FDA 4.01) (Study J00893)

EC50 14 d (average specific growth rate) = 5400 µg/L

NOEC 14 d (average specific growth rate) = 570 µg/L

Crustacean (Daphnia magna)

Acute toxicity (FDA 4.08)

EC50 48 h (immobilization) = >999000 µg/L (Study C01993)

Rainbow trout (Oncorhynchus mykiss)

Acute toxicity (FDA 4.11)

LC50 96 h (mortality) > 1043000 µg/L (Study F00993)

Fathead minnow (Pimephales promelas)

Acute toxicity (FDA 4.11)

LC50 96 h (mortality) > 1014000 µg/L (Study F01293)


Calculation of PNEC

PNEC = 5400 µg/L ÷ 1000

PNEC = 5.4 µg/L

The PNEC was calculated from the EC50 for algae because algae are the most sensitive of the species tested in short-term studies. An assessment factor of 1000 was used because this is a short-term study.


Environmental risk classification (PEC/PNEC Ratio)

PEC/PNEC = 0,006 ÷ 5,4 = 0,0011

The PEC/PNEC ratio of less than 0,1 justifies the phrase “Use of gemcitabine has been considered to result in insignificant environmental risk.”


Degradation


Biotic Degradation

Inherent degradability:

In a biodegradation study, radiolabeled gemcitabine was incubated with activated sludge inoculum for 28 days. Over the course of the study, approximately 25% of the compound was converted to an inactive uridine metabolite and 70% remained as gemcitabine. There was no significant adsorption of gemcitabine or the metabolite to the sludge (FDA 3.11). (Study N00394).


Abiotic Degradation

Hydrolysis:

Less than 10% disappearance of gemcitabine was observed when incubated in the dark in water buffered at pH 5, 7 or 9 for 5 days at 50°C (FDA 3.09). (Study N00194).

Photolysis

At pH 5, 7, and 9, gemcitabine has no significant ultraviolet absorption above 290 nm and, therefore, is not expected to undergo substantial direct photolysis in aqueous solutions (FDA 3.05). (Study N00594).


Justification of the degradation phrase:

While gemcitabine did show some degradation in an inherent biodegradation test, it did not meet the criteria for inherent biodegradability (70% degradation). Additionally, there are no other data to support the degradation of gemcitabine in the environment. Therefore, gemcitabine is classified as potentially persistent.

Bioaccumulation

Partitioning coefficient:

Log Dow = 0,053 at pH 5

Log Dow = 0,053 at pH 7

Log Dow = 0,052 at pH 9

(FDA 3.02) (Study N00494)


Justification of chosen bioaccumulation phrase:

Because the log Dow at pH 7 is less than 4, gemcitabine has a low potential for bioaccumulation.


Excretion (metabolism)

Gemcitabine is extensively metabolized to a uracil metabolite such that the excreted residue is comprised mainly of the uracil metabolite while gemcitabine was less than 10% of the excreted dose. The uracil metabolite does not have pharmacological activity.

(Gemcitabine Package Insert; http://pi.lilly.com/us/gemzar.pdf).


PBT/vPvB ASSESSMENT

Because it does not have a high potential to bioaccumulate, gemcitabine does not fulfill the criteria for PBT and, therefore, is not regarded as a PBT/vPvB substance.


References

ECHA, European Chemicals Agency. 2016 Guidance on information requirements and chemical safety assessment. Chapter R.16: Environmental Exposure Estimation. Version 3.0 https://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

Gemcitabine Package Insert. 2017.  http://pi.lilly.com/us/gemzar.pdfGemzar®. Safety Data Sheet. Issue date: 11-21-2014. http://ehs.lilly.com/msds/Gemzar.pdf

Study C01993. 1994. The 48-hour acute toxicity of gemcitabine (LY188011) to Daphnia magna in a static test system. FDA Technical Assistance Handbook 4.08. Eli Lilly and Company.

Study F00993. The acute toxicity of gemcitabine (LY188011) to rainbow trout (Oncorhynchus mykiss) in a static test system. FDA Technical Assistance Handbook 4.11. Eli Lilly and Company.

Study F01293. 1994. The acute toxicity of gemcitabine (LY188011) to fathead minnows (Pimephales promelas) in a static test system. FDA Technical Assistance Handbook 4.11. Eli Lilly and Company.

Study J00893. 1994. The 14-day acute toxicity of gemcitabine hydrochloride (LY188011 HCl) to the freshwater green alga (Selenastrum capricornutum) in a static test system. FDA Technical Assistance Handbook 4.01. Eli Lilly and Company.

Study N00194. 1994. Hydrolysis of gemcitabine HCl (LY188011 HCl) as a function of pH. FDA Technical Assistance Handbook 3.09. Eli Lilly and Company.

Study N00394. 1994. A study to determine the aerobic biodegradation of 14C-gemcitabine HCl (LY188011 HCl) in water using a 14CO2 evolution test method. FDA Technical Assistance Handbook 3.11 Eli Lilly and Company.

Study N00494. 1994. A study to determine the octanol/water partition coefficient of gemcitabine HCl (LY188011 HCl) at pH 5, 7, and 9. FDA Technical Assistance Handbook 3.02. Eli Lilly and Company.

Study N00594. 1994. The ultraviolet-visible absorption spectra of gemcitabine HCl (LY188011 HCl) in water at pH 5, 7, and 9. FDA Technical Assistance Handbook 3.05. Eli Lilly and Company.

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