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 = 0,0028 μg/L

Where:

A = 20,51 kg (total sold amount API in Sweden year 2020, 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. I)

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies (Ref. II)

Algae (Desmodesmus subspicatus)

Growth inhibition test (guideline European standard EN ISO 8692:1989 (ISO, 1989b)

LOEC 72 h = 10 mg/L

EC₅₀ 72 h (growth rate) = 45 mg/L

Crustacean, Giant water flea (Daphnia magna, invertebrate, acute test)

Acute immobilization test (European Standard EN ISO 6341:1996 (ISO, 1989a)

LOEC 48 h = 50 mg/L

EC₅₀ 48 h (Immobility) = 110 mg/L

Bacteria (Pseudomonas putida):

Growth inhibition test (guideline International Standardization Organization Standard EN ISO 10712:1995 and the Czech Standard (CSN, 1995)

LOEC 16 h = 50 mg/L

EC₅₀ 16 h (growth rate) = 100 mg/L

Based on the most sensitive acute species; Algae (Desmodesmus subspicatus) 72 h LOEC of 10 mg/L (equivalent to 10000 µg/L) and an assessment factor of 1000 in accordance with ECHA guidance (Ref. I)

PNEC = 10 000 µg/L /1000 = 10 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0,0028 / 10 = 2,8X10^-4, PEC/PNEC ≤ 0,1 which justifies the phrase ‘Use of gemcitabine has been considered to result in insignificant environmental risk.’

Biotic degradation

Degradation: (Ref. VI)

Study type	Result	Remark
FDA 3.11	Not ready	70% of parent remained after 28 d
301 D	Not ready	42% after 28 d
302B	Not inherent	45% after 4 d, 50% at test end (28 d)
DT50 biodegradation 5	0.0049 d	5 times a 2 d cyclic act. sludge incubation
Hydrolysis DT50	0.28 d	dark; 22°C. pH not reported

Since gemcitabine fails to meet the above criteria, and there are no simulation studies or analytical monitoring data to support elimination within the ECHA persistence half-lives, the phrase ,The gemcitabine is potentially persistent, was chosen.

Bioaccumulation

BCF = 3 (Ref. V)

LogP = 0,14 (Ref IV)

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. Martín J., Camacho-Muñoz D., Luis Santos J., Aparicio I., Alonso E. Occurrence and Ecotoxicological Risk Assessment of 14 Cytostatic Drugs in Wastewater. Water Air Soil Pollut (2014) 225:1896

3. Kummerer K, Al-Ahmad A. Biodegradability of the anti-tumour agents 5-fluorouracil, cytarabine, and gemcitabine: impact of the chemical structure and synergistic toxicity with hospital effluent. Acta Hydrochim Hydrobiol 1997;25(4):166–72.

4. https://go.drugbank.com/drugs/DB00441

5. Booker V., Halsall C., Llewellyn N., Johnson A., Williams R. Prioritising anticancer drugs for environmental monitoring and risk assessment purposes. Science of the Total Environment 473–474 (2014) 159–170