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) = 1.37*10^-6 * 184.95 * 100 = 0.25 μg/L

Where:

A = 184.95 kg imatinib (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) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008).

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Selenastrum capricornutum) (OECD201) (NOTOX Project 270225):

EC50 72 h (growth rate) = 6.8 mg/L

NOEC 72 h = 0.96 mg/L

Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) = 80.0 mg/L (ISO 6341) (NOTOX Project 270236)

Chronic toxicity

NOEC 21 days (reproduction) = 5.6 mg/L (OECD 211) (NOTOX Project 485999)

Fish:

Acute toxicity (Cyprinus carpio, carp)

LC₅₀ 96 hours = 82 mg/L (OECD 203) (NOTOX Project 306214)

Chronic toxicity (Pimephales promelas, fathead minnow)

NOEC 30 days (time of hatching, hatching success, survival, growth, development of larvae) = 10.0 mg/L; no effect up to the highest concentration tested (OECD 210) (NOTOX Project 486000)

Other ecotoxicity data:

Bacterial respiration inhibition

EC₅₀ 3 h = 232 mg/L (activated sludge respiration inhibition) (OECD209) (NOTOX Project 270247)

Sediment-dwelling organisms (Chironomus riparius, non-biting midge)

NOEC 28 days (emergence rate) = 1.8 mg/L (OECD 219) (NOTOX Project 488608)

PNEC derivation:

PNEC = 96 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used if three chronic toxicity studies from three trophic levels are available. The NOEC for the green algae Selenastrum capricornutum has been used for this calculation.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.25 μg/L / 96.0 μg/L = 0.00264, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of imatinib has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

9 - 12 % degradation in 28 days, not readily biodegradable (OECD 301B). (NOTOX Project 270258)

Simulation studies:

DT₅₀ (total system) = 82.0 – 111.0 days (OECD 308) (NOTOX Project 486002)

Sediments were extracted with 80/20 (v/v) methanol/buffer pH11.

Upon addition of imatinib mesylate to the water layer, imatinib partitioned between the water and sediment layer. Radioactivity in the water layer decreased to < 5% of applied after 29 days of incubation. Mineralisation did not occur. Bound residues accounted for maximum 30 % and 40 % of applied. No relevant metabolites were detected.

Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, imatinib can be classified as ‘Imatinib is slowly degraded in the environment' (DT₅₀ for total system ≤ 120 days).

Bioaccumulation

Partitioning coefficient:

logD at pH 7.4 = 2.34 (Kil et al. 2007)

[N-11C-methyl]imatinib hydrochloride solution (50 Al) was added to a test tube containing 2.5 ml of octanol and 2.5 ml of phosphate buffered solution (pH 7.4). The solution was vortexed for 2 min and centrifuged for 2 min at maximum speed. An aliquot (0.1 Al) was taken from an organic layer, and another aliquot (1.0 Al) was taken from an aqueous layer. Then 2.0 ml of sample from the organic layer was added to a second test tube containing 0.5 ml of octanol and 2.5 ml of phosphate-buffered solution (pH 7.4). The same treatment is applied to the second test tube. These repeated procedures were applied to six test tubes so that 12 samples (six from the aqueous layer and six from the organic layer) were obtained. Each sample was counted by a well counter (Picker, Cleveland, OH) to yield the ratio of decay-corrected counts in octanol to decay-corrected counts in buffer.

Justification of chosen bioaccumulation phrase:

Since log P < 4, imatinib has low potential for bioaccumulation.

Excretion (metabolism)

Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was eliminated within 7 days in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20 % feces), the remainder being metabolites (GLIVEC^® (imatinib mesylate) Core Data Sheet).

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• NOTOX Project 270225. Fresh water algal growth inhibition test with STI571/DS. Final report: 17 December 1999.                         

• NOTOX Project 270236. Acute toxicity study in Daphnia magna with STI571/DS (static). Final report: 09 December 1999.                                          

• NOTOX Project 485999. Daphnia magna, reproduction test with imatinib mesylate (semi-static). Final report: 17 March 2008.               

• NOTOX Project 306214. 96-hour acute toxicity study in carp with STI571/DS (static). Final report: 12 December 2000.    

• NOTOX Project 486000. Fish early-life stage toxicity test with imatinib mesylate (semi-static). Final report: 20 March 2008.                                     

• NOTOX Project 332911. Activated sludge respiration inhibition test with STI571/DS (contact time: 3 hours). Final report: 15 October 1999.

• NOTOX Project 488608. Sediment-water Chironomid toxicity test using water spiked with imatinib mesylate. Final report: 15 December 2008.

• NOTOX Project 270258. Determination of ‘ready’ biodegradability: carbon dioxide (CO₂) evolution test (modified Sturm test) with STI571/DS. Final report: 09 November 1999.

• NOTOX Project 486002. Aerobic degradation of imatinib mesylate in two water/sediment systems. Final report: 15 April 2008.

• Kil KE, Ding YS, Lin KS, et al. (2007). Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec). Nuclear Medicine and Biology; 34:153–163.

• GLIVEC^® (imatinib mesilate) Core Data Sheet Version 2.3. 24 August 2017.