Detaljerad miljöinformation

Upon release of wastewater effluents into the aquatic compartment, based on an aqueous dissipation rate (DT₅₀) of 0.7 and 1.2 days, crizotinib is expected to rapidly dissipate from the water to the sediment with approximately 18.4% to 43.3% becoming irreversibly bound. Degradation products observed in all water and sediment extracts, ranging from <10% to 39.7% of the dose indicate that crizotinib is expected to undergo primary degradation in the water-sediment compartment. Total system half-life values were 4.6 and 37.1 days.

Physical properties⁴

Molecular weight: 450.3 Daltons

Solubility at pH 6.8 at 37°C: 100 000 µg/L

pKa for the functional group piperidinium cation: 9.4

pKa for the functional group pyridinium cation: 5.6

Vapor pressure at 25 °C: <1×10^-7 mmHg

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 = 0.000871 μg/L

Where:

A =	6.36 kg (total sold amount API in Sweden year 2021)3
R =	0% removal rate (worst case scenario)
P =	number of inhabitants in Sweden = 10×106
V (L/day) =	wastewater volume per capita and day = 200 (ECHA default)1
D =	factor for waste water dilution by surface water flow = 10 (ECHA default)1

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Activated sludge microorgansims (guideline OECD 209)⁵

EC₁₅ (respiration inhibition) = 834 500 μg/L

EC₅₀ (respiration inhibition) = > 1000 000 μg/L

Green alga (Pseudokirchneriella subcapitata) (guideline OECD 201)⁶

EC₅₀ 96 h (growth rate, chronic toxicity) = >47 μg/L

NOEC 96 h (growth rate, chronic toxicity) = 9.3 μg/L

Daphnids (Daphnia magna) (guideline OECD 211)⁷

LOEC 21 days (reproduction, chronic toxicity) = >130 μg/L

NOEC 21 days (reproduction, chronic toxicity) = 130 μg/L

Fathead Minnow (Pimephales promleas) (guideline OECD 210)⁸

LOEC 33 days (growth, chronic toxicity) = 120 μg/L

NOEC 33 days (growth, chronic toxicity) = 70 μg/L

Midge (Chironomus riparius) (guideline OECD 218)⁹

LOEC 28 days (emergence, chronic toxicity) = 234 000 μg/kg

NOEC 28 days (emergence, chronic toxicity) = 108 000 μg/kg

Based on the lowest NOEC for the species Pseudokirchneriella subcapitata and using the assessment factor² of 10, the PNEC is calculated to 9.3 / 10 = 0.93 µg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0. 000871 / 0.93 = 0.000937, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ”Use of crizotinib has been considered to result in insignificant environmental risk.”

Adsorption (guideline OECD 106)¹⁰

Solid	Kd (L/Kg)	Koc (L/Kg)
Activated sludge (Cambridge WWTP)	5765	14 125
HOM soil (TB-PF)	2196	50 119
LOM soil (Speyer #2.1)	383	50 119
HOM sediment (Brandywine Creek)	2580	70 795
LOM sediment (Choptank River)	277	138 038

HOM = high organic matter, LOM = low organic matter

Degradation

Biotic degradation

Water-sediment transformation simulation (guideline OECD 308)¹¹

Length of Study: 103 days

High organic sediment system: Brandywine Creek

Low organic sediment system: Choptank River

Sediment extraction solvent: THF: MeOH 1:2

Supplemental extraction solvents: Water, methanol or hexane

The results from the study are shown in the table below.

Data on day 103	Brandywine Creek	Choptank River
Total system
Half-life (days)	4.6	37.1
Total 14CO2 (% of AR)	1.6	3.6
% Parent (% of AR)	29.5	13.0
Aerobic Water Layer
Half-life (days)	0.7	1.2
Parent (% of AR)	0.2	3.7
Sediment Layer
Bound/NER (% of AR)	43.3	18.4
Parent (% of AR)	29.3	9.3

ND = not detected, NER = non-extractable residues, AR = applied radioactivity

Justification of chosen degradation phrase

The total system DT₅₀ value (water-sediment transformation simulation, OECD 308) was calculated to up to 37.1 days in the low organic content sediment. Furthermore, at the end of the study, 29.5% of the parent substance was measured in the high organic content sediment. Therefore, the phrase ”crizotinib is slowly degraded in the environment” is chosen to describe the degradation characteristics of the substance.

Bioaccumulation

Bioconcentration factor (BCF) (guideline OECD 305)¹²

Species: Bluegill (Lepomis macrochirus)

Length of uptake exposure: 25 days

Whole fish kinetic BCF: 10

Partitioning coefficient (guideline OECD 107)¹³

pH	Log Pow
4	0.169
7	1.83
9	3.88

Justification of chosen bioaccumulation phrase

Since BCF < 500 and log P is <4, ”crizotinib has low potential for bioaccumulation”.

References

1. ECHA, European Chemicals Agency. 2016 Guidance on information requirements and chemical safety assessment chapter R16.

2. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment chapter R10.

3. IQVIA KG Consumption 2021 report.

4. Xalkori Environmental risk assessment. January 2016.

5. Study report 260E-240. Crizotinib: An activated sludge, respiration inhibition test. September 2011.

6. Study report 260A-213B. Crizotinib: A 96-hour toxicity test with the freshwater alga (Pseudokirchneriella subcapitata). February 2013.

7. Study report 260A-214A. Crizotinib: A flow-through life-cycle toxicity test with the cladoceran (Daphnia magna). March 2013.

8. Study report 260A-216. Crizotinib: An early life-stage toxicity test with the fathead minnow (Pimephales promleas). March 2013.

9. Study report 260A-215. Crizotinib: A prolonged sediment toxicity test with Chironomus riparius using spiked sediment. March 2013.

10. Study report 260E-239. Crizotinib: Adsorption/desorption characteristics in representative soils, sediments, and activated sludge solids. January 2013.

11. Study report 260E-238. Crizotinib: Aerobic transformation in aquatic sediment systems. November 2016.

12. Study report 260A-219. Crizotinib: A bioconcentration test with the bluegill (Lepomis macrochirus). March 2013.

13. Study report 260C-140. Determination of the n-octanol/water partition coefficient of crizotinib (PF-2341066) by the shake flask method. February 2011.