Detaljerad miljöinformation

Biodegradation studies conducted in sludge indicate bosutinib will undergo minimal degradation during the wastewater treatment process. Based on a sludge sorption coefficient (Kd) of 3791, 38.5% removal through sorption to sludge during the wastewater treatment process may be expected. Upon release of wastewater effluents into the aquatic environment, bosutinib residues will reside in the water and sediment compartments. Based on aqueous dissipation half-lives of 1.1 and 5.9 days, bosutinib is expected to rapidly dissipate from the water to the sediment with approximately 30% to 41% becoming irreversibly bound. Degradation products observed in all sediment extracts, ranging from <10% to 21.7% of the dose, indicate that bosutinib is expected to undergo primary degradation in the sediment, however, the overall total system DT₅₀ values were >100 days for the two water-sediment systems study, indicating that bosutinib may be persistent in the sediment compartment.

Physical properties⁵

Solubility at pH 6.8: 20 mg/L

pKa for functional group 4-piperazine-methyl nitrogen: 7.9

pKa for functional group quinoline: 4.8

pKa for functional group 1-piperazine nitrogen: 3.8

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 = 6.10×10^-4 μg/L

Where:

A =	7.24263288 kg (total sold amount API in Sweden year 2021)3
R =	38.48% removal rate (due to loss by adsorption to sludge particles, see section ”Degradation” where the lowest removal rate has been chosen for a conservative estimation)
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 microorganisms (guideline OECD 209)⁶

EC₁₅ (respiration inhibition) = 1000 000 µg/L

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

Green alga (Raphidocelis subcapitata) (guideline OECD 201)⁷

EC₅₀ 72 h (biomass, chronic toxicity) = 93 µg/L

NOEC 72 h (biomass, chronic toxicity) = 30 μg/L

EC₅₀ 72 h (growth rate, chronic toxicity) = 203 µg/L

NOEC 72 h (growth rate, chronic toxicity) = 30 μg/L

Daphnids (Daphnia magna) (guideline OECD 211)⁸

LOEC 21 days (reproduction, chronic toxicity) = 273 μg/L

NOEC 21 days (reproduction, chronic toxicity) = 145 μg/L

Fathead minnow (Pimphales promelas) (guideline OECD 210)⁹

LOEC 32 days (reproduction, chronic toxicity) = 139 μg/L

NOEC 32 days (reproduction, chronic toxicity) = 66 μg/L

Midge (Chironomus riparius) (guideline OECD 218 using sediment with 2.5% organic carbon)¹⁰

LOEC 28 days (emergence, chronic toxicity) = >10 000 μg/kg

NOEC 28 days (emergence, chronic toxicity) = 10 000 μg/kg

Earthworm (Eisenia fetida) (guideline OECD 207)¹²

EC₅₀ 14 days (survival, acute toxicity) = >10 000 µg/kg

Plant toxicity (guideline OECD 208)¹³

Onion (Allium cepa) EC₅₀ 21 days (emergence, chronic toxicity) = >10 000 µg/kg

Ryegrass (Lolium perenne) EC₅₀ 21 days (emergence, chronic toxicity) = >10 000 µg/kg

Turnip (Brassica rapa) EC₅₀ 21 days (emergence, chronic toxicity) = >10 000 µg/kg

Cucumber (Cucumis sativa) EC₅₀ 21 days (emergence, chronic toxicity) = >10 000 µg/kg

Lettuce (Lactuca sativa) EC₅₀ 21 days (emergence, chronic toxicity) = >10 000 µg/kg

Tomato (Lycopersicon esculentum) EC₅₀ 28 days (emergence, chronic toxicity) = >10 000 µg/kg

Collembola (Folsomia candida) (guideline OECD 232)¹⁴

LOEC 28 days (survival, chronic toxicity) = 500 μg/kg

NOEC 28 days (survival, chronic toxicity) = 250 μg/kg

LOEC 28 days (reproduction, chronic toxicity) = 500 μg/kg

NOEC 28 days (reproduction, chronic toxicity) = 250 μg/kg

Based on the lowest NOEC for the species Green alga (Raphidocelis subcapitata) and using the assessment factor² of 10, the PNEC is calculated to 30/10 = 3 µg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 6.10×10^-4 / 3 = 2.03×10^-4, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ”Use of bosutinib has been considered to result in insignificant environmental risk”.

Degradation

Biotic degradation

Simulation studies (guideline OECD 308)¹⁷

Two sediments and their associated waters were utilized in a freshwater-sediment total system degradation study: Brandywine Creek (high organic content, 4.43%) and Choptank River (low organic content, 0.98%). Test systems were dosed with ¹⁴C-labeled bosutinib at a nominal concentration of 0.46 mg/L in the water layer. Test systems were incubated at approximately 20 ºC for up to 100 days, and maintained under aerobic conditions by gently bubbling air into the water layers.

Bosutinib disappeared rapidly from the water layers in both Brandywine Creek and Choptank River test systems. The disappearance times of 50% of parent (DT₅₀) from the water layers were 1.1 and 5.9 days, respectively. Most of the bosutinib migrated to the sediment layers.

The fractions of radiolabeled residues that could not be extracted from the sediment layers at the end of the study were 40.6% and 30.1%, respectively. Sediments were extracted four times with THF+ 1% NH₄OH. Supplemental extractions were performed using water, methanol or hexane, however the mean amount of ¹⁴C extracted from the solids was <10% for each solvent.

The maximum amount of mineralisation or ultimate biodegradation observed was 0.0% and 0.2% for Choptank River and Brandywine Creek, respectively. At the end of the 100 day study, 0.0% and 0.2% of the parent compound applied radioactivity remained in the Brandywine Creek and Choptank River system, respectively.

The mean amounts of the parent compound in the total test systems (water layers plus sediment extracts) at the end of the 100 day study were 50% and 48%, respectively. The overall DT₅₀ and DT₉₀ values for the total test systems is estimated to >180 days.

WWTP degradation (guideline OECD 314B)¹⁸

An activated sludge biodegradation study was conducted to evaluate evaluate the rate and extent of primary biodegradation and mineralization of bosutinib in activated sludge, i.e. an estimation on the removal of bosutinib from wastewater. Samples were removed from the test vessels over a 28 day period. The conversion of radiolabeled test substance to ¹⁴CO₂ was measured by trapping ¹⁴CO₂ in base traps and quantifying dissolved ¹⁴CO₂. Disappearance of parent test substance and the formation of metabolites were determined by radiochromatography. In addition, the sludge solids were combusted to determine the amount of radioactivity remaining with the solids. At the end of the study, 0.24% was mineralised into ¹⁴CO₂ and 44.92% remained as non‑extractable residues in the solid phase. Parent compound remaining the end of the study was 38.10%.

The solvent used to extract the mixed liquor samples was selected based on an extraction efficiency evaluation conducted prior to the start of the study. Four different solvents were evaluated (MeOH, ACN, EtOAc and H₂O). MeOH in combination with H₂O (water was included as an extraction solvent to recover very polar metabolites) provided the highest extraction efficiency and thus used in the study.

Abiotic degradation

Adsorption (guideline OECD 106)⁴

Test results from an adsorption-desorption study, show that bosutinib tends to adsorp to organic content, allowing for a greater amount of the parent compound to be handled in the WWTP and thus prevent release into the environment.

Solid	Kd (L/Kg)		Koc (L/Kg)
Activated sludge		3791		10 233
HOM sediment (BC)		5330		97 724
LOM sediment (CR)		2262		275 423

Using the formula (0.165×Kd) / (0.165×Kd + 1000) where 0.165 represents the grams of sludge wasted per 1000 grams of wastewater treatment plants' aqueous effluent, we can calculate the ratio removed by the WWTP. The Kd value for the activated sludge has been chosen as it most appropriately represents the conditions in a WWTP.

Using the calculation (0.165×3791) / (0.165×3791 + 1000) = 0.3848 indicates that 38.48% of the active substance bosutinib is removed by the WWTP according to this study.

Justification of chosen degradation phrase

The simulation study shows that the substance is potentially persistent, seeing that a total system DT₅₀ was estimated to >180 days. Therefore, the phrase “bosutinib is potentially persistent” is chosen.

Bioaccumulation

Bioconcentration factor (BCF) in Bluegill (Lepomis macrochirus)¹¹

Test results (guideline OECD 305) after 31 days of exposure to bosutinib, show a whole fish kinetic bioconcentration factor of 49 and 54 after a low-level (5.4 µg/L) and high-level (60 µg/L) exposure respectively.

Following a depuration period of 60 days, the t_1/2 was calculated to 23.3 and 24.2 days after a high-level and low-level exposure, respectively. 

Partitioning coefficient¹⁶

Log D_ow = 1.09 at pH 5 (guideline OECD 107)

Log D_ow = 3.34 at pH 8 (guideline OECD 107)

Justification of chosen bioaccumulation phrase

Since BCF <500 and log D_ow <4 at pH 7, the phrase ”bosutinib has low potential for bioaccumulation” is chosen.

PBT/vPvB assessment

Considering that log D is measured of having a maximum of 3.34 at pH 8 and that the measured BCF is <2000, and the lowest measured NOEC was 30 µg/L, bosutinib is not deemed to be a PBT or vPvB compound.

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. Study 395E-118: [¹⁴C] SKI-606: Screening of adsorption characteristcs in sediments and activated sludge solids. February 2012.

5. Bosulif Environmental risk assessment. June 2017.

6. Study report 395E-102: SKI-606: An activated sludge, respiration inhibition test. April 2011.

7. Study report 395A-102: SKI-606: A 72-hour toxicity test with the freshwater alga (Pseudokirchneriella subcapitata). December 2008.

8. Study report 395A-106: SKI-606: A flow-through life-cycle toxicity test with the cladoceran (Daphnia magna). December 2008.

9. Study report 395A-105: SKI-606: An early life-stage toxicity test with the fathead minnow (Pimephales promelas). December 2008.

10. Study report 260A-204: [¹⁴C] SKI-606: A prolonged sediment toxicity test with Chironomus riparius using spiked sediment. February 2012.

11. Study report 260A-212: Bosutinib: A bioconcentration test with the (Lepomis macrochirus). October 2012.

12. Study report 260-120: Bosutinib: An acute toxicity study with the earthworm in an artificial soil substrate. September 2011.

13. Study report 260-121: Bosutinib: A toxicity test to determine the effects on seedling emergence and growth of terrestrial plants. September 2011.

14. Study report 2438.6663: Bosutinib (SKI-606) – Chronic Toxicity to Collembola (Folsomia candida). October 2011.

15. Study report 260E-236: Bosutinib: Soil microorganisms – Nitrogen transformation test. July 2011.

16. Study report 395C-108: Determination of n-octanol/water partition coefficient of SKI-606. August 2008.

17. Study report 395E-116: SKI-606: Aerobic transformation in aquatic sediment systems. April 2017.

18. Study report 395E-120: [¹⁴C] SKI-606: Biodegradation in activated sludge. October 2009.