Detaljerad miljöinformation

Upon release of effluents from the water treatment plant, based on an aqueous dissipation DT₅₀ of 0.5‑1.7 days, palbociclib is expected to rapidly dissipate from the water to the sediment, with approximately 23.6 and 54.8% becoming irreversibly bound. Based on sediment DT₅₀ values of 62.1 and >100 days, palbociclib has the potential to persist in certain sediment compartments, particularly those consisting of fine textured solids with higher organic carbon content. Total water-sediment system DT₅₀ values ranged from 0.6 to 1.5 days.

Physical properties

Molecular formula: C₂₄H₂₉N₇O₂

Molecular weight: 447.54 Daltons

Solubility in unbuffered water⁴: 1400 µg/L

pKa for the functional group pyridine nitrogen: 3.9

pKa for the functional group secondary piperazine nitrogen: 7.4

Vapor pressure: <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 = 2.14×10^-3 μg/L

Where:

A =	15.636075 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) = 1400 000 μg/L

EC₅₀ (respiration inhibition) = >1400 000 μg/L

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

LOEC 96 h (growth rate, chronic toxicity) = 2900 μg/L

NOEC 96 h (growth rate, chronic toxicity) = 900 μg/L

Daphnids (Daphnia magna) (guideline OECD 211)⁷

LOEC 21 days (reproduction, chronic toxicity) = 490 μg/L

NOEC 21 days (reproduction, chronic toxicity) = 270 μg/L

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

LOEC 32 days (growth, chronic toxicity) = 250 μg/L

NOEC 32 days (growth, chronic toxicity) = 130 μg/L

Midge (Chironomus riparius) (guideline OECD 218)⁹

LOEC 28 days (emergence, chronic toxicity) = 946 000 μg/kg

NOEC 28 days (emergence, chronic toxicity) = 513 000 μg/kg

Based on the lowest NOEC for the species Pimephales promelas and using the assessment factor² of 10, the PNEC is calculated to 130 / 10 = 13 µg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 2.14×10^-3 / 13 = 1.65×10^-4, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ”Use of palbociclib has been considered to result in insignificant environmental risk”.

Adsorption (guideline OECD 106)¹¹

Solid	Kd (L/Kg)	Koc (L/Kg)
Activated sludge (Denton)	2506	7586
Activated sludge (Cambridge)	1789	6026
High-organic matter soil (TB-PF)	24 226	575 440
Sandy soil (Speyer 2.1)	1036	134 896
High-organic matter sediment (Brandywine creek)	3548	85 114
Low-organic matter sediment (Choptank River)	6535	1 096 478

Degradation

Biotic degradation

Simulation studies (guideline OECD 308)¹⁰

Length of study: 100 days

High organic sediment system: Brandywine creek

Low organic sediment system: Choptank river

Sediment extraction solvent: THF+0.5% NH₄OH

Supplemental extraction solvents: Water, methanol or hexane

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

Data on day 100	Brandywine creek		Choptank river
Total system
Half-life (days)	1.5		0.6
Parent (% of radioactivity)	4.1		4.3
Total 14CO2 (% of radioactivity)	0.5		1.0
Aerobic Water Layer
Half-life (days)	1.7		0.5
Parent (% of radioactivity)	ND		ND
Sediment Layer
Half-life (days)	>100		62.1
Bound (% of radioactivity)	54.8		23.6
Extractables (% of radioactivity)	41.2		52.7
Parent (% of radioactivity)	4.1		4.3

ND = not detected

^# Bound residue (NER) was determined using challenging extraction conditions in accordance with OECD 308, Annex 2. Therefore, the reported % bound in this regulatory accepted GLP study may be considered not bioavailable.

As no clear pattern of decline of parent substance was observed in the Brandywine Creek sediment extracts, the sediment layer DT₅₀ is reported as >100 days, however the amount of parent was <5% of the applied radioactivity at all timepoints tested.

Justification of chosen degradation phrase

The simulation study (OECD 308) shows that the total system DT₅₀ is in between 0.6 and 1.5 days. This is well below the DT₅₀ ≤32 days criterium for making the assessment that ”palbociclib is degraded in the environment”.

Bioaccumulation

Partitioning coefficient (guideline OECD 107)¹²

Log D_ow = 0.228 at pH 5

Log D_ow = 1.11 at pH 7

Log D_ow = 2.26 at pH 9

Justification of chosen bioaccumulation phrase

Since log D_ow < 4 at pH 7, palbociclib 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. Palbociclib Environmental risk assessment. May 2015.

5. Study report BR0847/B: PD-332,991: Activated sludge respiration inhibition test. October 2013.

6. Study report BR0864B: PD-332,991: Determination of toxicity to the green alga Pseudokirchneriella subcapitata. January 2014.

7. Study report BR0865B: PD-332,991: Determination of effects on reproduction to Daphnia magna. January 2014.

8. Study report BR0837/B: PD-332,991: Determination of effects on the Early Life-Stage of the fathead minnow (Pimephales promelas). February 2014.

9. Study report BR0886/B: PD-332,991: Determination of effects in sediment on emergence of the midge, Chironomus riparius. April 2014.

10. Study report 260E-290: Palbociclib: Aerobic transformation in aquatic sediment systems. January 2017.

11. Study report 260E-277: Palbociclib: Adsorption/desorption charachteristics in representative soils, sediments, and activated sludge solids. June 2014.

12. Study report 260C-170: Determination of the n-octanol/water partition coefficient of palbociclib by the shake flask method. June 2014.