Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (µg/L)    

= (A x 1 000 000 000 x (100 – R)) ÷ (365 x P x V x D x 100)

            = (8.3566 x 1 000 000 000 x (100 – 0)) ÷ (365 x 10 000 000 x 200 x 10 x 100)

            = 0.00114 µg/L

           

Where:

A = 8.3566 kg (total amount of abemaciclib sold in Sweden 2022, data from IQVIA).  This amount is not adjusted for metabolism

R = Assumed 0% removal rate due to adsorption to sludge, volatilization, hydrolysis or biodegradation

P = 10 000 000 population of Sweden

V = 200 L of wastewater per capita per day (ECHA, 2017a)

D = 10 dilution of wastewater by surface water flow (ECHA, 2017a)

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Algae (Pseudokirchneriella subcapitata)

(OECD 201) (Study 1982.6447, 2017)

            EC₅₀ 72 hr (yield) = 19 µg/L

            NOEC 72 hr (yield) = 5.9 µg/L

Crustacean (Daphnia magna)

            Acute toxicity

            EC₅₀ 48 h (immobilization) > 43 000* µg/L

(OECD 202) (Study 1982.6453, 2016)

            Chronic toxicity

            NOEC 21 days (most sensitive endpoints: reproduction, length) = 20 µg/L

(OECD 211) (Study 1982.6455, 2016)

Fish (Pimephales promelas)

            Acute toxicity

            LC₅₀ 96 h (mortality) = 6 200 µg/L

(OECD 203) (Study 1982.6454, 2016)

            Chronic toxicity

NOEC 4 d embryos + 28 d post-hatch (most sensitive endpoints: length, wet and dry weight) = 75 µg/L

(OECD 210) (Study 1982.6451, 2016)

*highest concentration tested

Calculation of PNEC

PNEC = 0.59 µg/L

PNEC (µg/L) = lowest NOEC ÷ 10. NOEC of 5.9 µg/L is the lowest of three chronic toxicity values in aquatic species. 10 is the assessment factor used because long-term results were available from three trophic levels: fish, daphnids and algae.

Environmental Risk Classification (PEC/PNEC Ratio)

PEC/PNEC = 0.00114 µg/L ÷ 0.59 µg/L = 0.00194

The PEC/PNEC ratio of less than 0.1 justifies the phrase “Use of abemaciclib has been considered to result in insignificant environmental risk.”

Degradation

Biotic Degradation

Inherent degradability: 

¹⁴C-abemaciclib was aerobically incubated with activated sewage sludge for 28 days at 22°C, using two conditions: (1) fed with synthetic sewage to maintain dissolved organic carbon levels and (2) not fed (OECD 302A, OECD 314B). The disappearance half-life (DT50) of abemaciclib was estimated to be 85.6 for the 'fed' condition and 107 days for 'not fed'. After 28 days, multiple transformation products (all more polar than abemaciclib) were observed totaling 32% (fed) and 21% (not fed) of the applied radioactivity. Less than 1% of applied radioactivity evolved as ¹⁴CO2. (Study 1982.6449, 2017)

Simulation studies:

Transformation of ¹⁴C-abemaciclib was evaluated over 100 days in two static, aerobic water-sediment systems at 20°C (OECD 308). After 100 days, almost all radioactivity had partitioned to sediment and less than 1% had evolved as ¹⁴CO2. After 100 days, approximately 67% of the applied radioactivity could be extracted from the sediment of both systems with three to four sequential extractions using 80:20 acetonitrile:0.1M ammonium carbonate. Pre-study validation analyses demonstrated an extraction efficiency of approximately 95%. Most of the radioactivity that could be extracted from the total system at Day 100 was identified as abemaciclib (57 and 42%, in sediments 1 and 2) and transformation products more polar than abemaciclib (10% and 30%, in sediments 1 and 2). No single transformation product was 10% or more of applied radioactivity in sediment 1. In sediment 2, two transformation products were more than 10% at Day 58, but these declined to <10% by Day 100. These two transformation products were formed by loss of the ethyl-piperazine ring followed by oxidation. The remainder of the applied radioactivity (approximately 25 and 20%) was unextractable despite supplemental extractions with solvents of varying polarity (0.1M borate in acetonitrile at pH 9, 0.01M sodium hydroxide, and hexane). Therefore, these unextractable residues are considered to be not bioavailable. For the two water-sediment systems, the disappearance half-life values (DT50) of abemaciclib from the total system were 193 and 60 days. (Study 1982.6446, 2017)

Abiotic Degradation

Hydrolysis:

Abemaciclib is hydrolytically stable.  Less than 10% of abemaciclib was degraded when incubated at 50°C in sterile, anoxic aqueous buffers at pH 4, 7 and 9 in the dark (OECD 111). (Study 1982.6448, 2016) 

Justification of the degradation phrase:

There was evidence of biotransformation of abemaciclib in biotic degradation studies. Abemaciclib does not meet the criteria for inherent biodegradability. In the OECD 308 study, the DT50 for one water sediment system (60 d) was slowly degraded while the DT50 for the other water sediment (193 d) was potentially persistent. Therefore, abemaciclib is slowly degraded in the environment.

Bioaccumulation

Bioconcentration factor (BCF):

The bioaccumulation potential of abemaciclib in fish was experimentally determined using two concentrations of abemaciclib (separated by a factor of 10) (OECD 305). The growth-corrected, lipid-normalized kinetic BCF values are 383 and 289 L/kg (low and high concentration, respectively). (Study 151A-149, 2018)

Justification of the bioaccumulation phrase:

Because the BCF is less than 500 L/kg, abemaciclib has low potential for bioaccumulation.

Excretion (metabolism)

Abemaciclib is extensively metabolized in humans following oral administration.  No removal by human metabolism was used to calculate the PEC.

PBT/vPvB Assessment

Abemaciclib is slowly degraded in the environment. Abemaciclib meets CLP Hazard Statement Code H360 (toxic to reproduction in mammals) (ECHA, 2017b) and has an aquatic NOEC < 10 µg/L. According to established EU criteria, abemaciclib does not meet the criteria for bioaccumulative (ECHA 2017a). Therefore, abemaciclib is not a PBT or vPvB substance.

References

ECHA, European Chemicals Agency.  2017a. Guidance on information requirements and chemical safety assessment.  Chapter R.11: PBT/vPvB Assessment and Chapter R.16: Environmental Exposure Estimation. 

ECHA, European Chemicals Agency. 2017b. Guidance on the Application of the CLP Criteria. Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures. Draft Version 5.0.

Study 1982.6447, 2017. LY2835219 – 72-Hour Toxicity Test with the Freshwater Green Alga, Pseudokirchneriella subcapitata, Following OECD Guideline 201 - Amended.

Study 1982.6453, 2017. LY2835219 - Acute Toxicity to Water Fleas (Daphnia magna) Under Static Conditions, Following OECD Guideline #202 - Amended.

Study 1982.6455, 2016. LY2835219 - Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static Renewal Conditions Following OECD Guideline #211 - Amended.

Study 1982.6454, 2016. LY2835219 - Acute Toxicity to Fathead Minnow (Pimephales promelas), Under Static-Renewal Conditions, Following OECD Guideline #203.

Study 1982.6451, 2017. LY2835219 – Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas), Following OECD Guideline #210 - Amended.

Study 1982.6449, 2017. [¹⁴C]LY2835219 – Determination of the Inherent Biodegradability in Activated Sludge under Aerobic Conditions.

Study 1982.6446, 2017. [¹⁴C]LY2835219 – Aerobic Transformation in Aquatic Sediments Following OECD Guideline 308.

Study 1982.6448, 2016. Determination of the Abiotic Degradation of [¹⁴C]LY2835219 by Hydrolysis at Three Different pH Values Following OECD Guideline 111.

Study 151A-149, 2018. LY2835219 – An Aqueous Exposure Bioaccumulation Test with the Bluegill (Lepomis macrochirus) - OECD Guideline 305 - Amended.