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)

            = (1.8073 x 1 000 000 000 x (100 – 0)) ÷ (365 x 10 000 000 x 200 x 10 x 100)

            = 0.00025 µg/L

           

Where:

A = 1.8073 kg (total amount of baricitinib sold in Sweden 2022, data from IQVIA).  This amount is not adjusted for metabolism

R = Assumed 0% removal rate in a sewage treatment plant

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 151A-129, 2014)

            EC₅₀ 72 hr > 23 000* µg/L

            NOEC 72 hr = 3 100 µg/L

Crustacean (Daphnia magna)

            Acute toxicity

            EC₅₀ 48 h (immobilization) = 22 000 µg/L

(OECD 202) (Study 151A-130, 2013)

            Chronic toxicity

NOEC 21 days (most sensitive endpoints: reproduction, survival) = 2 100 µg/L

(OECD 211) (Study 151A-132, 2013)

Fish (Pimephales promelas)

            Acute toxicity

            LC₅₀ 96 h (mortality) > 18 000* µg/L

(OECD 203) (Study 151A-131, 2013)

            Chronic toxicity

NOEC 5 d embryos + 28 d post-hatch (most sensitive endpoint: wet weight) = 600 µg/L (OECD 210) (Study 151A-133, 2013)

*highest concentration tested

Calculation of PNEC

PNEC = 60 µg/L

PNEC (µg/L) = lowest NOEC ÷ 10. NOEC of 600 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 = 0.00025 µg/L ÷ 60 µg/L = 0.0000041

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

Degradation

Biotic Degradation

Inherent degradability: 

¹⁴C-Baricitinib was aerobically incubated with activated sewage sludge for 28 days at 20°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 baricitinib was estimated to be 38 to 53 days for the “fed” condition and 16 to 17 days for “not fed”. After 28 days, several transformation products (all more polar than baricitinib) were observed totaling approximately 25% (fed) and 40% (not fed) of the applied radioactivity. Two transformation products were more than 10% of applied radioactivity. Less than 2% of applied radioactivity evolved as ¹⁴CO₂. (Study 151E-131, 2013) 

Simulation studies:

Transformation of ¹⁴C-baricitinib was evaluated over 153 days in two static, aerobic water-sediment systems at 20°C (OECD 308). After 153 days, most radioactivity had partitioned to sediment and less than 1% had evolved as ¹⁴CO_2. After 153 days, approximately 52 and 48% of the applied radioactivity (sediment 1 and sediment 2, respectively) could be extracted from the sediment using two or three sequential extractions with 10% acetone in ethyl acetate, while approximately 37 and 33% was unextractable from the sediment. Most of the radioactivity in the extractable residue was identified as baricitinib. All observed transformation products in the water and sediment extracts were more polar than baricitinib, and no single transformation product exceeded 10% of applied radioactivity. Supplemental extractions using solvents of varying polarity (water, 1% formic acid in methanol, 1% ammonium hydroxide in 50:50 methanol:acetonitrile, and hexane) were not able to remove the unextractable residues. Therefore, these unextractable residues are considered to be not bioavailable. For the two water-sediment systems, the disappearance half-life values (DT50) of baricitinib from the total system were 165 and 132 days. (Study 151E-132, 2013)

Abiotic Degradation

Hydrolysis:

Baricitinib is hydrolytically stable.  Less than 10% of baricitinib was degraded when incubated at 50°C in anoxic, sterile aqueous buffers at pH 4, 7 and 9 in the dark (OECD 111). (Study 151E-128, 2012) 

Justification of the degradation phrase:

There was evidence of biotransformation of baricitinib in biotic degradation studies. In the OECD 308 study, the DT50 values for the two water sediment systems were both greater than 120 days. Therefore, baricitinib is potentially persistent in the environment.

Bioaccumulation

Partitioning coefficient:

Log Kow = 1.38, 1.42, and 1.50 at the the pH values of 4, 7, and 9, respectively

(OECD 107). (Study 151C-143, 2013)

Justification of chosen bioaccumulation phrase:

Since log Kow is less than 4, baricitinib has a low potential for bioaccumulation.

Excretion (metabolism)

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

PBT/vPvB Assessment

Baricitinib is potentially persistent in the environment. Baricitinib is not toxic to aquatic organisms because the chronic NOEC is not less than 10 µg/L and it does not meet criteria for carcinogenicity, mutagenicity, or reproductive toxicity as defined in ECHA (2017b). According to established EU criteria, baricitinib does not meet the criteria for bioaccumulative (ECHA 2017a). Therefore, baricitinib 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 151A-129, 2014. LY3009104 – A 72-Hour Toxicity Test with the Freshwater Green Alga (Pseudokirchneriella subcapitata) following OECD Guideline 201.

Study 151A-130, 2013. LY3009104 – A 48-hour static acute toxicity test with the cladoceran (Daphnia magna) following OECD guideline 202.

Study 151A-132, 2013. LY3009104 – A semi-static life-cycle toxicity test with the cladoceran (Daphnia magna) following OECD Guideline 211.

Study 151A-131, 2013. LY3009104 – A 96-hour static acute toxicity test with the fathead minnow (Pimephales promelas) following OECD Guideline 203.

Study 151A-133, 2013. LY3009104 – Early life-stage toxicity test with the fathead minnow (Pimephales promelas), following OECD Guideline #210.

Study 151E-131, 2013. Biodegradation of ¹⁴C LY3009104 in activated sludge following OECD Guidelines 302A and 314B.

Study 151E-132, 2013. [14C]LY2835219 – Aerobic Transformation of ¹⁴C LY3009104 in Aquatic Sediments Following OECD Guideline 308.

Study 151E-128, 2012. ¹⁴C LY3009104 - An evaluation of hydrolysis as a function of pH following OECD Guideline 111.

Study 151C-143, 2013. LY3009104 – Determination of the n-octanol/water partition coefficient by the shake flask method following OECD Guideline 107.