Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

The 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 = 0.00137 μg/L

Where:

A = 10 kg (forecasted sales of less than 10 kg five years after launch)

R = 0 % removal rate as a conservative estimate

P = number of inhabitants in Sweden = 10 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default)¹

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default)¹

Excretion (metabolism) 

In a human biotransformation study, metabolism was the major route of elimination for deucravacitinib, with 59.3% of the dose being eliminated as metabolites². No removal is used as a worst case scenario for the PEC calculation above.

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Activated sludge (OECD 209)³

EC₁₀/EC₅₀ > 1000 mg/L (highest dose tested)

NOEC = 1000 mg/L

Algae (Pseudokirchneriella subcapitata) (OECD 201)⁴

EC₅₀ 72 h (growth rate) > 5 mg/L

NOEC 72 h (growth rate) = 1.3 mg/L

Crustacean (Daphnia magna)

Chronic Toxicity (OECD 211)⁵

NOEC 21 days (survival) = 9.8 mg/L

NOEC 21 days (growth/reproduction) = 3.1 mg/L

Fish (Fathead Minnow; Pimephales promelas)

Chronic Toxicity (OECD 210)⁶

NOEC 32 days/28 days post hatch (hatching success/percent live and normal          larvae/survival/growth) = 0.92 mg/L (highest dose tested)

                             

The PNEC for aquatic organisms is based on the lowest NOEC of 0.92 mg/L, noted in the fish chronic toxicity study.  An assessment factor of 10 is applied to the ecotoxicity base set of three chronic studies.

PNEC_aquatic = (0.92 mg/L)/10 = (920 µg/L)/10 = 92 µg/L

Environmental Risk Classification (PEC/PNEC Ratio)

PEC/ PNECaquatic = 0.00137 μg/L / 92 μg/L = 1.49 x 10^-5. PEC/ PNECaquatic < 0.1 which justifies the phrase “Use of deucravacitinib has been considered to result in insignificant environmental risk”

Degradation

Biotic degradation

Ready Degradability (OECD 301B)⁷:

-0.10% biodegradation over 28 days; not readily biodegradable

Simulation Studies (OECD 308)⁸:

The rate and route of transformation for deucravacitnib was studied in two United States aquatic sediment systems: Taunton River and Weweantic River water/sediment test systems.  They were significantly different based on the texture and percentage organic carbon of the sediment.  Sediment samples were extracted up to two times each with 4/1 acetonitrile/0.005 M potassium carbonate in purified reagent water (v/v) and 4/1 acetonitrile/0.1 M hydrochloric acid in purified reagent water (v/v), respectively, and analyzed by LSC for recovery of radioactivity and by HPLC-RAM for determination and profiling of major transformation products ≥10% applied radioactivity (% AR) or ≥5% AR at two consecutive sampling intervals. The post-extracted sediment samples were combusted and analyzed by LSC for determination of non-extractable residues. The volatile trapping solutions were analyzed by LSC for determination of ¹⁴CO2 and volatile organics. In both aerobic sediment systems deucravacitinib declined in the water phase over time (< 2% of initial concentration on day 99) and increased in the sediment phase (50.7-62.4% of initial radioactivity on day 99). Individual transformation products did not exceed 10 % of applied radioactivity in both systems. Negligible (<0.5%) ultimate biodegradation was observed in both test systems. No radioactivity above the limit of quantification (LOQ) was observed as volatile organic compounds.  Average material balance ranged from 94.1 to 104% over the course of the study for both the Taunton River and Weweantic River test systems.  Non-extractable residues (NER) increased over the course of the incubation period. At the end of the study, the average non-extractable residues in the test systems represented 42.4 and 27.7% AR for the Taunton River and Weweantic River test systems, respectively. Since >10% AR was recovered in the non-extractable residues, additional characterization was performed by soxhlet extraction and organic matter fractionation (OMF). Additional extractions with polar (dichloromethane) and non-polar (chloroform) solvents removed negligible residues for both test systems.  The majority of NER observed from OMF were found in the humin fraction for both test systems.  The half-life (DT₅₀) of deucravacitinib in water layer at 12°C for Taunton River and Weweantic River sediment systems was 14 and 14.8 days, respectively.  The total system half-life (DT₅₀) of deucravacitinib at 12°C for Taunton River and Weweantic River sediment systems was 211 and 330 days, respectively. 

Based on the OECD 301B study, deucravacitinib is not readily biodegradable.  Based on the DT₅₀s determined in the OECD 308 study and the 2012 FASS guidance for pharmaceutical companies v3.0, the phrase “deucravacitinib is potentially persistent” is justified.

Bioaccumulation

Partitioning Coefficient (OECD 107)⁹:

LogDow values at pH 4, 7 and 9 was reported as 2.33, 2.44 and 2.39, respectively.            

Justification of chosen bioaccumulation phrase:

Since logDow at pH 7 < 4, the phrase “deucravacitinib has low potential for bioaccumulation” is justified.

Soil Sorption/Desorption

Determination of the Koc Coefficient (OECD 106)¹⁰

An OECD 106 study was conducted in three soils with varying characteristics (pH, organic carbon, clay content and soil texture) and two sludges from different wastewater treatment plants.  Kocs in the three soils at equilibrium ranged from 25181-35306 L/kg.  The Kocs in the two sludges at equilibrium were 209 and 328 L/kg. 

PBT/vPvB Assessment

Deucravacitinib does not meet the criteria to be considered a PBT or vPvB substance.

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

2. BMS-986165 Biotransformation Of [14C] BMS-986165 In Humans Following A Single Oral Dose Administration Report NCPK431 Bristol-Myers Squibb Company (2018) Document Control Number 930121945

3. BMS-986165-01 – Activated Sludge Respiration Inhibition Test Following OECD Guideline 209 (Study No. 12534.6517) Bristol-Myers Squibb One Squibb Drive, 2018,  Document Control Number 930166170

4. BMS-986165-01 - 72-Hour Toxicity Test with the Freshwater Green Alga, Raphidocelis subcapitata, OECD 201, (Study No. 12534.6512), Bristol-Myers Squibb, 2018, Document Control Number 930166169

5. BMS-986165-01 - Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static-Renewal Conditions OECD 211 (Study No. 12534.6513), Bristol-Myers Squibb, 2018, Document Control Number 930166174

6. BMS-986165-01 – Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas) OECD 210, (Study No. 12534.6514), Bristol-Myers Squibb (2020) Document Control Number 930166150

7. BMS-986165-01 - Determination of the Biodegradability of a Test Substance Based on OECD Method 301B (CO2 Evolution Test) OECD 301, Method B (Study No. 12534.6516) Bristol-Myers Squibb Company; 2018. Document Control Number 930166143

8. [14C]BMS-986165-05 - Aerobic Transformation in Aquatic Sediment Systems, OECD 308 (Study No. 12534.6520), Bristol-Myers Squibb, 2018, Document Control Number 930166172

9. BMS-986165-01 – Determining the Partitioning Coefficient (n-Octanol/Water) by the Slow-Stirring Method Following OECD Guideline 123 and Shake Flask Method Following OECD Guideline 107 (Study No. 12534.6511) Bristol-Myers Squibb, 2018, Document Control Number 930166168

10. [14C]BMS-986165-05: Determining the Adsorption Coefficient (Koc) Following OECD Guideline 106 (Study No. 12534.6515), Bristol-Myers Squibb, 2018, Document Control Number 930166166