Detaljerad miljöinformation

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 = 0.0012 μg/L

Where:

A = 8.4 kg (total sold amount API in Sweden year 2023, data from IQVIA) (Ref. I)

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 10 *10⁶ 

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

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. II)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Pseudokirchneriella subcapitata) (OECD 201) (Reference III): 

EC₅₀ 72h > 5.8 mg/L

NOEC 72h = 5.8 mg/L

No effects noted for any endpoint (yield and growth rate)

Crustacean, water flea (Daphnia magna) (OECD 211) (Ref. IV): 

Chronic toxicity

NOEC 21d = 0.38 mg/L (reproduction)

Fish, fathead minnow (Pimephales promelas) (OECD 210) (Ref. V): 

Chronic toxicity

NOEC 32d = 1 mg/L

No effects noted for any endpoint (hatching, survival, growth)

PNEC = 38 μg/L (0.38 mg/ L/ 10 based on the most sensitive NOEC for the daphnia and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0012/38 = 3E-05, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of doravirine has been considered to result in insignificant environmental risk.

Biotic degradation

Biodegradation in Activated Sludge

2% to CO₂ in 28 days (OECD 314B) (Ref VI)

[¹⁴C] doravirine was evaluated for biodegradability in wastewater according to OECD Guideline 314B. Activated sludge was dosed with approximately 1 mg/L [¹⁴C] doravirine. Mass balance of the biotic sludge system ranged from 96.0 to 102% of the applied radioactivity (% AR) over the course of the study. Ultimate biodegradation (conversion to CO₂) occurred at 2.1% AR in the biotic activated sludge test solutions at day 28. Two minor regions of radioactivity (<10% AR) were observed in the HPLC analyses of the biotic sludge in addition to the parent peak. The overall primary biodegradation half-life of doravirine in the biotic sludge was calculated to be 158 days. The elimination rate constant, k_e, was 0.0044 days^-1.

  

Sediment Transformation (OECD 308) (Ref. VII):

DT₅₀ (total system) = 136-154 days

Transformation of [¹⁴C] doravirine was evaluated in two aerobic sediment/water systems at 20°C for 102 days following OECD Guideline 308. Sediment/water systems were dosed with 1 mg/L [¹⁴C] doravirine. Carbon dioxide (CO₂) produced due to biodegradation was trapped and measured over the test period.

Water-sediment samples were analyzed at 0, 3, 13, 27, 56, and 102 days of incubation. Approximately 150 mL of acetonitrile was added to each sediment sample and the sample was capped and hand shaken to homogenize. The samples were then placed on a shaker table at approximately 200 rpm for 10 minutes and then centrifuged at 1000 rpm for 10 minutes. The sample extracts were transferred to a graduated cylinder, the volume was recorded, and samples were analyzed by LSC (2 × 1.0 mL). With the exception of the day 0 samples, the extraction procedure was repeated two times for each sampling interval; once using 80/20 acetonitrile/purified reagent water (v/v) and once using 80/20/0.1 acetonitrile/purified reagent water/formic acid (v/v/v) for a total of three extractions. Due to < 2% AR recovered from the second extraction, the day 0 sediment samples were only extracted a total of two times. The extracts were then combined and duplicate 1.0-mL aliquots were analyzed by LSC. A portion of the combined extracts was then concentrated to near dryness under vacuum by rotary evaporation using minimal heating. The concentrated sample was transferred to a graduated glass conical test tube, the flask was rinsed with a portion of 50/50 acetonitrile/purified reagent water (v/v), and the rinses were added to the test tube. The resulting volume was recorded and the samples vortexed for 30 seconds, then shaken to mix. Duplicate 0.1-mL aliquots of the concentrated samples were subsampled for LSC analysis. A portion of the concentrate was centrifuged at 10,000 rpm for five minutes to precipitate any solids and samples were analyzed by LSC (1 × 0.05 mL). A portion of the centrifuged sample was transferred into an autosampler vial and analyzed by HPLC/RAM. An aliquot (20 µL) of the appropriate MK-1439 stock solution was added to each vial prior to HPLC/RAM analysis. Average recovery ranged from 90 to 110% over the 102 day test period.

The half-life of doravirine in the total water/sediment test systems was 136 to 154 days at 20°C (corresponding to 290 to 329 days at 12°C). Evidence of primary biodegradation was observed for [¹⁴C] doravirine in the aerobic water/sediment test systems. Several minor peaks were observed in some of the chromatograms for the Taunton River and Weweantic River test samples. In all cases, these minor peaks represented less than 10% AR in the water and sediment extracts and were not characterized further.

Ultimate biodegradation of [¹⁴C] doravirine was observed in the aerobic samples with evolution of 14CO₂ reaching an average maximum of 5.06 and 2.04 % AR for the Taunton River and Weweantic River aerobic test samples, respectively, at day 102. Generation of volatile organic compounds was negligible and observed at an average maximum of 0.0114 and 0.0110% AR for the Taunton River and Weweantic River aerobic test samples, respectively, at day 102.

Justification of chosen biotic degradation phrase:

Since half-life >120 days for total system, doravirine is potentially persistent.

Bioaccumulation

Partitioning coefficient (OECD 107) (Ref.VIII): 

Log K_ow = 2.08 at pH 7

Justification of chosen bioaccumulation phrase:

Since log K_ow < 4, doravirine has low potential for bioaccumulation.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2024 (data 2023)”.

2. 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

3. Softcheck KA. Doravirine (MK-1439) - 72-hour toxicity test with the freshwater green alga, Pseudokirchneriella subcapitata following OECD guideline 201. Wareham (MA): Smithers Viscient; 7 Jan 2016. Study No. 359.6979.

4. Shaw AC. MK-1439 - full life-cycle toxicity test with water fleas, Daphnia magna, under static renewal conditions following OECD guideline 211. Wareham (MA): Smithers Viscient; 16 Mar 2018. Report No. 359.6981.

5. Sayers LE. MK-1439 - early life-stage toxicity test with fathead minnow (Pimephales promelas): OECD Guideline 210, OCSPP Guideline 850.1400. Wareham (MA): Smithers Viscient; 16 March 2018. Study No. 359.6980.

6. Griffith AW. [14C]MK-1439 - Determination of the biodegradability of a test substance in activated sludge based on OECD method 314B. Wareham (MA): Smithers Viscient; 1 Jul 2016. Study No. 359.6985.

7. Letourneau M. [14C]MK-1439 - Aerobic transformation in aquatic sediment systems following OECD guideline 308. Wareham (MA): Smithers Viscient; 27 Sep 2016. Study No. 359.6984.

8. Grenier AC. MK-1439 - Determining the partition coefficient (noctanol/water) by the flask-shaking method following OECD guideline 107. Smithers Viscient; 17 Dec 2012. Study No.359.6676.