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 = 0.00016 μg/L

Where:

A = 1.15 kg (total sold amount API in Sweden year 2020, 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 > 8.8 mg/L

NOEC 72h = 8.8 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 = 1.2 mg/L (reproduction and length)

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 = 100 μg/L (1 mg/ L/ 10 based on the most sensitive NOEC for the fathead minnow and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.00016 /100 = 1.6 x 10^-6, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of letermovir has been considered to result in insignificant environmental risk.

Biotic degradation

Biodegradation in Activated Sludge

1% to CO₂ in 28 days (OECD 314B) (Ref VI)

DT₅₀ = 6.7 days

[¹⁴C] letermovir was evaluated for biodegradability in wastewater according to OECD Guideline 314B. Activated sludge was dosed with approximately 1 mg/L [¹⁴C] letermovir. Mass balance of the biotic sludge system ranged from 94.0 to 99.2% of the applied radioactivity (% AR) over the course of the study. Ultimate biodegradation (conversion to CO₂) occurred at 1% AR in the biotic activated sludge test solutions at day 28. Five regions of radioactivity were observed in the HPLC/RAM analyses of the biotic sludge in addition to the parent peak. Two metabolites M1 and M2 were measured in concentrations greater than 10% by Day 28 (identified in the OECD 308 study, below). The overall primary biodegradation half-life of letermovir in the biotic sludge was calculated to be 6.7 days. The elimination rate constant, k_e, was 0.1028 days^-1.

 

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

Ultimate degradation < 1%

DT₅₀ (total system) = 22-34 days

Transformation of [¹⁴C] letermovir was also evaluated in two aerobic sediment/water systems at 20°C for 100 days following OECD Guideline 308. Sediment/water systems were dosed with 1 mg/L [¹⁴C] letermovir. Carbon dioxide (CO₂) produced due to biodegradation was trapped and measured over the test period.

At each sampling interval, duplicate incubation vessels per water/sediment system were removed from each test system and the water layers were separated from sediment layers. The water layer from each test vessel was analyzed separately for [ 14C] letermovir and degradates. The sediment was then extracted once with 80:20 acetonitrile:purified reagent water (v:v) and once with 80:20:0.1 acetonitrile:purified reagent water:formic (v:v:v) for a total of two extractions. Beginning on day 3, the sediment was extracted a third time using 80:20:0.5 acetonitrile:purified reagent water:formic acid (v:v:v). The water and sediment extracts were radioassayed by LSC and then analyzed by high performance liquid chromatography with radiochemical detection (HPLC/RAM) to quantify [14C] letermovir and degradation products in the fractions. Radioactivity in the post extracted solids (sediment bound, PES) was quantified by combustion analysis and the liquid volatile organic traps were radioassayed by liquid scintillation counting (LSC). Average recovery ranged from 94.1 to 95.8% over the 100 day test period.

Ultimate biodegradation of [¹⁴C] letermovir was observed in the aerobic samples with evolution of ¹⁴CO₂ reaching an average maximum of 0.303 and 0.328% AR for the Taunton River and Weweantic River aerobic test samples, respectively, at Day 100. Generation of volatile organic compounds was negligible and observed < LOQ for the Taunton River aerobic test samples and at an average maximum of 0.026% AR for the Weweantic River aerobic test samples at Day 100.

 

Evidence of primary biodegradation was observed for [¹⁴C] letermovir in the aerobic water/sediment test systems. Two major peaks (≥ 10% AR) were observed in some of the chromatograms for the Taunton River and Weweantic River samples (Met 1 and 7). 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.

Further degradation of Met 1 was not apparent. Percentages in the total system continued to increase or remain constant through Day 100. For Met 7, further degradation was only noted in the Taunton River system. Percentages were 14% at Day 14 and decreased to 5.8% by Day 100. Linear regression of the data suggests a total system half-life of about 65days for Met 7. No trend in the percentage of Met 7 was observed in the Wewantic River system.

Proposed structures for observed major degradates Met 1 and Met 7 were determined by LC-MS/MS. A proposed transformation pathway for [¹⁴C] letermovir was determined based on these proposed structures and HPLC-RAM analysis as presented below. Met 1 is proposed to be formed by dealkyation and then acetylation at the N proximate to the quinazoline moiety in letermovir. Met 7 is proposed to be formed by demethylation at the anisole moiety in letermovir.

Justification of chosen biotic degradation phrase:

Since half-life ≤ 120 days for total system, letermovir is slowly degraded in the environment.

Bioaccumulation

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

Log K_ow = 2.29 at pH 7

Justification of chosen bioaccumulation phrase:

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

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2021 (data 2020)”.

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. Smithers Viscient, 2014. "Letermovir − 72-Hour Toxicity Test with the Freshwater Green Alga, Pseudokirchneriella subcapitata, Following OECD Guideline 201", Smithers Viscient, Wareham, MA, USA; Report 359.6857, 15 Jan 2015.

4. Smithers Viscient, 2015. "MK-8228 – Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static Renewal Conditions Following OECD Guideline #211", Smithers Viscient, Wareham, MA, USA; Report 359.6925, 23 December 2015.

5. Smithers Viscient, 2016. "MK-8228 – Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas)", Smithers Viscient, Wareham, MA, USA; Report 359.6924, 07 March 2016.

6. Smithers Viscient, 2016. "[14C]MK-8228 – Determination of the Biodegradability of a Test Substance in Activated Sludge Based on OECD Method 314B", Smithers Viscient, Wareham, MA, USA; Report 359.6929, 06 April 2016.

7. Smithers Viscient, 2016. "MK-8228 - Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308", Smithers Viscient, Wareham, MA, USA; Report 359.6928, 10 June 2016.

8. Smithers Viscient, 2016. "MK-8228 - Determining the Partitioning Coefficient (nOctanol/Water) by the Shake-Flask Method Following OECD Guideline 107", Smithers Viscient, Wareham, MA, USA; Report 359.6922, 27 January 2016.