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 = 0.07 μg/L

Where:

A = 505 kg (total sold amount API in Sweden year 2021, 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 = 69 mg/L (growth rate)

NOEC 72h = 18 mg/L

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

Chronic toxicity

NOEC 21d = 12 mg/L (reproduction)

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

Chronic toxicity

NOEC 32d = 9 mg/L

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

PNEC = 900 μg/L (9 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 = 0.07/900 = 7.7E-05, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of tenofovir disoproxil fumarate has been considered to result in insignificant environmental risk.

Biotic degradation

Biodegradation in Activated Sludge

3.66% to CO₂ in 28 days (OECD 314B) (Ref VI)

[¹⁴C] Tenofovir DF was evaluated for biodegradability in wastewater according to OECD Guideline 314B. Activated sludge was dosed with approximately 1 mg/L [¹⁴C] tenofovir DF. [¹⁴C] Tenofovir DF underwent partial primary and ultimate biodegradation over the course of the 28-day study. Mass balance of the biotic sludge system ranged from 94.1 to 100% of the applied radioactivity (% AR). Ultimate biodegradation (conversion to CO₂) at 28 days was 3.66% AR in the biotic activated sludge test solution and did not occur in the abiotic activated sludge test solutions. [¹⁴C] Tenofovir DF was detected in the biotic sludge at 102% AR on day 0, decreased to 31.6% on day 14, and was not detected through Day 28. One region of radioactivity and a polar region >10% AR were observed in the HPLC analyses of the biotic sludge starting on Day 3. The elimination rate constant, k_e, was -0.1628 day^-1.

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

DT₅₀ (total system) = 1.68 – 3.4 days

Aerobic biodegradation of [¹⁴C] tenofovir DF was also evaluated in two sediment/water systems at 20°C for 28 days following OECD Guideline 308. Sediment/water systems were dosed with 1 mg/L [¹⁴C] tenofovir DF. Carbon dioxide (CO₂) produced due to biodegradation was trapped and measured over the test period. Sediment and water samples were extracted and analyzed to determine extractable radioactivity. Water/sediment samples were analyzed at 0, 1, 3, 7, 14, and 28 days of incubation for the Taunton River and Weweantic River test systems. Sediment samples were extracted once with approximately 150 mL of 85/11/4 acetone/purified reagent water/phosphoric acid (v/v/v) and hand shaken to transfer the sediment fraction to a 250-mL Nalgene bottle. The sediment sample was placed on a shaker table at approximately 200 rpm for 10 minutes and then centrifuged at 3000 rpm for 10 minutes. The sediment extract was transferred to a graduated cylinder, the volume recorded, and analyzed by LSC. The extraction procedure was repeated up to two more times for each sampling interval for a total of up to three extractions. The extracts were then combined and analyzed by LSC. The extraction process was terminated after the first extraction for the day 0 sampling interval since >95% AR was recovered from test samples. Day 0 sediment extracts contained <2.5% AR for each sample and therefore, no further analysis was conducted.

The post-extraction solids (PES) 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. Non-extractable residues in day 28 PES samples were additionally characterized by extraction with a polar and non-polar solvent.

Average recovery ranged from 88.4 to 101% over the course of the study for both the Taunton River and Weweantic River test systems.

The results showed that [¹⁴C] tenofovir DF was degraded in total water/sediment systems with an observed half-life of 1.68 and 3.4 days at 20°C in the Taunton and Weweantic Systems, respectively. Corresponding half-lives at 12^oC were calculated using the Arrhenius equation and were determined to be 4.74 and 9.09 days (Total System). Half-lives for the water layer were 1.26 days and 3.38 days at 20°C in the Taunton and Weweantic Systems, respectively. Corresponding half-lives at 12°C were calculated using the Arrhenius equation and were determined to be 2.88 and 7.44 days (Water Layer). Half-lives for the sediment extracts were 0.789 days and 5.83 days at 20°C in the Taunton and Weweantic Systems, respectively. Corresponding half-lives at 12°C were calculated using the Arrhenius equation and were determined to be 1.68 and 12.4 days (Sediment Extracts). Tenofovir DF does not undergo significant mineralization and CO₂ production during the study ranged from 2.0 to 2.3%.

Evidence of primary biodegradation was observed for [¹⁴C] tenofovir DF in the aerobic water/sediment test systems. Three major transformation products (≥10% AR) developed in both the Taunton River and Weweantic River total systems over the course of the study and were designated as polars, TP 2, and TP 4. An additional major transformation product (≥10% AR) developed in the Taunton River total system and was designated as TP 1. These transformation products were identified by LC-MS/MS. Other minor peaks, not exceeding 5.0% AR at more than one interval, were observed in the water layer and sediment extracts and were not characterized further.

Justification of chosen biotic degradation phrase:

Since half-life < 32 days for total system, tenofovir disoproxil fumarate is degraded in the environment.

Bioaccumulation

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

Log Kow = 1.06 at pH 7

Justification of chosen bioaccumulation phrase:

Since log Kow < 4, tenofovir disoproxil fumarate has low potential for bioaccumulation.

References

1. Data from IQVIA ”Consumption assessment in kg for input to environmental classification - updated 2022 (data 2021)”.

   
   

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, 2019. “Tenofovir DF - 72-hour toxicity test with the freshwater green alga, Raphidocelis subcapitata: OECD 201”. Wareham (MA): Smithers Viscient; 25 Mar 2019. 66 p. Smithers Viscient Study No. 359.7085.

   
   

4. Smithers Viscient, 2019. “Tenofovir DF - full life-cycle toxicity test with water fleas, Daphnia magna, under flow-through conditions: OECD 211”. Wareham (MA): Smithers Viscient; 7 Feb 2019. 68 p. Smithers Viscient Study No. 359.7088.

   
   

5. Smithers Viscient, 2019. “Tenofovir DF - early life-stage toxicity test with fathead minnow (Pimephales promelas): OECD 210”. Wareham (MA): Smithers Viscient; 16 Apr 2019. 101 p.Smithers Viscient Study No. 359.7087.

   
   

6. Smithers Viscient, 2019. “[14C]Tenofovir DF - determination of the biodegradability of a test substance in activated sludge based on OECD Method 314B”. Wareham (MA): Smithers Viscient; 19 Mar 2019. 64 p. Smithers Viscient Study No. 359.7082.

   
   

7. Smithers Viscient, 2019. “[14C]Tenofovir DF - aerobic transformation in aquatic sediment systems: OECD 308”. Wareham (MA): Smithers Viscient; 15 Apr 2019. 198 p. Smithers Viscient Study No. 359.7083.

   
   

8. Smithers Viscient, 2019. “Tenofovir DF - determining the partitioning coefficient (n-octanol/water) by the shake-flask method following OECD guideline 107”. Wareham (MA): Smithers Viscient; 21 Jan 2019. 76 p. Smithers Viscient Study No. 359.7080.