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 = 0.00013 μg/L

Where:

A = 0.93 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 > 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 = 0.00013 /38 = 3.4E-06, 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 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. 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.

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 = 0.028 μg/L

Where:

A = 205.36 kg (total sold amount API in Sweden year 2020, data from IQVIA).

R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10*10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Selenastrum caprocornutum):

IC50 72h (growth) > 96,900 μg/L (OECD 201) (Reference 7)

NOEC > 96,900 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 1,000,000 μg/L (OECD 202) (Reference 5)

NOEC > 1,000,000 μg/L

Water flea (Ceriodaphnia dubia):

Chronic toxicity

EC50 7 days (reproduction) > 100,000 μg/L (EPA 1002) (Reference 10)

NOEC = 100,000 μg/L

Water flea (Daphnia magna):

Chronic toxicity

EC50 21 days (reproduction) > 100,000 μg/L (OECD 211) (Reference 12)

NOEC = 100,000 μg/L

Rainbow Trout (Juvenilee Oncorhyncus mykiss):

Acute toxicity

LC50 96 h (lethality) > 97,700 μg/L (OECD 203) (Reference 8)

NOEC = 97,700 μg/L

Fathead Minnow (Pimephales promelas):

Chronic toxicity

LC50 96 h (lethality) > 10,000 μg/L (OECD 210) (Reference 13)

NOEC = 10,000 μg/L

Other ecotoxicity data:

Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 1,000,000 μg/L (OECD 209) (Reference 11)

NOEC = 1,000,000 μg/L

Chironomid (Chironomus riparius)

NOEC 28 days (development) = 100,000 μg/kg (OECD 218) (Reference 14)

PNEC = 10,000/10 = 1,000 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for fish (= 10,000 ug/L) has been used for this calculation since it represents the lowest value for all three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.028/1,000 = 2.80 x 10^-5, i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of lamivudine has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

< 1% degradation in 28 days (OECD 301B) (Reference 4)

Inherent degradability:

0% degradation in 28 days (OECD 302B) (Reference 9)

4% primary (loss of parent) degradation in 28 days

15-24% degradion in soil (TAD 3.12) (Reference 3)

Simulation studies:

Water-sediment study:

50% (DT₅₀) decline (total system) = 22-29 days (OECD 308) (Reference 14)

Total Lamivudine (day 100) = 0.4% - 0.6%

CO₂ = 8.50% - 12.60%

Total Non-extractable residue = (day 100) = 18.60% - 19.10%

Extraction methods: The non-extractable radioactivity in the samples taken at 100 days was characterised using an acid/base fractionation procedure. Sediment debris was extracted with 0.5 M sodium hydroxide by shaking on an orbital shaker overnight at ambient temperature. The debris was separated by centrifugation and the supernatant removed. The debris was washed with 0.5 M sodium hydroxide and allowed to air-dry. The supernatant was adjusted to pH 1 with concentrated hydrochloric acid and left to stand at ambient temperature. The sample was centrifuged, the precipitate washed with 1 M HCl and the supernatant combined with these washings. The volume of this solution, the fulvic acid fraction, was measured and duplicate aliquots taken for radio-assay. The precipitate, the humic acid fraction, was dissolved in 0.5 M sodium hydroxide.

Abiotic degradation

Hydrolysis:

Half-life, pH 7 > 1 year (OECD 111) (Reference 4)

Photolysis:

No data

Justification of chosen degradation phrase:

Lamivudine is not readily biodegradable nor inherently biodegradable.

Lamivudine DT50 < 32 days and the presence of the parent is < 15%.

The phrase “Lamivudine is degraded in the environment” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = -1.44 at pH7. (TAD 3.02) (Reference 3)

Log Dow at pH5 = -1.17

Log Dow at pH7 = -1.44

Log Dow at pH9 = -1.86

Justification of chosen bioaccumulation phrase:

Since log Dow < 4, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions of lamivudine with other medicinal products is low due to the small extent of hepatic metabolism (5-10%) and low plasma protein binding. (Reference 2)

PBT/vPvB assessment

Lamivudine does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Lamivudine does not fulfil the criteria for PBT and/or vBvP based on a log Dow < 4.

Please, also see Safety data sheets on http://www.msds-gsk.com/ExtMSDSlist.asp.

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

2. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Epivir (Lamivudine) 150mg film coated Tablets. ViiV Healthcare, May 2013.

3. Munro S. GR109714X: Determination of Physico-Chemical Properties. Report No. 93/GLX088/0358. Pharmaco-LSR, March 1994.

4. Cowlyn TC. GR109714X: Determination of Hydrolysis as a Function of pH. Report No. 93/GLX092/0266. Pharmaco-LSR, January 1994.

5. Jenkins CA. GR109714X: Acute Toxicity to Daphnia magna. Report No. 93/GLX090/0145. Pharmaco-LSR, February 1994.

6. Jenkins WR. GR109714X: Assessment of its Ready Biodegradability Modified Sturm Test. Report No. 93/GLX091/0141. Pharmaco-LSR, February 1994.

7. Jenkins CA. GR109714X: Determination of 72-hour EC50 to Green Alga. Report No. 95/GLX174/0358. Pharmaco-LSR, March 1995.

8. Jenkins CA. GR109714X: Acute Toxcity to Rainbow Trout. Report No. 95/GLX173/0172. Pharmaco-LSR, March 1995.

9. Schaefer EC. Lamivudine: An Evaluation of Inherent Biodegradability Using the Zahn-Wellens/EMPA Test. Report No. 374E-123 Wildlife International Limited, July 2004.

10. Goodband TJ. Lamivudine: Daphnid, Ceriodaphnia dubia Survival and Reproduction Test. Report No. 1127/1214. Safepharm Laboratories Limited, November 2006.

11. Best N. Lamivudine: Toxicity to Activated Sludge in a Respiration Inhibition Test. Report No. 41500234. Harlan Laboratories Limited, June 2015.

12. Harris S. Lamivudine: Daphnia magna Reproduction Test. Report No. 41500232. Harlan Laboratories Limited, August 2015.

13. Ablit S. Lamivudine: Fish, Early Life Stage Toxicity. Report No. 41500231. Harlan Laboratories Limited, October 2015.

14. Sacker D. Lamivudine: Sediment-Water Chironomid Toxicity Test Using Spiked Sediment. Report No. WV65TS. Envigo Research Limited, January 2017.

15. Grist A. Lamivudine: Aerobic Transformation in Aquatic Sediment Systems. Report No. TMR0048. Harlan Laboratories Limited, February 2017.

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.