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 = 0.0095 μg/L

Where:

A = 69 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 (Selenastrum capricornutum) (OECD 201) (Ref. III):

EC₅₀ 96 h (growth rate) = 66 mg/L

NOEC 96 h (growth rate) = 3.8 mg/L

Crustacean, water flea (Daphnia magna):

Acute toxicity (OECD 202) (Ref. IV)

LC50 48 h (mortality) > 100 mg/L

Non-toxic up to highest concentration tested

Chronic toxicity (OECD 211) (Ref. V)

NOEC 21 day (reproduction) = 9.5 mg/L

Non-toxic up to highest concentration tested

Fish, fathead minnow (Pimephales promelas):

Acute toxicity (OECD 203) (Ref.VI)

LC50 96 h (mortality) > 100 mg/L

Non-toxic up to highest concentration tested

Chronic toxicity (OECD 210) (Ref. VII)

NOEC 33 days = 9.3 mg/L

Non-toxic up to highest concentration tested

Fish, sheepshead minnow (Cyprinodon variegatus): (OECD 203) (Ref.VIII)

Acute toxicity

LC₅₀ 96 h (mortality) > 100 mg/L

Non-toxic up to highest concentration tested

PNEC = 380 µg/L (3.8 mg/L / 10) based on the chronic NOEC for the algae (growth rate) and an assessment factor (AF) of 10)

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0095/380 = 2E-05, i.e. PEC/PNEC ≤ .1 which justifies the phrase "Use of raltegravir has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Biodegradation Simulation Screening (OECD 314) (Ref. IX)

75% biodegradation by Day 28

8% to CO₂ after 28 days

67% to transformation products

DT₅₀ = 9 days

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

DT₅₀ (water) = 6 days

3 - 7% to CO₂ after 100 days

A GLP transformation study was conducted to assess the potential biodegradation of raltegravir in aerobic and anaerobic aquatic sediment systems. Two sediments and their associated waters were utilized in both the aerobic and anaerobic segments of the study. Test systems were dosed with 14C-labeled test material at a nominal test concentration of 0.75 mg/L in the aqueous layer and incubated at approximately 20ºC for up to 100 days. Treated sediment-water systems were maintained under a gentle stream of compressed air (aerobic conditions) or nitrogen gas (anaerobic conditions). Effluent gases were passed through a sorbent material to trap organic volatiles, followed by a strong alkali solution to trap evolved CO2 (carbon dioxide). Duplicate incubation chambers of each sediment-water type and condition were sacrificed on Days 0, 14, 28, 49, 70 and 100. Water and sediment samples were analyzed separately for total 14C-radioactivity, parent test substance and radiolabeled metabolites. Analogous anaerobic sediment-water test chambers were also established to assess 14C-methane evolution at regular sampling intervals using a specialized mineralization apparatus and were sacrificed on Day 100 for analysis of total radioactivity and potential metabolites. Untreated test chambers and solvent control chambers were utilized to characterize the sediment-water systems during the study.

Sediment layers were extracted on the day of collection. The weights of the sediment layers, after decanting the overlying waters, were recorded. Sediment layers were quantitatively transferred from the original test vessels into 500-mL HDPE bottles using 200 mL of acidified (2% v/v acetic acid) ethyl acetate. The bottles were placed in an ultrasonic bath for at least five minutes, shaken for at least 30 minutes at 250 rpm on a gyratory shaker table, and then centrifuged at approximately 1200 rpm for five minutes to effect separation. The solvent extracts were decanted and transferred to glass bottles. The sediment layer from each sacrificed test vessel was extracted an additional two times utilizing the same procedure and 100 mL aliquots of the extraction solvent. The three extracts from each sediment layer were combined and the volume recorded. Each combined sediment extract was then transferred to a separate glass bottle and triplicate aliquots of the extracts were removed for analysis by LSC. The bottles were placed in refrigerated storage for up to 14 days before continuing with the method.

The sediment extracts were removed from refrigerated storage, and a measured portion of each extract was transferred to a round-bottom flask. The remaining sediment extracts were placed in refrigerated storage. The samples were rotary-evaporated until all solvent had been removed, and only the acidic aqueous portion remained. The concentrated extracts were transferred to graduated cylinders, and the volumes recorded. The round-bottom flasks were rinsed three times with small volumes (1 to 2 mL) of acetonitrile (ACN), and the rinses were combined with the concentrated extracts. The round-bottom flasks were then rinsed three times with small volumes (2 to 4 mL) of water. The water rinses were combined with the concentrated extracts, and the final volumes were recorded. Concentrated sediment extracts were transferred to glass vials, and triplicate aliquots were removed for LSC analysis to determine the total radioactivity associated with the concentrated samples. A portion of each extract was transferred to an auto-sampler vial for radiolabeled distribution analysis by HPLC/β-RAM. The remaining concentrated sediment extracts were placed in refrigerated storage.

The weights of the sediment solids remaining after the acidified ethyl acetate procedures were determined. Five sub-samples from each sediment were removed and weighed for combustion analyses using a PerkinElmer Model 307 Sample Oxidizer. The combusted samples were analyzed by LSC to determine total radioactivity associated with the solids and complete subsequent mass balance calculations. The remaining sediment solids were placed in refrigerated storage.

The Day 100 mass balance for the aerobic test systems is presented below (Table 1).

Table 1
Day 100 Mass Balance Results for the Aerobic Sediments
in the OECD 308 Study

Day 100 Mass Balance	Brandywine – aerobic	Choptank – aerobic
% to CO2	3.0	7.6
Aqueous Total % - As parent - As metabolites	3.1 0 3.1	32.3 2.5 29.8
Sediment Extractable Total % - As parent - As metabolites	22.9 20.8 1.6	24.8 22.2 2.6
Sediment Non-Extractable %	61.4	31.9
Total %	90.5	96.6

Ultimate biodegradation occurred to a limited extent in both the aerobic and anaerobic systems. The maximum percentage transformed to CO₂ was 7.6% in the Choptank aerobic test system. At the completion of the OECD 308 study, the majority of the mass was found in the sediment portion (both sediment extractable and non-extractable). For the Brandywine test system, at Day 100, only 3.1% of the total radioactivity remained in the aqueous phase, all as metabolites. In the Choptank test system, a greater percentage remained in the aqueous phase (32.3%) but similarly, the majority component as a mixture of metabolites (29.8% vs. 2.5%). Based on quantification of the HPLC results, no individual metabolites were present at quantities > 10%.

For the sediment extractable portion at Day 100, 22.9% (Brandywine) and 24.8% (Choptank) of the total radioactivity remained, with the majority (20.8% and 22.2%) as parent. For the sediment non-extractable portion, 61.4% and 31.9% of total radioactivity was measured at the end of the study in Brandywine and Choptank, respectively. The decreasing amount of parent observed in the sediment extractable fraction was a function of the increase in the non-extractable residue over time. DT₅₀ values calculated with the sediment data represent adsorption kinetics and the length of time for 50% of the applied activity to become irreversibly bound. DT₅₀ values for this physical process were 90 days, 90 days and 182 days for Brandywine Creek anaerobic, Choptank River aerobic and Choptank River, anaerobic, respectively.

The times of disappearance of 50 percent of the parent (DT₅₀) from the aqueous layers in the sediment-water systems were 6.4 to 6.5 days and 5.2 to 6.8 days in the aerobic and anaerobic test systems, respectively.

Abiotic degradation

Photolysis (Phototransformation of Chemicals in Water – Direct and Indirect Photolysis, OECD Guideline for Testing of Chemicals, Proposal for a New Guideline,) (Ref. XI)

Test results indicate a “definite potential for phototransformation at 295 – 800 nm” based on molar absorption.

Justification of chosen degradation phrase:

Given the total system half-life was not calculated in the Sediment Transformation study (OECD 308), the phrase raltegravir is potentially persistent was chosen.

Bioaccumulation

Partitioning coefficient:

Log D_ow = -0.3 at pH 7 (OECD 107). (Ref.XII)

Justification of chosen bioaccumulation phrase:

Since log D_ow < 4 at pH 7, the substance 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. Wildlife International, 2006. "MK-0518: A 96-Hour Toxicity Test with the Freshwater Alga (Pseudokirchneriella subcapitata)," Study No., 105C-111, WIL, Easton, MD, USA 04 May 2006.

   
   

4. Toxikon, 2004. "48-Hour Acute Toxicity Test Conducted Utilizing L-000900612 on the Water Flea, Daphnia magna," Study No. 040242N4, TOXIKON, Jupiter, FL, November 2004.

   
   

5. Wildlife International, 2007. "MK-0518: A Flow-Through Life Cycle Toxicity Test with the Cladoceran (Daphnia magna)," Study No., 105A-151, WIL, Easton, MD, USA, 02 February 2007.

   
   

6. Toxikon, 2004. "96-Hour Acute Limit Toxicity Test Conducted Utilizing L-000900612 on the Fathead minnow, Pimephales promelas," Study No. 040242N3, TOXIKON, Jupiter, FL, November 2004.

   
   

7. Wildlife International, 2007. "MK-0518: An Early Life-Stage Toxicity Test with the Fathead Minnow (Pimephales promelas)," Study No., 105A-152, WIL, Easton, MD, USA, 22 January 2007.

   
   

8. Toxikon, 2004. "96-Hour Acute Limit Toxicity Test Conducted Utilizing L-000900612 on the Sheepshead minnow, Cyprinodon variegatus," Study No. 040242N5, TOXIKON, Jupiter, FL, November 2004.

   
   

9. Wildlife International, 2007. "MK-0518: Dieaway in Activated Sludge," Study No., 105E-112, WIL, Easton, MD, USA, 02 March 2007.

   
   

10. Wildlife International, 2007. "MK-0518: Aerobic and Anaerobic Transformation in Aquatic Sediment Systems," Study No., 105E-116, WIL, Easton, MD, USA, 23 July 2007.

    
    

11. Wildlife International, 2006, "Phototransformation Potential of MK-0518," Study No., 105C-109, WIL, Easton, MD, USA, 13 October 2006.

    
    

12. Wildlife International, 2012. “Determination of the n-octanol/water partition coefficient of MK-0518 by the shake flask method,” Study No. 105C-148, WIL, Easton MD, USA, 15 May 2012.