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 = 0.064 μg/L

Where:

A = 467.74 kg (total sold amount API in Sweden year 2022, data from IQVIA). Total volume of Abacavir = 24.16 Kg. Total volume of Abacavir sulphate = 340.28 Kg. Total volume of Abacavir hydrochloride monohydrate = 103.30 Kg. Total abacavir = 24.16 + 340.28 + 103.30 = 467.74.

.

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) = 57,400 μg/L (OECD 201) (Reference 8)

NOEC = 30,000 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 139,000 μg/L (OECD 202) (Reference 3)

NOEC = 79,000 μg/L

Water flea (Ceriodaphnia dubia):

Chronic toxicity

EC50 7 days (reproduction) = 10,000 μg/L (EPA 1002) (Reference 11)

NOEC = 5,600 μg/L

Fathead Minnow (Juvenilee Pimephales promelas):

Acute toxicity

LC50 96 h (lethality) > 95,000 μg/L (OECD 203) (Reference 9)

NOEC = 95,000 μg/L

Chronic Toxicity

NOEC 32 days (mortality) = 10,000 μg/L (OECD 210) (Reference 12)

Other ecotoxicity data:

Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 71,400 μg/L (OECD 209) (Reference 7)

Chironomid (Chironomus riparius)

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

PNEC = 5,600/10 = 560 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for water flea (= 5,600 ug/L) has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.064/560 = 1.00 x 10^-4, i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of abacavir has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

27% degradation in 28 days (OECD 301B) (Reference 5)

Inherent degradability:

100% primary (loss of parent) degradation in 14 days (OECD 302B) (Reference 10)

Data on the evaluation of degradation products is not available and therefore loss of parent API does not inform summary degradation phrase.

Simulation studies:

Water-sediment study:

50% (DT₅₀ parent) degradation in 9.10 – 15.0 days (OECD 308) (Reference 13)

Data on the evaluation of degradation products is not available and therefore loss of parent API in the OECD 308 is not used to assign a classification.

Non-extractable residue = 37.80% - 62.60%

Abiotic degradation

Hydrolysis:

Half-life, pH 7 > 1 year (TAD 3.09) (Reference 4)

Photolysis:

No Data

Justification of chosen degradation phrase:

Abacavir is not readily biodegradable nor inherently biodegradable. The phrase “Abacavir is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = 1.20 at pH 7 (OECD 107) (Reference 3)

Log Dow at pH 5 = 0.90

Log Dow at pH 7 = 1.20

Log Dow at pH 9 = 1.20

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose being renally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5'-carboxylic acid and 5'-glucuronide which account for about 66% of the administered dose. The metabolites are excreted in the urine.

The mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces (Reference 2).

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 Ziagen (Abacavir) 300mg Film Coated Tablets. ViiV Healthcare UK Ltd., March 2013.

3. Sydney P. 1592U89: Determination of the Physico-Chemical Properties. Report No. 96/GLX179/1022. Huntingdon Life Sciences Ltd, October 1997.

4. Sydney P. 1592U89: Determination of Hydrolysis as a Function of pH. Report No. 96/GLX181/0864. Huntingdon Life Sciences Ltd, October 1997.

5. Jenkins WR. 1592U89: Activated Sludge – Respiration Inhibition Test. Report No. GLX180/970062. Huntingdon Life Sciences Ltd, September 1997.

6. Jenkins CA. 1592U89: Acute Toxicity to Daphnia magna. Report No. 96/GLX180/1068. Huntingdon Life Sciences Ltd, September 1997.

7. Jenkins WR. 1592U89: Biotic Degradation with a Composite Innoculum. Modified Sturm Test. Report No. GLX183/970063. Huntingdon Life Sciences Ltd, September 1997.

8. Swarbrick RH. Abacavir sulphate: Toxicity to Green alga Selenastrum capricornutum. Report No. BL7702/B. Brixham Environmental Laboratory, October 2004.

9. Warbrick RH. Abacavir sulphate: Acute Toxicity to Rainbow trout Oncorhynchus mykiss. Report No. BL7703/B. Brixham Environmental Laboratory, October 2004.

10. Swarbrick RH and Smyth DV. Abacavir sulphate: Determination of Inherent Biodegradability (Zahn-Wellens Test). Report No. BL7704/B. Brixham Environmental Laboratory, March 2006.

11. Young BE and Kent SJ. Abacavir sulphate: Determination of the 3-brood (7 day) Chronic Toxicity of Ceriodaphnia dubia. Report No. BL8144/B. Brixham Environmental Laboratories, March 2006.

12. Ablitt, S. Abacavir hemisulphate:Fish, Early Life Stage Toxicity. Report No. 41500228. Envigo Research Limited, October 2015.

13. Unsworth, R and Carter, J. Abacavir hemisulphate: Aerobic Transformation in Aquatic Sediment Systems. Report No. TMR0047. Envigo Research Limited, November 2016.

14. Ablitt, S. Abacavir hemisulphate: Sediment-Water Chironomid Toxicity Test Using Spiked Sediment. Report No. VG43JK. Envigo Research 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 = 0.028 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.