Detaljerad miljöinformation

Detailed background information

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 = 1.08 x 10^-2 μg/L

Where:

A = 78.90 kg (total sold amount API free base in Sweden year 2022, data from IQVIA). Total volume of Dolutegravir sodium 83.05 = 78.90 Dolutegravir free base. Total Dolutegravir = 78.90.

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 (Pseudokirchneriella subcapitata):

IC50 96h (biomass) = 233 μg/L (OECD 201) (Reference 5)

NOEC = 95 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 6,430 μg/L (OECD 202) (Reference 6)

Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 834 μg/L (OECD 211) (Reference 7)

Rainbow Trout:

Acute toxicity

No data

Fathead minnow (Juvenile Pimephales promelas):

Chronic toxicity

NOEC 28 days (mortality) = 220 μg/L (OECD 210) (Reference 8)

Other ecotoxicity data:

Chironomid (Chironomus riparius)

NOEC 28 days (reproduction) = 858,000 μg/kg (OECD 218) (Reference 9)

Microorganisms in activated sludge

EC50 3 hours (Inhibition) = 24,000 μg/L (OECD 209) (Reference 3)

Terrestrial toxicity

Earthworm (Eisenia foetida)

LC50 14 days (mortality) > 1,000,000 μg/kg (OECD 207) (Reference 12)

NOEC = 1,000,000 μg/kg

Collembola (Folsomia candida)

NOEC 28 days (reproduction) = 29,000 μg/kg (ISO 11267:1999) (Reference 13)

Soil microorganisms

NOEC = 984,000 μg/kg (OECD 216) (Reference 14)

Onion (Allium cepa), Pea (Pisum sativum)

NOEC 23 days (emergence) = 12,000 μg/kg (OECD208) (Reference 15)

PNEC = 95/10 = 9.50 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for green alga (= 95 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 = 1.08 x 10^-2/9.5 = 1.14 x 10^-3, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of dolutegravir has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

No data

Inherent degradability:

0% degradation in 28 days (OECD 302B) (Reference 10)

18% primary degradation of parent in 28 days

This substance is not inherently biodegradable.

Simulation studies:

Water-sediment study:

50% (DT50) degradation in > 1,000 days (OECD 308) (Reference 11)

Non-extractable residue = 8.70% - 9.30%

Soil Degradation:

Aerobic transformation in soil (OECD 307) (Reference 16)

Degradation rates

DT₅₀ = 1,000 days

DT₉₀ = 1,000 days

Non-extractable residue < 10%

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

Dolutegravir is not readily biodegradable nor inherently biodegradable. This substance is predicted to degrade in water sediment systems ≥ 120 days. Non-extractable residues represent < 10% of the total material. The phrase “Dolutegravir is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow < 1 at pH 7 (OECD 107) (Reference 4)

Log Dow at pH 5 = -2.28

Log Dow at pH 7 = -2.45

Log Dow at pH 9 = -3.21

Justification of chosen bioaccumulation phrase:

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

Excretion (metabolism)

Dolutegravir is primarily metabolized through glucuronidation via UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose) (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 Tivicay (Dolutegravir sodium) 50mg film coated tablets. GlaxoSmithKline, January 2014.

3. Graham R and Alderman D. GSK1349572: Activated Sludge Respiration Inhibition Test. Report No. 8236109. Covance Laboratories Limited, January 2010.

4. Moseley RH. GSK1349572A: Determination of the n-octanol: water partition coefficient. Report No. 8240319. Covance Laboratories Limited, October 2011.

5. Last G, Flenely A and Goodband T. GSK1349572A: Inhibition of Growth to the Alga Pseudokirchneriella subcapitata. Report No. 8240286. Covance Laboratories Limited, November 2012.

6. Burke J and Scholey A. GSK1349572A: GSK 1349572A: Acute toxicity to Daphnia magna. Report No. 8204501. Covance Laboratories Limited, November 2010.

7. Burke J. Chronic effects of GSK1349572A to Daphnia magna. Report No. 8236107. Covance Laboratories Limited, April 2012.

8. Burke J, Jakes M and Goodband T. Fish Early Life Stage Test (Pimephales promelas) with GSK1349572A. Report No. 8240288. Smithers Viscient Limited, November 2012.

9. Last G and Goodband T. GSK1349572A: Sediment-Water Chironomus riparius Toxicity Test using Spiked Sediment. Report No. 8252363. Smithers Viscient Limited, November 2012.

10. Graham R and Alderman D. GSK1349572A: Assessment of Inherent Biodegradability by Measurement of Carbon Dioxide Evolution with Specific Analysis. Report No. 8204497. Covance Laboratories Limited, October 2010.

11. Dixon K and Fletcher T. [14C]-GSK1349572A: Degradation in Water-Sediment Systems under Aerobic Conditions. Report No. 8240289. Smithers Viscient Limited, June 2012.

12. Muddiman KJ. GSK1349572A: Acute toxicity to the earthworm Eisenia fetida. Report No. 8252367. Smithers Viscient Limited, July 2012.

13. Muddiman KJ. GSK1349572A: Determination of the Effects on Reproduction of the Collembolan Folsomia candida. Report No. 8252368. Smithers Viscient Limited, November 2012.

14. Schöbinger U. Effects of GSK1349572A on the Activity of the Soil Microflora - Nitrogen Transformation Test. Report No. S11-03815. Eurofins Agricultural Services, November 2012.

15. Muddiman KJ. GSK1349572A: Seedling Emergence and GrowthTest. Report No. 8252366. Smithers Viscient Limited, November 2012.

16. Dixon K and Fletcher T. [14C]-GSK1349572A: Aerobic Soil Metabolism and Degradation. Report No. 8252364. Smithers Viscient Limited, September 2012.