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 = 0.00137 μg/L

Where:

A = 1.0 – 10 kg (market forecast range for API in Sweden year 2021, data from GSK Manufacturing Strategy). The upper range, 10 kg, has been used in the PEC calculation.

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):

NOEC 96h (growth = 77 μg/L (OECD 201) (Reference 3)

Water flea (Daphnia magna):

Acute toxicity

No data

Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (development) = 92 μg/L (OECD 211) (Reference 4)

Rainbow Trout:

Acute toxicity

No data

Fathead Minnow (Pimephales promelas)

Chronic toxicity

NOEC 28 days (survival) = 95 μg/L (OECD 210) (Reference 5)

Other ecotoxicity data:

Chironomid (Chironomus riparius)

NOEC 28 days (reproduction) = 1,000,000 μg/kg (OECD 218) (Reference 6)

Microorganisms in activated sludge

EC50 3 hours (Inhibition) = 1,000,000 μg/L (OECD 209) (Reference 7)

PNEC = 77/10 = 7.70 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for alga (= 77ug/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 = 0.00137/7.7 = 1.78 x 10^-4, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of cabotegravir 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 8)

27% primary degradation of parent API in 28 days

This substance is not inherently biodegradable.

Simulation studies:

Water-sediment study:

Total System: 50% (DT₅₀) dissipation = 1.25 – 6.62 days (OECD 308) (Reference 9)

Total Parent Extracted at Day 100 = 1.0% – 2.2%

Non-extractable residue at Day 100 = 80.80% - 99.10%

Extraction and non-extractable methods

For the Calwich Abbey Lake and Emperor Lake aquatic sediment systems, it was considered that all reasonable efforts were made to extract the radioactivity from the sediments. For the Calwich Abbey Lake sediment most of the radioactivity was associated with the humin (82.1% AR) fraction, as characterised at day 61. For the Emperor Lake sediment most of the radioactivity was associated with the fulvic acid (25.8% AR) and humin (62.3% AR) fractions, as characterised at day 61.

The sediment samples were extracted with a series of solvents as follows:1. Ethanol at Time zero and Day 1; 2. Methanol  for All samples; 3. Methanol Day 7, 14, 30, 61 and 100. All extractions were conducted at ambient temperature. Approximately 200 mL of solvent was used for each extraction. Extractions were carried out by sonication for 15 minutes followed by shaking for 15 minutes at ambient temperature. The extract solution and sediment solids were separated by centrifugation at 3000 rpm for 15 minutes at ambient temperature. Duplicate weighed aliquots (1 mL) of each extract solution were taken for radio-assay. For the Day 1, 7, 14 and 30 sediment residues, further harsh extractions using acidic solvent mixtures (i.e. methanol/HCl, 1/1, v/v, either 1 or 5 M of HCl) were conducted. The radioactivity recovered using the harsh extractions are reported with the non-extractable residues.

The non-extractable radioactivity in the samples taken at 61 days was characterized using anacid/base fractionation procedure. A sub-sample (25 or 50 g) of the sediment residue was extracted with 0.5 M sodium hydroxide (3 mL per g of sediment debris) by shaking on an orbital shaker for 24 – 36 hours at ambient temperature. The residue was separated by centrifugation and the supernatant removed. The residue was washed with 0.5 M sodium hydroxide (1 mL per g of sediment debris) and allowed to air-dry. This debris, the humin fraction, was air dried, weighed and triplicate weighed portions (approximately 0.3 g) taken for combustion and LSC. 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 (1 mL per g of sediment residue) and the supernatant combined with these washings.

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

Cabotegravir is not readily biodegradable nor inherently biodegradable. This substance is predicted to disappear and not be bioavailable in water sediment systems ≤ 32 days. According to Fass guidance the DT50 collectively represents the loss of parent from the test system due to its biological or chemical transformation, mineralization and/or irreversible binding to sediments. Non-extractable residues represent 80.80%-99.0% of the total parent material and in accordance with Fass guidance this represents the loss of parent from the test system i.e. the parent is not bioavailable. The phrase “Cabotegravir is degraded in the environment” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Dow = 1.62 at pH 7 (OECD 107) (Reference 10)

Log Dow at pH 5 = 1.64

Log Dow at pH 7 = 1.62

Log Dow at pH 9 = 0.962

Bioconcentration:

BCF = 125.60 – 137.20 (OECD 305) (Reference 15)

Justification of chosen bioaccumulation phrase:

Since BCF is < 500, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Cabotegravir is primarily metabolised by UGT1A1 with a minor UGT1A9 component. Cabotegravir is the predominant circulating compound in plasma, representing > 90% of plasma total radiocarbon. Following oral administration in humans, cabotegravir is primarily eliminated through metabolism; renal elimination of unchanged cabotegravir is low (<1% of the dose). Forty-seven percent of the total oral dose is excreted as unchanged cabotegravir in the faeces. It is unknown if all or part of this is due to unabsorbed drug or biliary excretion of the glucuronide conjugate, which can be further degraded to form the parent compound in the gut lumen. Cabotegravir was observed to be present in duodenal bile samples. The glucuronide metabolite was also present in some, but not all, of the duodenal bile samples. Twenty-seven percent of the total oral dose is excreted in the urine, primarily as a glucuronide metabolite (75% of urine radioactivity, 20% of total dose).

Cabotegravir mean apparent terminal phase half-life is absorption-rate limited and is estimated to be 5.6 to 11.5 weeks after a single dose IM injection. The significantly longer apparent half-life compared to oral reflects elimination from the injection site into the systemic circulation. The apparent CL/F was 0.151 L/h. (Reference 2).

PBT/vPvB assessment

Cabotegravir 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). Cabotegravir does not fulfil the criteria for PBT and/or vBvP based on 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. Vocabria EPAR Product Information, European Medicines Agency, January 2021.

3. Vryenhoef, H.; GSK1265744B (Cabotegravir): Algal Growth Inhibition Test; Envigo Research Limited Study KX95FC; December 06, 2017.

4. Sacker, D.; GSK1265744B (Cabotegravir): Daphnia magna Reproduction Test; Envigo Research Limited Study PY80TX; May 04, 2018.

5. Sacker, D.; GSK1265744B (Cabotegravir): Fish, Early Life Stage Toxicity Test; Envigo Research Limited Study DH59FS; May 25, 2018.

6. Sacker, D.; GSK1265744B (Cabotegravir): Sediment-Water Chironomid Toxicity Test Using Spiked Sediment; Envigo Research Limited Study LS30FH; May 15, 2019.

7. Best, N.; GSK1265744B: Toxicity to Activated Sludge in a Respiration Inhibition Test; Envigo Research Limited Study 41502255; September 23, 2017.

8. Best, N.; GSK1265744B: Assessment of Inherent Biodegradability; Modified MITI (II) Envigo Research Limited Study 41502255; February 09, 2016.

9. Best, N.; Cabotegravir (GSK1265744B): Aerobic Transformation in Aquatic Sediment Systems; Envigo Research Limited Study LS30FH; February 09, 2016.

10. Tarran, D.A.; GSK1265744B (Cabotegravir): Determination of Partition Coefficient; Envigo Research Limited Study LS30FH; January 03, 2018.