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 = 0.000105864 µg/L

Where:

A = total actual API sales in Sweden for the most recent year 0.77272888 kg (total sold amount API in the most recent sales data for Sweden (2022) was distributed by IQVIA in 2023)

R = 0

P = number of inhabitants in Sweden = 10 *10⁶

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

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (guideline e.g. OECD 201) [Reference II]

EγC₅₀ 72 h (yield) > 0.77 µg/L

NOECγ (yield) ≥ 0.77 µg/L

E_rC₅₀ 72 h (growth) > 0.77 µg/L

NOEC_r (growth) ≥ 0.77 µg/L

Crustacean (Daphnia magna) (water-flea):

Acute toxicity

Not available.

Chronic toxicity

Reproduction test with water-flea (Daphnia magna) (OECD 211) [Reference III]:

NOEC 21 days (endpoint: mortality) ≥ 4.7 µg/L

Fish:

Acute toxicity

Not available.

Chronic toxicity

Fish early life stage test with zebra fish (Brachydanio rerio) (OECD 210) [Reference IV]:

NOEC 28 days (endpoint: mortality) ≥ 4.1 µg/L

Other ecotoxicity data:

Activated sludge respiration inhibition test (OECD 209) [Reference IX]

EC₅₀ 3h > 1000 mg/L

NOEC 3h ≥ 1000 mg/L

PNEC (µg/l) = lowest NOEC/10, where 10 is the assessment factor used. NOEC for the green alga Pseudokirchneriella subcapitata of 0.77 µg/L has been used for this calculation since it is the most sensitive of the three tested species.

PNEC = 0.77 µg/L/10 = 0.077 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000105864 /0.077 = 0.00137485528 i.e. PEC/PNEC ≤ 0.1

The calculated PEC/PNEC ratio is ≤ 0.1. Hence, risk assessment procedures would indicate that bedaquiline would have insignificant long-term risk to the environment. However, the half-life in the environment is > 120 days, the BCF is > 2000 and the chronic toxicity is < 0.01 mg/L (NOEC). Bedaquiline should therefore be regarded as a PBT substance, according to ECHA Guidance criteria, and as such the current PEC/PNEC ratio may underestimate the potential for long-term risk to aquatic organisms.

Degradation

Biotic degradation

Ready degradability:

Bedaquiline was investigated for its ready biodegradation in a 28-day manometric respirometry test according to OECD 301F [Reference V]:

Result: Not readily biodegradable.

Inherent degradability: -

Simulation studies:

Aerobic degradation in aquatic sediment systems:

Bedaquiline was investigated for its aerobic degradation in a 100-day aquatic sediment test, according to OECD 308 [Reference VI]:

The rates of dissipation (DT₅₀ and DT₉₀) of bedaquiline from the water phase and the entire system were calculated using first order kinetics:

System	Water		Total system
	DT50 (Days)	DT90 (Days)	DT50 (Days)	DT90 (Days)
River	2.7	9.0	257	>1 year
Pond	2.3	7.7	163	>1 year

In aerobic aquatic sediment systems, bedaquiline rapidly dissipated from the water phase by adsorption to the sediment. Once in the sediment, bedaquiline was slowly degraded and formation of bound residues was observed.

Conclusion for degradation: Bedaquiline is potentially persistent.

Abiotic degradation

Hydrolysis: -

Photolysis: -

Bioaccumulation

Partition coefficient octanol/water:

The partition coefficient octanol/water was determined using the shaking flask method. [Reference VII] log D_ow = 2.93 (pH = 3)

Bioconcentration factor (BCF):

The bioconcentration and depuration characteristics of bedaquiline in the rainbow trout in a flow through system were examined according to OECD 305 [Reference VIII].

BCF_low dose = 1433

BCF_high dose = 2049

The BCF value of the high dose indicates that bedaquiline bioconcentrates in the rainbow trout.

Conclusion for bioaccumulation: Bedaquiline has high potential for bioaccumulation.

Excretion (metabolism)

-

PBT/vPvB assessment

	PBT-criteria	Results for BDQ
Persistence	Half-life in freshwater: DT50 > 40 days Half-life in sediment: DT50 > 120 days	DT50,river = 2.7 days DT50,system = 257 days
Bioaccumulation	BCF > 2000	BCF = 1433 (low dose) and 2049 (high dose)
Toxicity	Chronic NOEC < 10 µg/L	NOECalgae = 0.77 µg/L NOECdaphnia = 4.7 µg/L NOECfish = 4.1 µg/L

Conclusion for PBT-assessment:

According to the established EU-criteria bedaquiline should be regarded as a PBT substance.

References

1. 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 

2. Peither A., TMC207 (R403323) – Toxicity to Pseudokirchneriella subcapitata in a 72-hour algal growth inhibition test; Harlan Laboratories Study C29660; TMC207-TiDP13-NC214; December 14, 2010.

3. Peither A., Effect of TMC207 (R403323) on survival and reproduction of Daphnia magna in a semi-static test over three weeks; Harlan Laboratories Study C29682; TMC207-TiDP13-NC215; December 14, 2010.

4. Peither A., Toxic effects of TMC207 (R403323) to zebra fish (Brachydanio rerio) in an early-life stage toxicity test; Harlan Laboratories Study C29693; TMC207-TiDP13-NC216; December 14, 2010.

5. Memmert U., Ready biodegradability of TMC207 (R403323) in a manometric respirometry test; Harlan Laboratories Study C29750; TMC207-TiDP13-NC219; July 7, 2009.

6. Mégel V., 14C-TMC207 – Route and rate of degradation in aerobic aquatic sediment systems; Harlan Laboratories Study C29636; TMC207-TiDP13-NC211; May 11, 2010.

7. Habeck C., TMC207 (R403323) – Determination of the partition coefficient (n-octanol/water); Harlan Laboratories Study C29748; TMC207-TiDP13-NC218; November 3, 2009.

8. Kenner O., Bioconcentration of 14C-TMC207 – Flow-through test in the rainbow trout (Onchorhynchus mykiss); Harlan Laboratories Study C29704; TMC207-TiDP13-NC217; August 17, 2010.

9. Memmert U., Toxicity of TMC207 (R403323) to activated sludge in a respiration inhibition test; Harlan Laboratories Study C29658; TMC207-TiDP13-NC213; June 19, 2009.