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) = 1,5*10^-6*A(100-R)

PEC = 33,08 x 10^–7 (μg/L)

Where:

A = 0,02205 kg (total sold amount API in Sweden year 2018, data from IQVIA).

R = 0% removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available.

P = number of inhabitants in Sweden = 9 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ref. 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ref. 1)

Predicted No Effect Concentration (PNEC)

Data not available

Environmental risk classification (PEC/PNEC ratio)

Risk of environmental impact of brigatinib cannot be excluded, since there is not sufficient ecotoxicity data available.

Degradation

Environmental data on the degradation of brigatinib was assessed by the Drug Safety Research and Evaluation at Takeda Oncology. This was performed via a Manometric Respirometry Test with the aim to evaluate the ready biodegradability of brigatinib. Brigatinib was exposed to aerobic activated sludge from the aeration tank of a domestic waste water treatment plant for 28 days. This was followed by oxygen uptake of the microorganisms during exposure. Sodium benzoate was used as a control for comparison. The criterion for ready biodegradability under the conditions of a manometric respirometry test is the 10-day window, describing the period between reaching 10% degradation and 60% degradation. The period should not exceed 10 days. The test item brigatinib contains nitrogen, therefore the evaluation of biodegradation was evaluated on the theoretical oxygen demand of N03 (ThODNO3) based on the assumption that nitrification occurred and the theoretical oxygen demand of NH4 (ThODNH4) formed.

The mean biodegradation of brigatinib after 28 days was 0% (ThODNO3) and 0% (ThODNH4); the 10 day window failed. The degradation rate of brigatinib did not reach 60% within the 10 day window and/or after 28 days incubation; therefore it is not considered to be readily biodegradable (ref 3).

Bioaccumulation

Partitioning coefficient:

The partition coefficient (P_ow) of brigatinib between n-octanol and water was determined using the shake flask method (ref 4 & 5). According to the study, the logarithmic partition coefficient of the test item was determined to be: log Pow 1.62.

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

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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. Committee for Medicinal Products for Human Use (CHMP), 2011. Questions and

answers on ‘Guideline on the environmental risk assessment of medicinal products for human use’ (EMA/CHMP/SWP/44609/2010, 17 March 2011).

3. IBACON Project 96711163: Ready Biodegradability in a Manometric Respirometry Test (company data 2018)

4. Alunbrig EPAR, 20 September 2018.

5. IBACON Project 9676711186: Determination of the Partition Coefficient (n-octanol / water) (company data 2018).