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 = 2.89 x 10^-6 μg/L = 0.00289 ng/L

Where:

A = 0.01925 kg (total sold amount API in Sweden year 2018, 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 = 9 *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 (Scenedesmus subspicatus):

IC50 96h (growth) > 100,000 μg/L (OECD 201) (Reference 3)

NOEC = 100,000 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 1,070,000 μg/L (OECD 202) (Reference )

Water flea:

Chronic toxicity

No data

Rainbow Trout (Oncorhyncus mykiss):

Acute toxicity

LC50 96 h (lethality) > 100,000 μg/L (OECD 203) (Reference 4)

Fish:

Chronic toxicity

No data

Other ecotoxicity data:

Microorganisms in activated sludge:

EC50 3 h (inhibition) > 1,000,000 μg/L @ 3 hrs (OECD 209) (Reference 6)

PNEC = 100,000/1,000 = 100 μg/L

PNEC (ug/L) = lowest EC50/1000, where 1000 is the assessment factor applied for three acute-term EC50s. The EC50 for alga and fish are greater than values and therefore the Algal NOEC 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 = 2.89 x 10^-6 μg/L /100 μg/L = 2.89 x 10^-8, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of nelarabine has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

No data

Inherent degradability:

40% ultimate (DOC removal) degradation in 14 days (OECD 302). (Reference 5)

100% primary (parent removal) degradation in 14 days (OECD 302).

Soil degradation

22.62% - 30.41% degradation in 64 days (TAD 3.12). (Reference 8)

Abiotic degradation

Hydrolysis:

Half-Life at pH 7, 9.5 Hours (FDA TAD 3.09) (Reference 4)

Half-Life at pH 5, 21.3 Days

Half-Life at pH 9, 3.5 Hours

Photolysis:

No data

Justification of chosen degradation phrase:

Nelarabine is not readily degradable or inherently degradable. The phrase “Nelarabine is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log Pow < 1 (OECD 107) (Reference 7)

Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, the substance has low potential for bioaccumulation.

Excretion (metabolism)

The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolysed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid. Nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutes and 3 hours, respectively.

Nelarabine and ara-G are partially eliminated by the kidneys. In 28 adult patients, 24 hours after nelarabine infusion on day 1, mean urinary excretion of nelarabine and ara-G was 5.3 % and 23.2 % of the administered dose, respectively. Renal clearance averaged 9.0 l/h/m2 (151 %) for nelarabine and 2.6 l/h/m2 (83%) for ara-G in 21 adult patients. Because the timecourse of intracellular ara-GTP was prolonged, its elimination half-life could not be accurately estimated (Reference 2).

PBT/vPvB assessment

Nelarabine 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). Nelarabine does not fulfil the criteria for PBT and/or vBvP based on log Pow < 4.

References

• ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

• Pharmacokinetic properties: Meatbolism and Elimination. Summary of Product Characteristics Atriance (Nelarabin) 5mg/ml solution for infusion. GlaxoSmithKline, June 2013.

• Manson PS. 506U78: Inhibition of Growth to the Alga Selenastrum capricornutum Report No. 1990/375. Covance Laboratories Limited, July 2004.

• Manson PS. 506U78: Acute toxicity to Oncorhynchus mykiss. Report No. 1990/374. Covance Laboratories Limited, July 2004.

• Muth H. 506U78: Evaluation of the Anitmicrobial Effectiveness of 506U78 Injection, 5mg/mL. Report No. RD1999/00083/00. Glaxo Wellcome Research and Development, May 1999.

• Burwood C. 506U78: Assessment of inherent biodegradability by measurement of dissolved organic carbon elimination Report No. 1990/400. Covance Laboratories Limited, July 2004.

• Material Safety Data Sheet for Nelarabine. SDS number 123572. GlaxoSmithKline plc, May 2013.