Detaljerad miljöinformation

(Läs mer om detaljerad miljöinformation, riktad till experter, på engelska)

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 = 3.3*10^-5 μg/L

Where:

A = 0.2391 kg (total sold amount API in Sweden year 2021, data from IQVIA). Reduction of A may be justified based on metabolism data.

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

P = number of inhabitants in Sweden = 10 *10⁶

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

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

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of melphalan is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) at the time of registration was below the action limit 0.01 µg/L.

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Water flea, Daphnia magna:

EC₅₀ 48h > 10 000, ug/L (OECD 202)

Microorganisms in activated sludge:

EC₅₀ > 100 000, ug/L @ 3 hrs (OECD 209)

Since enough ecotoxicity data of relevance for the PNEC calculation is not available, the statement “Risk of environmental impact of melphalan cannot be excluded, since no ecotoxicity data are available” is used.

In Swedish: “Risk för miljöpåverkan av melfalan kan inte uteslutas då ekotoxikologiska data saknas” under the heading “Miljörisk”.

Environmental risk classification (PEC/PNEC ratio)

There is not enough data available to calculate PEC/PNEC ratio.

Degradation

There is no biodegradation data to assess persistence according to the fass.se guidelines. However, given the rapid hydrolysis rate (DT50 < 24 hrs) and the fact that melfalan is extensively metabolised, it is unlikely that biodegradation data on the drug substance will be relevant in assessing persistence. Rather than regarding the drug substance as potentially persistent it would be more appropriate to regard this substance as non-persistent while metabolic and hydrolysis products could be potentially persistent.

There is not sufficient data available concerning the biodegradability of melphalan, thus the phrase “The potential for persistence of melphalan cannot be excluded, due to lack of data” is assigned.

In Swedish: “Det kan inte uteslutas att melfalan är persistent, då data saknas” under the heading “Nedbrytning”.

Abiotic degradation

Compound is hydrolytically unstable (2).

Measured half-life is:

4.9 hr at pH5.

4.8 hr at pH7.

3.9 hr at pH9.

Bioaccumulation

There is no significant bioaccumulation potential. Log D_ow = -0,52 at pH7.4. (1)

Since the experimental Log D_ow < 4 for melphalan, the phrase “Melphalan has low potential for bioaccumulation” is assigned.

In Swedish: ”Melfalan har låg potential att bioackumuleras” under the heading ”Bioackumulering”.

Excretion (Metabolism)

Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. No other metabolites have been observed in humans. 10 to 15% of an administered dose is excreted unchanged. Absorption is incomplete and variable. 20 to 50% of a dose is excreted in the faeces. (3).

Other Hazard Notation

The compound is considered a carcinogen (R45), a mutagen (R46) and a reproductive hazard (R60,61).

References:

1. Selassie, CD et al; J med Chem 33: 1914-1919 (1990).

2. Flora, K.P., Smith, S.L., Cradock, J.C., Journal of Chromatography, 177 (1979) 91-97.

3. Goodman & Gilman, The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw-Hill, 2001.