Detaljerad miljöinformation

Detailed background information

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) = 1.37*10^-6 * 107.9739 * 100

PEC = 0.0148 μg/L

Where:

A = 107.9739 kg (total sold amount API in Sweden year 2021, 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 = 10 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus) (OECD201) (Ciba-Geigy Ecotoxicology Test No. 918247):

EC50 72 h (no information on endpoint available) > 100.0 mg/L

Crustacean (Daphnia magna):

Acute toxicity

EC50 48 h (immobilisation) = 20.2 mg/L (OECD202) (Ciba-Geigy Ecotoxicology Test No. 918248)

Fish:

Acute toxicity (Oncorhynchus mykiss, rainbow trout)

LC50 96 h (mortality) > 100.0 mg/L (OECD203) (Ciba-Geigy Ecotoxicology Test No. 918170)

Other ecotoxicity data:

Bacterial respiration inhibition

EC₅₀ 3h > 100.0 mg/L (activated sludge respiration inhibition) (OECD209) (Ciba-Geigy Ecotoxicology Test No. 918171)

PNEC derivation:

PNEC = 20.2 µg/L

PNEC (μg/L) = lowest EC₅₀/1000, where 1000 is the assessment factor used if three acute toxicity studies from three trophic levels are available. The immobilization of Daphnia magna has been used to derive the PNEC for ciclosporin.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0148 µg/L / 20.2 µg/L = 0.00073, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of ciclosporin has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

84.0 % degradation in 28 days, readily biodegradable (OECD301B). (Ciba-Geigy Ecotoxicology Test No. 918172)

Justification of chosen degradation phrase:

Ciclosporin has passed the criteria for ready biodegradation. Therefore, it can be classified as Ciclosporin is degraded in the environment.

Bioaccumulation

Partitioning coefficient:

Log P_ow = 2.92 (experimentally determined, measured in octanol/water by centrifugal partition chromatography) (El Tayar et. al. 1993)

Justification of chosen bioaccumulation phrase:

As the octanol/water partition coefficient of ciclosporin is below 4, the following statement is chosen: Ciclosporin has low potential for bioaccumulation.

Excretion (metabolism)

Ciclosporin is extensively metabolised to more than 15 metabolites. The main site of metabolism is the cytochrome P450-dependent mono-oxygenase system in the liver, and the main pathways of metabolism consist of mono- and dihydroxylation and n-demethylation at various positions of the molecule. All metabolites identified so far contain the intact peptide structure of the parent compound, some possess weak immunosuppressive activity (up to one-tenth that of the unchanged drug). Elimination is primarily biliary, with only 6% of an oral dose excreted in the urine and with less than 1% in the unchanged form. (Novartis Core Data Sheet Sandimmun^®)

PBT/vPvB assessment

Ciclosporin has been found to be readily biodegradable and can therefore not be considered a potential PBT or vPvB substance.

References

• ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

• Ciba-Geigy Ecotoxicology Test No. 918247                                                                                                                           

• Ciba-Geigy Ecotoxicology Test No. 918248                                                                                                     

• Ciba-Geigy Ecotoxicology Test No. 918170                                                                                                                           

• Ciba-Geigy Ecotoxicology Test No. 918171                                                                                                                           

• Ciba-Geigy Ecotoxicology Test No. 918172                                                                                                                           

• N. El Tayar et. al. 1993. Solvent-dependent conformation and hydrogen-bonding capacity of cyclosporin A: evidence from partition coefficients and molecular dynamics simulations. J. Med. Chem. 36, 3757-3764.

• Novartis Core Data Sheet Sandimmun^® (ciclosporin), Version 1.1. 05 August 2014.