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)

PEC = 0.000131 μg/L = 0.131 ng/L

Where:

A = 0.9555 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 (Pseudokirchneriella subcapitata) (OECD 201) (Harlan Laboratories Study D53915):

EC₁₀ 72 h (growth rate) = 1.9 µg/L

NOEC 72 h (growth rate) = 1.5 µg/L

Crustacean (Waterflea, Daphnia magna):

Acute toxicity

EC50 48 h (immobilisation) > 8.0 mg/L, maximum testing concentration due to the substance’s water solubility limit (92/69/EC (L383) C.2) (NOTOX Study No. 246768)

Chronic toxicity

NOEC 21 days (growth, body length) = 0.014 μg/L (OECD 211) (Harlan Laboratories Study C65478)

Fish (Zebrafish, Danio rerio):

Acute toxicity

LC50 96 h (lethality) > 18.4 mg/L, maximum testing concentration due to the substance's water solubility limit (92/69/EEC (L383) C1) (NOTOX Study No. 306113)

Chronic toxicity

NOEC 35 days (survival of larvae and juvenile fish, body length, body wet weight) = 2.1 μg/L (OECD 210) (Harlan Laboratories Study C65467)

Other ecotoxicity data:

Bacterial respiration inhibition (activated sludge microorganisms)

EC₂₀ 3 h > 1000.0 mg/L (87/302/EEC, Part C), (Ecotox Test No. G550 05)

Sediment-dwelling organisms (Chironomus riparius, non-biting midge)

NOEC 28 days (development rate of female midges) = 2.5 mg/kg (OECD 218) (Harlan Laboratories Study D45714)

PNEC = 0.014 μg/L / 10 = 0.0014 µg/L = 1.4 ng/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor used, if chronic toxicity values for 3 trophic levels are available. NOEC from Daphnia magna reproduction study (OECD 211) 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 = 0.131 ng/L / 1.4 ng/L = 0.0935, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of everolimus has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

2.0 % degradation in 28 days, not readily biodegradable (92/69/EC (L383) C.4-D). (Ecotox Test No. G 550 06)

Transformation in water-sediment systems:

DT50 in total system = 2.0 – 3.1 days (OECD 308). (Harlan Laboratories Study C67572)

Study duration: 103 days; <15% of parent in both total systems at the end of the study

Bound residues are considered as not bioavailable (sediment extraction: 4x with acetonitrile/water 4:1, 1x Soxhlet extraction using acetonitrile/water (4:1; v/v))

Justification of chosen degradation phrase:

According to the classification scheme proposed for the OECD308 studies in the update of the 'Environmental classification of pharmaceuticals at www.fass.se - Guidance for pharmaceutical companies' of 2012, everolimus can be classified as ‘Everolimus is degraded in the environment'.

Bioaccumulation

Bioconcentration factor (BCF):

Steady state BCF = 23 (plateau level at 10-14 days) (OECD 305). (Harlan Study Number D58696)

Partitioning coefficient:

Log Kow = 4.0 (92/69/EC (L383) A.8). (NOTOX Study No. 255667)

Justification of chosen bioaccumulation phrase:

Since BCF < 500, everolimus has low potential for bioaccumulation.

Excretion (metabolism)

Everolimus is extensively metabolised and elimination is essentially in the form of everolimus metabolites in the bile. Elimination half-life in cancer patients averaged 30 hours, which is similar to that in healthy subjects. After a single dose of [¹⁴C]everolimus in renal transplant patients, the majority (80%) of radioactivity was recovered in the faeces, only a minor amount (5%) was excreted in the urine over the 10-day collection period. Parent drug was not detected in urine and faeces.  (Novartis Core Data Sheet for AFINITOR (everolimus), Version 2.7, 17 June 2016)

PBT/vPvB assessment

Everolimus does not fulfil the criteria for persistence and bioaccumulation potential and can therefore not be regarded as 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

• Harlan Laboratories Study D53915. Everolimus BHT/DS 01. Toxicity to Pseudokirchneriella subcapitata in a 72-hour algal growth inhibition test. Final Report: 17 August 2012.

• NOTOX Study No. 246768. Acute toxicity study in Daphnia magna with RAD001 (static). Final report: 26. March 1999.

• Harlan Laboratories Study C65478. Effect of Everolimus BHT/DS 01 on survival, growth and reproduction of Daphnia magna in a semi-static test over three weeks. Final report: 18 January 2011.

• NOTOX Study No. 306113. 96-hour acute toxicity study in carp with RAD001 (static). Final report: 05. December 2000.

• Harlan Laboratories Study C65467 Everolimus BHT/DS 01: Toxic effects to zebra fish (Brachydanio rerio) in an early-life stage toxicity test. Final report: 28 February 2011.

• Ecotox Test No. G 550 05. Bacteria toxicity of RAD N BHT (Activated sludge respiration inhibition test). Final Report: 20 October 1998.

• Harlan Laboratories Study D45714. Everolimus BHT/DS 01: Effects on the development of sediment-dwelling larvae of Chironomus riparius in water-sediment systems with spiked sediment. Final Report: 18 June 2012.

• Ecotox Test No. G 550 06. Ready biodegradability of RAD001 N BHT (Manometric respirometry test). Final Report: 16 October 1998.

• Harlan Laboratories Study C67572. [¹⁴C]Everolimus BHT/DS 01: route and rate of degradation in aerobic aquatic sediment systems. Final Report: 17 February 2012.

• Harlan Study Number D58696. [¹⁴C]Everolimus: Bioconcentration flow-through test in the rainbow trout (Oncorhynchus mykiss). Final Report: 07 March 2013.

• NOTOX Study No. 255667. Determination of the partition coefficient (n-octanol/water) of RAD001. Final Report: 14 July 1999.

• Novartis Core Data Sheet for AFINITOR (everolimus), Version 2.7, 17 June 2016