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 = 0.086 μg/L

Where:

A = 573.23 kg (total sold amount API in Sweden year 2016, derived from free base and hydrochloride salt forms, data from Quintiles IMS). Reduction of A may be justified based on metabolism data.

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 (Pseudokirchneriella subspicata):

LOEC 72 h (growth rate) = 1.76 μg/L (OECD 201) (Reference 6)

NOEC = 0.53 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 350 μg/L (OECD 202) (Reference 10)

NOEC = 180 μg/L

Water flea (Daphnia magna):

Chronic toxicity

LOEC 21 days (reproduction) = 14 μg/L (OECD 201) (Reference 5)

NOEC = 5.50 μg/L

Rainbow Trout (Oncorhynchus mykiss)

Acute toxicity

EC50 96 h (lethality) = 1,010 μg/L (OECD 204) (Reference 13)

NOEC = 220 μg/L

Fathead minnow (Pimephales promelas)

Chronic toxicity

LOEC 32 days (reproduction) = 11,000 μg/L (OECD 201) (Reference 5)

NOEC = 47 μg/L

Other ecotoxicity data:

Microorganisms in activated sludge

IC50 3 h (Inhibition) > 100,000 μg/L (OECD 209) (Reference 9)

IC20 > 100 mg/L

The PNEC is based on the following data:

PNEC (µg/l) = lowest chronic NOEC / 10, where 10 is the assessment factor used.

A NOEC of 0.53 μg/l for green algae has been used for this calculation.

PNEC = 0.53 µg/L /10 = 53 ng/l

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for green algae (= 0.53 µg/L) 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 = 0.086/0.053 = 1.62, i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of terbinafine has been considered to result in moderate environmental risk.”

Environmental fate studies:

Degradation:

Degradation: 4% (aerobic, 28d, 20-24°C, OECD 301B) not readily biodegradable (Reference 11)

Transformation of test item in aerobic/water/sediment systems (OECD308, 101 days),

Degradation - DT50 (freshwater phase) = 3-8 days DT50 (total system) = 16-31 days (Reference 8).

Ultimate Biodegradation = 19.5% - 27.30%

Average of parent in % (total system) at day 101 = 5.2-7.1%

Extraction was done up to four times with ethanol. Method is acceptable as during work-up of day 0 sample <2% bound residues were determined.

The DT50 32 days therefore the phrase ‘The substance is degraded in the environment’ is chosen.

Justification of chosen degradation phrase:

Terbinafine is not readily biodegradable. In water sediment systems the DT50 for the total system is ≤ 32 days. Therefore the phrase ‘The substance is degraded in the environment’ is thus chosen.

Excretion/ Metabolism

Terbinafine is metabolised rapidly and extensively by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C9. Metabolisation follows 3 pathways: N-demethylation, allyl side-chain oxidation and aromatic ring oxidation. Biotransformation results in metabolites with no antifungal activity, which are excreted predominantly in the urine. No unchanged drug is recovered in the urine. (Reference 12)

Accumulation

Bioaccumulation: High Potential to bioaccumulate

BCF calculated: 5248 (Reference 2)

Partition Coefficient: log Kow 5,2 (22.0 °C, OECD107) (Reference 11)

Justification of chosen bioaccumulation phrase:

Since log Kow > 4, the substance has high potential for bioaccumulation.

Adsorption

Adsorption to sludge: Koc = 3346-4694 mL/g (2 sludges, OECD106) (Reference 7)

Adsorption to sludge = 88 - 90 %

Phys.chem. Properties:

Water Solubility: 4.83 g/L (25°C, OECD105)

PBT/vPvB assessment

Terbinafine 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). Terbinafine does not fulfil the criteria for PBT and/or vBvP based on degradation < 40 days.

References

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

2. Veith, G.D., DeFoe, D.L. and Bergstedt, B.V., 1979. Measuring and estimating the bioconcentration factor of chemicals on fish.

3. Journal of Fischeries Research Board of Canada, 36, 1040-1048.

4. Hamilton, M. SFO327 Terbinafine Hydrochl./DS 04: Early Life-StageToxicity Test with Fathead Minnow (Pimephales promelas), under flow-through conditions. Report Number 1096.004.122. Springborn Smithers Laboratories, November 2008.

5. Hamilton, M. SFO327 DS (Terbinafine Hydrochl./DS 04): Chronic reproduction test with daphnids (Daphnia magna) under flowthrough conditions. Report Number 1096.004.230. Springborn Smithers Laboratories, November 2008.

6. Beister, MA. SFO327 DS (Terbinafine Hydrochl./DS 04): Alga, growth inhibition test with Pseudokirchneriella subcapitata (syn. Selenastrum capricornutum) under static conditions. Report Number 1096.004.430, Springborn Smithers Laboratories, January 2009.

7. Van de Kolk, J. [14C] SF0327 DS: Adsorption/Desorption on 3 Soils and 2 Sludges using a Batch Equilibrium Method. Report Number 1094.004.712. Springborn Smithers Laboratories, August 2008

8. Hamilton, M. [14C] SF0327 DS: Aerobic Transformation in Aquatic Sediment Systems. Report Number 1096.004.750. Springborn Smithers Laboratories, December 2008.

9. Hoffmann, J. Test for Inhibitory Concentration on Aerobic Bacteria of Terbinafin-CH. Report Number 918218. Ciba-Geigy, November 1991.

10. Vial, A. Acute Toxicity Test of Terbinafin-CH on Daphnia. Report Number 918234. Ciba-Geigy, May 1992.

11. Material Safety Data Sheet for Lamicosil Cutaneous Solution. GlaxoSmithKline, April 2018.

12. Novartis Investigator’s Brochure Lamisil/SFO327M, S. Hauffe 2004