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) = 1.37*10^-6*A*(100-R) = 0.0886 μg/L

Where:

A = 996.51 kg (total sold amount API in Sweden year 2023, data from IQVIA / LIF)

R = 35.11 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10 *10⁶

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

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (green algae, Raphidocelis subcapitata):

NOEC 72 hours (growth rate) = 53 µg/L, EC₅₀ 72 hours (growth rate) = >950 µg/L. Guideline OECD 201. (Reference II)

Crustacean (waterflea, Daphnia magna):

Acute toxicity

EC₅₀ 48 hours (immobilization) = 3100 µg/L. Guideline FDA TAD 4.08. (Reference III)

EC₅₀ 48 hours (immobilization) = 830 µg/L. Guideline OECD 202. (Reference IV)

Chronic toxicity

NOEC 21 days (reproduction) = 78 µg/L. Guideline OECD 211. (Reference V)

Fish (Bluegill sunfish, Lepomis macrochirus)

Acute toxicity

LC₅₀ 96 hours (mortality) = 820 µg/L. Guideline FDA TAD 4.11. (Reference VI)

LC₅₀ 96 hours (mortality) = 382 µg/L. Guideline OECD 203. (Reference VII)

Fish (Rainbow trout, Oncorhynchus mykiss)

Acute toxicity

LC₅₀ 96 hours (mortality) = 325 µg/L. Guideline OECD 203. (Reference VIII)

Fish (Fathead minnow, Pimephales promelas)

Chronic toxicity

NOEC 28 days (hatching success, survival, growth, length, dry weight) = 84 µg/L. Guideline OECD 210. (Reference IX)

Sediment dwelling organism (Midge larvae, Chironomus riparius)

NOEC 28 days (emergence, development rate) = 80 mg/kg. Guideline OECD 218. (Reference X)

Activated sludge microorganisms

NOEC 3 hours (respiration inhibition) = >1000 mg/L. Guideline OECD 209. (Reference XI)

The PNEC was calculated by division of the lowest effect level (NOEC) of the most sensitive taxonomic group considering an appropriate assessment factor (AF). The most sensitive taxonomic group were algae and the lowest effect level was reported as NOEC = 53 µg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, crustaceans, and fish).

PNEC = 53 µg/L / 10 = 5.3 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.0886 µg/L / 5.3 µg/L = 0.02.

Justification of chosen environmental risk phrase:

A risk quotient of ≤ 0.1 qualifies for the phrase “Use of loratadine has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

In a study on the aerobic biodegradability in water a mixed microbial inoculum from soil and sewage treatment plant secondary effluent was exposed to ¹⁴C-loratadine at 0.102 mg/L in the dark at 22 ± 3ºC for 28 days.  Prior to the test the microbial inoculum was adapted to loratadine for a period of 13 days.  The test substance, reference substance (¹⁴C-glucose) and blank control were tested in triplicate.  Evolved ¹⁴CO₂ was measured at sixteen timepoints during the exposure period.  The study reported 0.1% biodegradation in 28 days, loratadine was not readily biodegradable. Guideline FDA TAD 3.11. (Reference XII)

Simulation studies:

A simulation test to assess the aerobic biodegradability in activated sludge according to OECD 314B was performed using ¹⁴C-loratadine. Single replicate test vessels per timepoint were prepared for the biotic, abiotic and positive control treatments and maintained in the dark at 20 ± 2ºC for 28 days.  500 mL of sludge inoculum obtained from a wastewater treatment plant dealing primarily with domestic sewage was used (the inoculum for the abiotic treatment was sterilised prior to use).  The biotic and abiotic test vessels were dosed with ¹⁴C-loratadine at approximately 0.50 mg/L. The positive control was dosed with ¹⁴C-sodium benzoate at approximately 1.0 mg/L. A flow-through system with trapping solutions was used during the incubation to capture any evolved ¹⁴CO₂ and/or volatiles. Samples were analysed at 0, 1, 3, 7, 14, 21 and 28 days after application. Sludge test solutions and trapping solutions were analysed directly by liquid scintillation counting (LSC).  Sludge extracts were analysed by liquid scintillation counting (LSC) and high performance liquid chromatography with radiochemical detection (radio-HPLC) to determine the amount of ¹⁴C-loratadine and quantify any transformation products.

The mass balance was >90.4% applied radioactivity (% AR) throughout the exposure period.  In both the biotic and abiotic systems there was minimal evolution of ¹⁴CO₂ and/or volatiles throughout the incubation period (≤0.4% AR). There was no observable primary degradation of ¹⁴C-loratadine in the abiotic system, while in the biotic system there was evidence with ¹⁴C-loratadine concentrations declining steadily to 38% AR after 28 days.  Two additional regions of radioactivity were detected with the first peaking at 8.4% AR on day 14 and the second peaking at 38.7% AR on day 21.  This study reported a primary degradation half-life for loratadine DT₅₀ = 20.32 days and an overall elimination rate constant k_e of 0.0341 days^-1. Guideline OECD 314B. (Reference XIII)

A further test was conducted considering the degradation of ¹⁴C-loratadine in water-sediment systems according to OECD 308. ¹⁴C-loratadine was applied to the water phase of two sediment/water systems with differing properties at approximately 0.5 mg/L and incubated in the dark at 20 ± 2ºC for 102 days. Duplicate samples were analysed at 0, 3, 14, 28, 56 and 102 days after application. A flow-through system with trapping solutions was used during the incubation to capture any evolved ¹⁴CO₂ and/or volatiles.  The water and sediment extracts were analysed by LSC and radio-HPLC to determine the amount of ¹⁴C-loratadine and quantify any transformation products. Sediment-bound residues were determined by oxidative combustion followed by LSC while trapping solutions were analysed directly by LSC.

The mass balance was >91.3% AR throughout the exposure period.  After 14 days the majority of radioactivity was associated with the sediment phase and at the end of incubation bound residues were at 16.3 ‑ 20.2% AR.  There was minimal evolution of ¹⁴CO₂ and volatiles throughout the incubation period (<1% AR).  Concentrations of ¹⁴C-loratadine declined slowly in the water-sediment systems with evidence of transformation products formation but combined they represented less than 10% AR.  This study reported a half-life of loratadine in water DT₅₀ = 13 - 20 days and in the total system DT₅₀ = 217 – 301 days. Guideline OECD 308. (Reference XIV)

Abiotic degradation

Hydrolysis:

This study reported the substance was hydrolytically stable. Guideline FDA TAD 3.09. (Reference XV)

Photolysis:

This study reported a DT₅₀ = 8.2 - 13.6 days. Guideline FDA TAD 3.10. (Reference XVI)

SimpleTreat modelling – elimination in sewage treatment plants

The SimpleTreat model (v4.1) was used to estimate the fraction of loratadine that is retained in sewage treatment plant and does not enter the surface water compartment. The calculation was based on experimental physico-chemical data of loratadine. Molecular weight: 382.9 g/mol, octanol-water partition coefficient (K_OW): 213.8 at pH 7, vapour pressure: <1.17 x 10^-4 Pa at 24°C, water solubility: 1.45 mg/L at pH 7 and 25°C, sludge organic carbon partition coefficient (K_OC): 3911 and biodegradation: none. (Reference XVII to XXI)

Justification if R does not equal 0, modelling results using SimpleTreat:

SimpleTreat calculated the release to surface water after sewage treatment as 64.89%, i.e., 35.11% was eliminated due to by sorption to sludge while there was no emission to air. The PEC calculation was refined taking account of this elimination.

Justification of chosen degradation phrase:

Loratadine is hydrolytically stable, not readily biodegradable with a whole water/sediment system DT₅₀ > 120 days, which qualifies for the phrase “Loratadine is potentially persistent.”

Bioaccumulation

Partitioning coefficient:

The octanol/water partition coefficient (Kow) was established using ¹⁴C-loratadine and the shake-flask method at 25^oC. Octanol and water concentrations were measured by LSC and Kow was determined at two concentrations and three pH levels (5, 7 and 9).

The log D_ow was reported as 2.33 at pH 7. Guideline FDA TAD 3.02. (Reference XVII)

Justification of chosen bioaccumulation phrase:

As the log D_ow was < 4 loratadine is not considered bioaccumulative which qualifies for the phrase “Loratadine has low potential for bioaccumulation.”

Excretion (metabolism)

Loratadine is metabolized to the active molecule desloratadine, excretion occurs mainly in the metabolized form (conjugated).

References

1. Technical Guidance for Deriving Environmental Quality Standards (EQS). 2011. Common Implementation Strategy for the Water Framework Directive (2000/60/EC). Guidance Document No. 27. European Commission. Technical Report – 2011 – 055. ISBN: 978-92-79-16228-2.

1. Loratadine - 72-Hour Acute Toxicity Test with Freshwater Green Alga, Pseudokirchneriella subcapitata, following OECD Guideline 201, Smithers Viscient Study no. 359.6397, Merck & Company (2011).

2. SCH 29851-Acute Toxicity to Daphnids (Daphnia magna) Under Static Conditions, Springborn Laboratories, Study no. 1560.0592.6192.110, Schering-Plough, Report no. P-5773 (1993).

3. SCH 29851-Acute Toxicity to Daphnia magna, Huntingdon Life Science Study no. ESN034/993311, Schering-Plough (2000).

4. Loratadine - Full Life-Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Static-Renewal Conditions, Following OECD Guideline #211, Smithers Viscient Study No. 359.6398, Merck & Company (2011).

5. SCH 29851-Acute Toxicity to Bullgill Sunfish (Lepomis macrochirus) Under Static Renewal Conditions, Springborn Laboratories, Study no. 1560.0592.6193.100, Schering-Plough, Report no. P-5775 (1993).

6. SCH 29851-Acute Toxicity to Bluegill Sunfish, Huntingdon Life Science Study no. ESN033/993694, Schering-Plough (2000).

7. SCH 29851-Acute Toxicity to Rainbow Trout, Huntingdon Life Science Study no. ESN035/995003, Schering-Plough (2000).

8. Loratadine – Early Life-Stage Toxicity Test with Fathead Minnow, Pimephales promelas, Following OECD Guideline #210, Smithers Viscient Study no. 359.6399, Merck & Company (2011).

9. Loratadine - Toxicity Test with Sediment-Dwelling Midges (Chironomus riparius) Under Static Conditions, Following OECD Guideline 218, Smithers Viscient Study No. 359.6515, Merck & Company (2012).

10. Loratadine – Activated Sludge Respiration Inhibition Test Following OECD Guideline 209, Smithers Viscient Study No. 359.6400, Merck & Company (2011).

11. SCH 29851-Aerobic Biodegradation in Water, Springborn Laboratories, Study no. 1560.0592.6194.725, Schering-Plough, Report no. P-5772 (1993).

12. [¹⁴C]Loratadine – Determination of the Biodegradability of a Test Substance in Activated Sludge Based on OECD Method 314B, Smithers Viscient Study No. 359.6391, Merck & Company (2011).

13. [¹⁴C]Loratadine – Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308, Smithers Viscient Study No. 359.6395, Merck & Company (2011).

14. SCH 29851-Determination of Aqueous Hydrolysis Rate Constant and Half-Life, Springborn Laboratories, Study no. 1560.0192.6179.715, Schering-Plough (1993).

15. SCH 29851-Determination of Aqueous Photolysis Rate Constant and Half-Life, Springborn Laboratories, Study no. 1560.0592.6195.720, Schering-Plough, Report no. P-5841 (1993).

16. SCH 29851-Determination of the n-Octonaol/Water Partition Coefficient, Springborn Laboratories, Study no. 1560.0192.6178.705, Schering-Plough (1993).

17. SCH 29851-Determination of Vapour Pressure, Springborn Laboratories, Study no. 1560.0192.6176.740, Schering-Plough (1993).

18. SCH 29851-Determination of Water Solubility, Springborn Laboratories, Study no. 1560.0192.6177.700, Schering-Plough (1993).

19. SCH 29851-Determination of the Sorption and Desorption Properties, Springborn Laboratories, Study no. 1560.0192.6180.710, Schering-Plough (1993).

20. [¹⁴C]Loratadine – Determining the Adsorption Coefficient (K_oc) Following OECD Guideline 106, Smithers Viscient Study No. 359.6390, Merck & Company (2011).