Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC) (Ref. 1) 

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100)

Where:

A (kg/yr)	7.75	Total sold amount API in Sweden year 2022, data from IQVIA (Ref. 2)
R (%)	0	Removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation); use 0 if no data is available (Ref. 1)
P	10*106	Number of inhabitants in Sweden
V (L/day)	200	Volume of wastewater per capita and day (default value) (Ref. 1,3)
D	10	Factor for dilution of wastewater by surface water flow (default value) (Ref. 1, 3)

(Note: the factor 10⁹ converts the quantity (A) from kg to μg).

PEC (μg/L) = (7.75*10⁹*(100-0))/(365*10*10⁶*200*10*100)

PEC = 0.00106 μg/L

Predicted No Effect Concentration (PNEC)

PNEC: Not determined; no ecotoxicology data is available.

Ecotoxicological Studies with Lopinavir

Short-term ecotoxicology studies were not available for lopinavir, but physico-chemical, environmental fate and ecotoxicology data were modelled based on measured data for ritonavir, a compound with a similar structural core. The relevance of the modelled data presented below is considered questionable due to the outdated version of software used to generate the data (ECOSAR V 0.99e) and the actual structural similarity of lopinavir and ritonavir. Generation of updated ecotoxicology data for lopinavir are being pursued. No observable effect concentrations (NOEC) were generated since the ritonavir studies from which the modelling was based resulted in NOECs at the maximum concentration evaluated. Due to the uncertainty regarding the validity of the modelled data, a conservative risk summary phrase was chosen.

Algae (Green Algae): Acute toxicity

EC₅₀ 96 h (growth) = 1.914 mg/L (1914 μg/L) (Ref. 4)

Crustacean (Daphnia magna): Acute toxicity

LC₅₀ 48 h (immobilization) = 2.652 mg/L (2652 μg/L) (Ref. 4)

Fish (Lepomis macrochirus): Acute toxicity

LC₅₀ 96 h (lethality) = 2.082 mg/L (2082 μg/L) (Ref. 4)

Environmental Risk Classification (PEC/PNEC ratio)

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

Degradation

The potential for persistence of lopinavir cannot be excluded, due to lack of data.

Justification of chosen biodegradation phrase:

No degradation data could be found. Therefore, the potential for persistence of lopinavir cannot be excluded due to lack of data.

Bioaccumulation

Lopinavir has high potential for bioaccumulation.

Log D_ow (Octanol Water Coefficient) = 4.7 (pH 7.4) (25°C) (Refs. 4 and 5)

The method used to derive the Log D_ow is unknown.

Justification of chosen bioaccumulation phrase:

Log D_ow = 4.7. As the log D_ow is ≥ 4.0, lopinavir has high potential for bioaccumulation.

Excretion and Pharmacological Activity

Lopinavir is excreted up to 22.0% as parent and up to 78% as metabolites. The parent compound and metabolite composition in excreta (urine and feces) was as follows: lopinavir, M-1, M-3/4, M-6 to M-8, M-9/10, M-l 1 to M-15, with the remaining radioactivity present as several unknown metabolites. (Ref. 6)

The in vitro antiviral activity for all metabolites is unknown except for two metabolites which have potency comparable to that of the parent drug. (Refs.7).

References

1. FASS.se. Environmental classification of pharmaceuticals at www.fass.se. Guidance for pharmaceutical companies. 2012 V 2.0.  2021.

2. IQVIA. 2022. IQVIA / LIF - kg consumption/2022.

3. European Chemicals Agency (ECHA).  Guidance on Information Requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment. Version 3.0. 2016.

4. Huntingdon Life Sciences. Environmental Risk Assessment of Lopinavir. November 2005.

5. Abbott. Abbott-157378 and Abbott-84538 (Ritonavir) Product Development Report. Preliminary Physical and Chemical Characterization of Abbott-157378 and Comparison with Abbott-84538 (Ritonavir). R&D/95/972. December 1995.

6. Abbott. Abbott-157378 Drug Metabolism Report No. 44 Metabolism and Disposition of [¹⁴C]ABT-378 Given in Combination with Ritonavir in Healthy Male Subjects Following a Single Oral Administration Protocol M97-723. R&D/99/031. January 1999.

7. Abbott. Abbott-157378 Drug Metabolism Report No. 57 Overview of Absorption, Distribution, Metabolism and Excretion of ABT-378 (Abbott-157378) in Animals. R&D/99/652. December 1999.

Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula (Ref 1):

PEC (µg/L) = (A*10⁹*(100-R))/(365*P*V*D*100)

Where:

A (kg/yr)	36,252 kg	Total API sold (kg) in Sweden in 2019 from IQVIA (Ref. 2)
R	0 %	Removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation); use 0 if no data is available. (Ref. 1)
P	9*106	Number of inhabitants in Sweden
V (L/day)	200	Volume of wastewater per capita and day (200 L/day is the default value) (Ref. 3)
D	10	Factor for dilution of waste water by surface water flow(10 is the default value) (Ref. 3); Note: The factor 109 converts the quantity distressed from kg to mcg.

PEC (µg/L) = (36,252*10⁹*(100-0))/(365*9,995*10⁶*200*10*100)

PEC = 0,00552 μg/L

Ecotoxicological Studies with Ritonavir

Microbial Growth Inhibition (FDA TAD 4.02) (Ref. 4, 5)

Minimum Inhibitory Concentration (MIC) (Growth Inhibition) > 5,0 mg/L (5000 µg/L)

The microbial growth inhibition study (FDA TAD 4.02) is designed to evalute the sensitivity of pure cultures of bacteria, fungi, and blue-green algae to chemicals. The objective of the study is to determine the lowest concentration of the chemical that will inhibit the growth of test microbial strains or species.

The following test organisms, including algae, were used in the microbial growth inhibition study of ritonavir. (Ref. 5)

Table 1: List of Test Organisms Used for Microbial Growth Inhibition Test of ABT-538
Genus & Speciesa	Representative Type	ATCC Number
Pseudomonas fluorescens	Bacteria	12842
Bacillus megaterium	Bacteria	6459
Azotobacter chroococcum	Nitogen-Fixing Bacterium	4412
Anabaena flos-aquae	Nitrogen Fixing Blue-Green Alga	22664
Aspergillus clavatus	Fungi	9192
Penicillium canescens	Fungi	10419
Chateomium globosum	Fungi	44699
aObtained from ATCC (American Type Culture Collection, Rockville, MD); the species listed here are commonly found in soils.

Crustacean (Daphnia magna): Acute toxicity (FDA TAD 4.08) (Ref. 6, 7)

EC50 48 h (Immobility, Abnormal Effects) > 1,5 mg/L (1500 μg/L)

NOEC 48 h = 1,50 mg/L

Crustacean (Hyalella azteca): Acute toxicity (FDA TAD 4.10) (Ref. 8, 9)

NOEC 96 h (Static acute toxicity: Mortality, Adverse Effects.) = 1,59 mg/L (1590 μg/L)

Fish (Lepomis macrochirus): Acute toxicity (FDA TAD 4.11) (Ref. 10, 11)

LC₅₀ 24 h(Mortality, Abnormal (Sublethal) Effects) > 1,63 mg/L (1630 μg/L)

LC₅₀ 48 h (Mortality, Abnormal (Sublethal) Effects) > 1,63 mg/L (1630 μg/L)

LC₅₀ 72 h (Mortality, Abnormal (Sublethal) Effects) > 1,63 mg/L (1630 μg/L)

LC₅₀ 96 h (Mortality, Abnormal (Sublethal) Effects) > 1,63 mg/L (1630 μg/L)

NOEC 96 h (Mortality, Abnormal (Sublethal) Effects) = 1,63 mg/L

Predicted No Effect Concentration (PNEC)

PNEC (μg/L) = lowest L(E)C₅₀/AF

AF = Assessment Factor= 1000

Organism	Endpoint
Microorganisms (spps)	MIC > 5000 μg/L
Daphnia magna	EC50 > 1500 μg/L
Lepomis macrochirus	LC50 > 1630 μg/L

The PNEC was determined in accordance with ECHA guidance (Ref. 12). Acute

toxicology studies provided L(E)C50 and MIC values from three trophic levels (algae,

crustacean, fish); therefore, 1000 was used as the assessment factor to calculate PNEC.

The EC₅₀ for Daphnia magna (1500 μg/L) was used for this calculation since it is the

most sensitive of the three tested species.

EC₅₀ = 1500 μg/L

PNEC (μg/L) = 1500/1000

PNEC = 1,5 μg/L

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC Ratio:

PEC = 0,00552 μg/L

PNEC = 1,5 μg/L

PEC/PNEC = 0,00552/1,5

PEC/PNEC = 0,0037

Justification of environmental risk classification:

Since PEC/PNEC ≤ 0,1, the use of ritonavir has been considered to result in insignificant environmental risk.

Degradation

Aerobic Biodegradation of ritonavir in water:

The aerobic biodegradation of ritonavir in water was evaluated using FDA TAD 3.11.

(Ref. 13) The mineralization of ritonavir to CO₂ was measured following both a 53-day and a 28-day incubation period. At the end of the 53-day period, 0,1% of the ¹⁴C from the radiolabelled ritonavir was mineralized to 14CO2; none of the ¹⁴C from ritonavir was mineralized to ¹⁴CO₂ during the 28-day study. (Ref. 14) Furthermore, extracts from the 28-day study were analysed using HPLC; of the radiolabeled material, 18,8% was ¹⁴C-ritonavir,18,7% was a polar ¹⁴C-degradant and the remaining material was composed of various other ¹⁴C-organic compounds. The radioactivity mass balance indicated that 97,3% of the ¹⁴C-ritonavir test substance was recovered at the end of the study as either parent ¹⁴C-ritonavir or as ¹⁴C-degradants. These results demonstrate that ritonavir did not undergo aerobic degradation in water. However, ritonavir was extensively degraded to ¹⁴C-metabolites in the FDA 3.11 test matrix. Thus, degradation appears to be a potential pathway for removal of ritonavir, especially considering its removal from the mineral salt solution containing activated

sludge and effluent inocula, which may reduce is potential environmental impact from wastewater treatment plant effluent. (Ref. 14)

Photodegradation of ritonavir in water:

Aqueous photodegradation of ritonavir (at pH 5, 7, and 9) was assessed using FDA TAD 3.10. (Ref. 15) Direct and indirect photolysis were investigated in the preliminary study. (Ref. 16) Compounds with absorbance in the range of 290-800 nm may be susceptible to photodegradation upon exposure to sunlight (direct photolysis). (Ref. 17) Following 24 hours of direct photolysis (exposure to simulated sunlight using a Xenon arc lamp), 98% of the compound remained in solution. As the ultraviolet/visible absorption spectrum of ritonavir shows absorption maxima at 197,5 and 240 nm, with a shoulder at 210 nm (Ref. 18), which is outside the range of 290-800 nm, it is reasonable that ritonavir is not susceptible to direct photodegradation. However, ritonavir degraded under indirect photolysis conditions (1% acetone as a sensitizing agent). Therefore, the definitive study was completed under indirect photolysis conditions. Results of the definitive study revealed ritonavir readily undergoes indirect photodegration in aqueous conditions with half-lives (DT₅₀) of 5,92, 2,23, and 1,43 hours under pH 5, 7, and 9, respectively.

Acetone is one of a number of sensitizers that are naturally found in surface waters (as well as soil); these sensitizers can promote indirect photolysis in natural waters.

Therefore, indirect photolysis may well be a significant removal mechanism of ritonavir in the environment. The identities of the major transformation products were not elucidated.

Justification of chosen degradation phrase:

The biodegradation of ritonavir was assessed using FDA TAD 3.11 (aerobic degradation in water). Based on the results of this study, ritonavir did not demonstrate significant aerobic mineralization in water (>60% theoretical CO₂ production). (Ref. 13) Additionally, ritonavir did not show ready biodegradability or inherent biodegradability as defined by OECD 301 and ECHA guidance, respectively. (Ref. 19, 20) Finally, there are no data from simulation studies (OECD 308) or analytical monitoring data to demonstration elimination within the ECHA defined persistence half-life. Therefore, the summary phrase “ritonavir is potentially persistent” has been selected. However, ritonavir may be extensively removed from the aquatic compartment following patient use and excretion by a combination of biodegradation and photodegradation, thereby potentially resulting in minimal release of ritonavir to the environment from wastewater treatment plant effluent, as well as minimal partitioning into sludge.

Bioaccumulation

Partitioning coefficient:

Two methods have been used to determine the Log Dow of ritonavir.

By the HPLC method, pH = 7,4, n = 2 (Ref. 18)

Dow= 4,7*10⁴

Log Dow = 4,7

By the shake-flask method, pH = 7,4, 25 °C, n=3 (Ref. 21)

Dow = 9,97 *10³

Log Dow = 3,99

Justification of chosen bioaccumulation phrase:

Log Dow at pH 7≥ 4,0 therefore, ritonavir has high potential for bioaccumulation.

References

1. FASS.se. Environmental classification of pharmaceuticals at www.fass.se. Guidance for pharmaceutical companies. 2012.

2. IQVIA. 2019. IQVIA / LIF - kg consumption/2019

3. European Chemicals Agency (ECHA). Guidance on Information Requirements

and Chemical Safety Assessment Chapter R.16: Environmental exposure

assessment. Version 3.0. 2016.

4. Food and Drug Administration. Environmental Assessment Technical Assistance

Document 4.02: Microbial Growth Inhibition. 1987.

5. ABC Laboratories, Inc. Microbial Growth Inhibition with ABT-538. Report

#41528. R&D/96/788. February 1994.

6. Food and Drug Administration. Environmental Assessment Technical Assistance

Document 4.08: Daphnia Acute Toxicity. 1987.

7. ABC Laboratories, Inc. Acute Toxicity of ABT-538 to Daphnia magna. Report

#41984. R&D/96/787. July 1995.

8. Food and Drug Administration. Environmental Assessment Technical Assistance

Document 4.10: Hyalella azteca Acute Toxicity. 1987.

9. ABC Laboratories, Inc. Acute Toxicity of ABT-538 to Hyalella Azteca. Report

#41985. R&D/96/786. May 1995.

10. Food and Drug Administration. Environmental Assessment Technical Assistance

Document 4.11: Freshwater Fish Acute Toxicity. 1987.

11. ABC Laboratories, Inc. Static Acute Toxicity of ABT-538 to Bluegill (Lepomis

macrochirus). Report #41986. R&D/96/784. July 1995

12. European Chemicals Agency (ECHA). Guidance on information requirements and

chemical safety assessment Chapter R.10: Characterisation of dose

[concentration]-response for environment. 2008.

13. Food and Drug Administration. Environmental Assessment Technical Assistance

Document 3.11: Aerobic Degradation in Water. 1987.

14. ABC Laboratories, Inc. Aerobic Biodegradation of 14C-ABT-538 in Water.

Report #41527. R&D/96/778. 1995.

15. Food and Drug Administration. Environmental Assessment Technical Assistance

Document 3.10: Photodegradation. 1987.

16. ABC Laboratories, Inc. Determination of the Aqueous Photodegradation of 14CABT-

538. Report #42793. R&D/96/796. 1995.

17. Larson R., Forney L, Grady, Jr. L, Klečka G. M, Masunaga S, Peijnenburg W, and

Wolfe L. Quantification of Persistence in Soil, Water, and Sediments. In Klečka,

G. et al., editors. Evaluation of Persistence and Long-Range Transport of Organic

Chemicals in the Environment. Pensacola: SETAC; 2000. p. 63-130

18. Abbott. Chemical and Physical Properties of Abbott-84538.0. R&D/95/220. 1995.

19. Organisation for Economic Co-operation and Development (OECD). OECD

Guideline for Testing of Chemicals: Ready Biodegradability (OECD 301). 1992.

20. European Chemicals Agency (ECHA). Guidance on Information Requirements

and Chemical Safety Assessment Chapter R.11: PBT/vPvB assessment Version

2.0. 2014.

21. Abbott. Abbott-84538 and Abbott-85556 Product Development Report. Acid

Dissociation Constants, Aqueous Solubility and Projected pH-Solubility Profile.

R&D/93/084. 1993.