Detaljerad miljöinformation

Identification and characterisation

Chemical name: Ceftriaxone disodium salt hemi(heptahydrate)

CAS number: 104376-79-6 [1]

Molecular weight: 661.6 [1]

Remark: -

Brand name: Rocephalin® med lidokain [1]

Chemical name: Ceftriaxone (active substance)

CAS number: 73384-59-5

Molecular weight: 554.5872

Physico-chemical properties

Aqueous solubility: 470 g/l (22 °C) [1]

Dissociation constant, pKa: 3, approximate value [3]

Melting point: >155 °C (with decomposition) [1]

Vapour pressure: ND

Boiling point: ND

K_H: <1*E–30 atm*m3/mol QSAR

QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris)

Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (μg/L) = (A x 1'000'000'000 x (100-R)) / (365 x P x V x D x 100) = 1.37 x 10^-6 x A x (100 - R) = 0.008 μg/l

(PEC is given for the activ substance Ceftriaxone)

Where: Ceftriaxone disodium salt hemi(heptahydrate) 102,0281 sales data from IQVIA / LIF - kg consumption 2021

A Sold quantity =85,5252 kg/y calculated data for the active ingredient Ceftriaxone

R Removal rate = 33.7 % calculated with Simple Treat 4.0 [16]

P Population of Sweden = 10 000 000

V Volume of Wastewater = 200 l/day Default value [2]

D Factor for Dilution = 10 Default value [2]

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Raphidocelis subcapitata): [5]

ErC50 72 h (growth rate) >100 mg/l (OECD 201)

EbC50 72 h (biomass) >100 mg/l (OECD 201)

NOEC 72 h (growth rate + biomass) = 100 mg/l (OECD 201)

Cyanobacteria (Synechococcus leopoliensis): [11]

ErC50 72 h (growth rate) = 0.586 mg/l active substance (OECD 201)

ErC10 72 h (growth rate) = 0.294 mg/l active substance (OECD 201)

EyC50 72 h (yield) = 0.324 mg/l active substance (OECD 201)

EyC10 72 h (yield) = 0.173 mg/l active substance (OECD 201)

NOEC 72 h (growth rate + yield) = 0.1 mg/l active substance (OECD 201)

Cyanobacteria (Anabaena flos-aquae): [13]

ErC50 72 h (growth rate) = 0.0061 mg/l active substance (OECD 201)

ErC10 72 h (growth rate) = 0.00331 mg/l active substance (OECD 201)

EyC50 72 h (yield) = 0.00385 mg/l active substance (OECD 201)

EyC10 72 h (yield) = 0.00186 mg/l active substance (OECD 201)

NOEC 72 h (growth rate + yield) = 0.0016 mg/l active substance (OECD 201)

Water-flea (Daphnia magna): [6]

EC50 48 h (immobilization) > 100 mg/l (OECD 202)

NOEC 48 h (immobilization) = 100 mg/l (OECD 202)

Daphnia magna Reproduction: [12]

NOEC 21 d (reproductive output) = 92.0 mg/l active substance (OECD 211)

NOEC 21 d (intrinsic rate of population increase) = 28.5 mg/l active substanc(OECD 211)

NOEC 21 d (overall) = 28.5 mg/l active substance (OECD 211)

Respiration inhibition test: [7]

NOEC 3 h (respiration inhibition) = 10 mg/l (OECD 209) [7]

Micro-organisms: [8]

28 d LOEC (toxicity control, CFU) = 0.005 mg/l (OECD 301 D)

PNEC Derivation

The PNEC is based on the following data:

PNEC (μg/l) = lowest ErC10/10, where 10 is the assessment factor used. An ErC10 of 0.00331 mg/l (3.31 μg/l) for the cyanobacteria Anabaena flos-aquae has been used for this calculation. Fish has been considered not to be the relevant species, due to the low acute toxicity. This is a joint assessment performed by the AMR Industry Alliance. [1]

PNEC =3.31 μg/l / 10 =0.331 μg/l active substance

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.008 μg/l

PNEC Predicted No Effect Concentration =0.331 μg/l

Ratio PEC/PNEC = 0.023

PEC/PNEC 0.008/0.331 = 0.023 = for Ceftriaxone active substance, which justifies the phrase 'Use of Ceftriaxone disodium has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability: [8]

3% after 28 days of incubation BOD/ThOD (OECD 301 D)

Inherent biodegradability: [7]

0% after 28 days of incubation BOD/ThOD (OECD 302 C)

Biodegradation in Activated Sludge (OECD 314 B) [15]

Total system DT50 primary: 0.000445 days

Total system DegT50 primary: 0.43 days

Degradation rate k based on DegT50 primary: 0.0672 h-1, used for calculation of elimination in SimpleTreat 4.0

Mineralisation DT50 ultimate: 188 days

DT50 primary: Time taken for 50% of parent to disappear by dissipation, including irreversible binding, and/or degradation processes

DegT50 primary: Time taken for 50% of parent to disappear by degradation processes alone; used for calculation in SimpleTreat

DT50 ultimate = DegT50 ultimate

Using the primary degradation rate of 0.0672 h-1 in SimpleTreat 4.0, this results in a biodegradation of 33.7% in sewage treatment. [16]

Substance specific analysis by LC-MS showed cleavage of the beta-lactam ring; demonstrating complete loss of antibiotic activity by Ceftriaxone and/or its metabolites.

Abiotic Degradation

Photodegradation:

t½ = 4 d (20 °C, light) [3]

Hydrolysis:

t½ = 61 d (4 °C, in the dark) [3]

t½ = 11 d (15 °C, in the dark) [3]

t½ = 5 d (20 °C, in the dark) [3]

t½ (20°C, buffer of ionic strength 0.6) = 8.9 h at pH 5.0, 7 d at pH 5.6, 18 d at pH 6.2, 36 d at pH 6.8, 32 d at pH 7.4, 16 d at pH 8.0; hydrolysis even faster at higher ionic

strength, i.e., faster in seawater or sewage than in 'clean' water. [9]

Ceftriaxone disodium salt hemi(heptahydrate) is neither readily, nor inherently biodegradable. However, biodegradation in sewage sludge according to OECD 314 B showed a fast primary degradation of Ceftriaxone with cleavage of the beta-lactam ring, thereby demonstrating that the antibiotic activity is completely lost during sewage treatment. With a primary degradation DegT50 of 0.43 days, this justifies the phrase 'Ceftriaxone disodium salt hemi(heptahydrate) is degraded in the environment.'

Bioaccumulation/Adsorption

logP_OW 0.025 pH 2.0 experimental, method unknown [1]

log D -1.2 pH 7.4 experimental, method unknown [10]

K_OC ≤2713 pH-sensitive, QSAR; low adsorption based on logP_ow

BCF <10 QSAR

Ceftriaxone disodium has low potential for bioaccumulation.

Excretion/metabolism

Ceftriaxone is metabolised in part (unquantified) to inactive compounds. [4]

References

1. F. Hoffmann-La Roche Ltd (2022): Environmental Risk Assessment Summary for Ceftriaxone. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm.

2. European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2.

3. Kümmerer K (2003): Eintrag von Antibiotika in die aquatische Umwelt; Anhang "Stoffdossier". Abschlussbericht, F&E-Vorhaben 298 63 722, Freiburg; www.iuk-freiburg.de/umweltforschung/index.htm.

4. Martindale (2005): Martindale, the complete drug reference, electronic version, online; 2005.

5. Study Report: NOTOX Project no. 180091: Fresh water algal growth inhibition test with Rocephin, December 1996.

6. Study Report: NOTOX Project no. 180012: Acute toxicity study in Daphnia magna with Rocephin, January 2008.

7. Study Report: Roche Project: Oekotoxikologische Beurteilung BWL, August 1983.

8. Alexy R, Kümpel T, Kümmerer K (2004): Assessment of degradation of 18 antibiotics in the Closed Bottle test. Chemosphere 57: 505–512.

9. Martinez-Pacheco R, Vila-Jato JL, Gómez-Amoza JL (1987): Effect of different factors on stability of ceftriaxone in solution. Il Farmaco 42(5): 131–137.

10. Zhu C, Jiang L, Chen T–M, Hwang K–K (2002): A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential. Eur J Med Chem 37: 399–407.

11. Study Report: Arcadis Project no. A18-00168: Ceftriaxone disodium salt hemi(heptahydrate). Cyanobacteria growth inhibition test with Synechococcus leopoliensis, September 2018.

12. Study Report: Arcadis Project no. A18-00169: Ceftriaxone disodium salt hemi(heptahydrate). Daphnia magna Reproduction Test, September 2018.

13. Study Report: Scymaris Project no. 1046.00305: Ceftriaxone disodium salt hemi(heptahydrate). Determination of toxicity to the blue-green alga Anabaena flos-aquae, August 2020

14. AMR Industry Alliance (2021): AMR Alliance Science-Based PNEC Targets for Risk Assessments. https://www.amrindustryalliance.org/shared-goals/common-antibiotic-manufacturing-framework/

15. Study Report: Scymaris Project no. 1046.00306: [14C]Ceftriaxone disodium salt hemi(heptahydrate): Biodegradation in Activated Sludge, May 2022

16. Struijs (2014). SimpleTreat 4.0: a model to predict fate and emission of chemicals in wastewater treatment plants. RIVM report 601353005/2014. Model downloaded from RIVM.

Detaljerad miljöinformation

The assessment for Lidocaine is based on the following entries of sales data fromsales data from IQVIA / LIF - kg consumption 2021:

Substance	CAS no.	M	kg (2021)
Lidocaine	137-58-6	234.3408	1237.9284
Lidocaine hydrochloride (monohydrat)	6108-05-0	288.8165	863.4509
Lidocaine hydrochloride (water free)	73-78-9	270.8017	11.2757
Lidocaine (total)			1948.2753

Identification and characterisation

Chemical name: Lidocaine

CAS number: 137-58-6

Molecular weight: 234.3408 [1]

Remark: -

Brand name: Rocephalin® med lidokain [1]

Physico-chemical properties

Water solubility:

4000 mg/l as Lidocaine base [10]

680000 mg/l as Lidocaine hydrochloride monohydrate [10]

Dissociation constant, pKa:

8.05 (in 170 mM NaCl at 25 °C, with no added buffers) [9]

7.84 (25 °C) [10]

Melting point:

68–69 °C as Lidocaine base [10]

76–79 °C as Lidocaine hydrochloride monohydrate [10]

Vapour pressure: ND

Boiling point: ND

K_H: 8.77*E–09 atm*m3/mol QSAR

QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris)

Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (μg/L) = (A x 1'000'000'000 x (100-R)) / (365 x P x V x D x 100) = 1.37 x 10^-6 x A x (100 - R) = 0.267 μg/l

Where:

A Sold quantity = 1948.2753 kg/y sales data from IQVIA / LIF - kg consumption 2020

R Removal rate = 0 % Default value [2]

P Population of Sweden = 10 000 000

V Volume of Wastewater = 200 l/day Default value [2]

D Factor for Dilution = 10 Default value [2]

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Scenedesmus vacuolatus): [4]

ErC50 24 h (growth rate) at pH 6.5 = 135 mg/l (no standard method)

ErC50 24 h (growth rate) at pH 7.5 = 161 mg/l (no standard method)

ErC50 24 h (growth rate) at pH 8.5 = 142 mg/l (no standard method)

ErC50 24 h (growth rate) at pH 9.0 = 128 mg/l (no standard method)

ErC50 24 h (growth rate) at pH 10.0 = 108 mg/l (no standard method)

(Algae were maintained as batch cultures in Talaquil medium at 25 °C under photosynthetically active radiation (PAR) of 170 ± 20μEm−2 s−1. The buffer constitution of the medium was increased to 20 mM to reach pH-stability over the test period. The buffer constitution was varied with pH as follows: 20mM MES (2-(N morpholino)ethanesulfonic acid, CAS 4432-31-9) was used for pH 6.5, 20 mM MOPS (3-(Nmorpholino) propanesulfonic acid, CAS 1132-61-2) for pH 7.5, 20 mM HEPPS (4 (2-hydroxyethyl)-1-piperazinepropanesulfonic acid, CAS 16052-06-5) for pH 8.5, 20 mM CHES (2-(cyclohexylamino)ethanesulfonic acid, CAS 103-47-9) for pH 9.0, and 20 mM CAPS (3- (cyclohexylamino)-1-propanesulfonic acid, CAS 1135-40-6) for pH 10.0. Algae were grown in medium at the different pH values for at least 3 days before the experiment to allow for adaptation. The test was conducted using OD-readings for the determination of the growth rate μ during 24 h.) [4]

Water-flea (Daphnia magna): cited in: [5]

EC50 48 h (immobilization) = 112 mg/l (OECD 202)

Thamnocephalus platyurus (anostracan crustacean) [8]

LC50 24 h (mortality) = 81.7 mg/l (Thamnotoxkit microbiotest)

Zebra fish (Danio rerio): cited in: [5]

LC50 96 h (mortality) = 106 mg/l (OECD 203)

Zebra fish (Danio rerio) Embryo Test: [11]

LC50 24 h (mortality) = 23 mg/l (OECD 236, adapted)

Micro-organisms:

ND

PNEC Derivation

The PNEC is based on the following data:

PNEC (μg/l) = lowest LC50/1000, where 1000 is the assessment factor used. An LC50 of 23000 μg/l in the Zebra fish (Danio rerio) Embryo Test has been used for this calculation.

PNEC = 23000 / 1000 = 23 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.267 μg/L

PNEC Predicted No Effect Concentration = 23 μg/L

Ratio PEC/PNEC = 0.012

PEC/PNEC = 0.267/23 = 0.012 for Lidocaine which justifies the phrase 'Use of Lidocaine has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability: ND

Inherent biodegradability: ND

Other degradation information: [6]

Degradation in surface water t½ = 92 d (laboratory, 23 °C, in the dark), t½ = 110 d (field, 2-28 °C, in the dark)

Abiotic Degradation

Photodegradation: t½ = 0.4 d (laboratory, light), t½ = 1.3 d (field, light) [6]

Hydrolysis: ND

Lidocaine is neither readily, nor inherently biodegradable. This justifies the phrase 'Lidocaine is potentially persistent.'

Bioaccumulation/Adsorption

logP_OW 1.66 QSAR [3]

logP_OW 2.44 method unknown, cited in: [3]

logD_OW 1.63 (pH 7.4, 25 °C) [9]

logD_OW 1.66 (phosphate buffer, pH 7.4, 25 °C) [10]

K_OC ≤420 QSAR [3]

BCF <20 QSAR [3]

Lidocaine has low potential for bioaccumulation (log D_OW <4 at pH 7.4).

Excretion/metabolism

Lidocaine is metabolized chiefly by the liver. Its major degradative pathway is conversion to monoethylglycinexylidide by oxidative N-deethylation followed by hydrolysis to 2,6-xylidine. Further conversion of 2,6-xylidine to 4-hydroxy-2,6-xylidine appears to occur in man, since the latter compound excreted in urine over a 24-hour period has accounted for over 70% of an orally administered dose of lidocaine. No more than 10% of the dose is excreted as parent lidocaine. [7]

References

1. F. Hoffmann-La Roche Ltd (2021): Environmental Risk Assessment Summary for Lidocaine. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm.

2. European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2.

3. US Environmental Protection Agency, EPI (Estimation Programs Interface) Suite™ v4.11.

4. Neuwoehner J, Escher BI. 2011. The pH-dependent toxicity of basic pharmaceuticals in the green algae. Aquatic Toxicology 101:266-275.

5. Landesumweltamt Brandenburg (LUA). 2002. Ökotoxikologische Bewertung von Humanarzneimitteln in aquatischen Ökosystemen, Band 39, Studien und Tagungsberichte (ISSN 0948-0838).

6. Rúa-Gómez PC, Püttmann W. 2013. Degradation of lidocaine, tramadol, venlafaxine and the metabolites O-desmethyltramadol and O-desmethylvenlafaxine in surface waters. Chemosphere 90:1952–1959.

7. Collinsworth KA, Kalman SM, Harrison DC. 1974. The clinical pharmacology of lidocaine as an antiarrhythymic drug. Circulation. 50(6):1217-30.

8. Nałecz-Jawecki G, Persoone G. 2006. Toxicity of selected pharmaceuticals to the anostracan crustacean Thamnocephalus platyurus: comparison of sublethal and lethal effect levels with the 1h Rapidtoxkit and the 24h Thamnotoxkit microbiotests. Environ Sci Pollut Res Int. 13(1):22-7.

9. Strichartz GR, Sanchez V, Arthur GR, Chafetz R, Martin D. 1990. Fundamental properties of local anesthetics. II. Measured octanol:buffer partition coefficients and pKa values of clinically used drugs. Anesth Analg. 71(2):158-70.

10. Gröningsson K, Lindgren J-E, Lundberg E, Sandberg R, Wahlén A. 1985. Lidocaine Base and Hydrochloride. Analytical Profiles of Drug Substances. 14:207-243.

11. Lomba L, Ribate MP, Zuriaga E, García CB, Giner B. 2019. Acute and subacute effects of drugs in embryos of Danio rerio . QSAR grouping and modelling. Ecotoxicol Environ Saf. 172:232-239.