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Rocephalin® med lidokain

Roche

Pulver och vätska till injektionsvätska, lösning 1 g
(Pulver: vitt till gulorange kristallint. Lösning: klar färglös.)

Antibiotikum av cefalosporintyp, betalaktamasstabilt

Aktiva substanser:
ATC-kod: J01DD54
Utbytbarhet: Ej utbytbar
Läkemedel från Roche omfattas av Läkemedelsförsäkringen.
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Miljöinformation

Miljöpåverkan

Ceftriaxon

Miljörisk: Användning av ceftriaxon har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Ceftriaxon är potentiellt persistent.
Bioackumulering: Ceftriaxon har låg potential att bioackumuleras.


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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

KH: <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) = 1.5 x 10-6 x A x (100 - R) = 0.011 μg/L


Where: 90.8649 (total sold amount API in Sweden year 2017, data from IQVIA)

A Sold quantity = 76.1677 kg/y calculated data for the active ingredient Ceftriaxon

R Removal rate = 0 % Defaul value [2]

P Population of Sweden = 9000000

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, 13]

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, 13]

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)


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, 13]

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 (mg/l) = lowest NOEC/10, where 10 is the assessment factor used. A NOEC of 0.1 mg/l (100 μg/l) for Cyanobacteria 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. [13]


PNEC = 100 / 10 = 10 μg/l active substance


Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.011 μg/L

PNEC Predicted No Effect Concentration = 10 μg/L

Ratio PEC/PNEC = 0.001


PEC/PNEC = 0.011/10 = 0.001 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)


Other degradation information: ND


Abiotic Degradation

Photodegradation:

= 4 d (20 °C, light) [3]


Hydrolysis:

= 61 d (4 °C, in the dark) [3]

= 11 d (15 °C, in the dark) [3]

= 5 d (20 °C, in the dark) [3]

(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. This justifies the phrase 'Ceftriaxone disodium salt hemi(heptahydrate) is potentially persistent.'


Bioaccumulation/Adsorption

logPOW 0.025 pH 2.0 experimental, method unknown [1]

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

KOC ≤2713 pH-sensitive, QSAR; low adsorption based on logPow

BCF <10 QSAR


Ceftriaxone disodium has low potential for bioaccumulation.


Excretion/metabolism

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


PBT/vPvB Assessment

P: Freshwater half-life 36 d, based on hydrolysis (worst-case at 20 °C) [9]

Sediment half-life ND

Persistence criteria fulfilled? not P


B: BCF (experimental)

alternatively, base or acid? a

alternatively, logDOW(p H 7) ≤0.5 , log Pow, Log D [1, 10]

Bioaccumulation criteria fulfilled? not B


T: chronic NOEC < 0.01 mg/l? ND

CMR substance? n not CMR [1]

Endocrine-disrupting effects? n ND

T criteria fulfilled? potentially T


PBT Assessment: not PBT


References

1. F. Hoffmann-La Roche Ltd (2016): Safety Data Sheet for Ceftriaxone disodium, 20.09.2017; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheets-row.htm

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

assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

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. AMR Industry Alliance Antibiotic Discharge Targets. List of Predicted No-Effect Concentrations (PNECs). Version: 21 September 2018. https://www.amrindustryalliance.org/wp content/uploads/2018/09/AMR_Industry_Alliance_List-of-Predicted-No Effect Concentrations-PNECs.pdf



Lidokain

Miljörisk: Användning av lidokain har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Lidokain är potentiellt persistent.
Bioackumulering: Lidokain har låg potential att bioackumuleras.


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Detaljerad miljöinformation

The assessment for Lidocaine is based on the following entries of sales data from IQVIA - kg consumption/2017:


Substance

CAS no.

M

kg (2017)

Lidocaine

137-58-6

234.3408

1542.7976

Lidocaine hydrochloride (water free)

73-78-9

270.8017

11.5451

Lidocaine hydrochloride (monohydrat)

6108-05-0

288.8165

816.0772

Lidocaine (total)



2214.9394


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

KH: 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) = 1.5 x 10-6 x A x (100 - R) = 0.332 μg/L


Where:

A Sold quantity = 2214.9394 kg/y calculaed sales data for Lidocaine (total) (total sold amount API in Sweden year 2017, data from IQVIA)

R Removal rate = 0 % Default value [2]

P Population of Sweden = 9000000

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 (mg/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 = 0.332 μg/L

PNEC Predicted No Effect Concentration = 23 μg/L

Ratio PEC/PNEC = 0.014


PEC/PNEC = 0.332/23 = 0.014 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 = 92 d (laboratory, 23 °C, in the dark), = 110 d (field, 2-28 °C, in the dark)


Abiotic Degradation

Photodegradation: = 0.4 d (laboratory, light), = 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

logPOW 1.66 QSAR [3]

logPOW 2.44 method unknown, cited in: [3]

logDOW 1.63 (pH 7.4, 25 °C) [9]

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

KOC ≤420 QSAR [3]

BCF <20 QSAR [3]


Lidocaine has low potential for bioaccumulation (log DOW <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 (2015): Safety Data Sheet for Lidocaine, 15.12.2015; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheets-row.htm

2. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

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.