26/03/2010 Carbamazepin_WFD_dossiers_draft_final.doc

Carbamazepine

1  Chemical identity

Common name / Carbamazepine
Chemical name (IUPAC) / 5H-Dibenz[b,f]azepine-5-carbamide
Synonym(s) / Proprietary names: Tegretol, Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Telesmin, Teril, Timonil, Trimonil, Epimaz, Carbama/Carbamaze, Amizepin, Hermolepsin, and Degranol
Chemical class (when available/relevant) / Dibenzazepine; urea derivative
CAS number / 298-46-4
EU number / 206-062-7
Molecular formula / C15H12N2O
Molecular structure /
Molecular weight (g.mol-1) / 236,27

2  Existing evaluations and Regulatory information

Annex III EQS Dir. (2008/105/EC) / Not Included
Existing Substances Reg. (793/93/EC) / Not applicable / Liste No
Pesticides(91/414/EEC) / Not included in Annex I
Biocides (98/8/EC) / Not included in Annex I
PBT substances / Not investigated
Substances of Very High Concern (1907/2006/EC) / No
POPs (Stockholm convention) / No
Other relevant chemical regulation (veterinary products, medicament, ...) / According to German Federal Water Act (WHG) carbamapezin is classified as water hazardous class 2, WGK 2, [14] Umweltbundesamt (2000).
Endocrine disrupter / Available information / Not investigated

3  Proposed Quality Standards (QS)

3.1 Environmental Quality Standard (EQS)

As quality criteria for aquatic bioceonoses in Germany are specified PNEC values at 17µg/L (LUA BRB 2002) and 2,5µg/L (http://blak-uis.server.de/servlet/is/2146/P-2c.pdf).

Add any comment on possible residual uncertainty.

Value / Comments
Proposed AA-EQS for [matrix] [unit]
Corresponding AA-EQS in [water] [µg.L-1] / Critical QS is QS--.
See section 7
Proposed MAC-EQS for [freshwater] [µg.L-1]
Proposed MAC-EQS for [marine waters] [µg.L-1] / See section 7.1

3.2 Specific Quality Standard (QS)

Protection objective[1] / Unit / Value / Comments
Pelagic community (freshwater) / [µg.l-1] / 0,5 µg/L / See section 7.1
Pelagic community (marine waters) / [µg.l-1]
Benthic community (freshwater) / [µg.kg-1 dw] / e.g. EqP,
see section 7.1
[µg.l-1]
Benthic community (marine) / [µg.kg-1 dw]
[µg.l-1] / -
Predators (secondary poisoning) / [µg.kg-1biota ww] / See section 7.2
[µg.l-1] / (freshwaters)
(marine waters)
Human health via consumption of fishery products / [µg.kg-1biota ww] / See section 7.3
[µg.l-1] / (freshwaters)
(marine waters)
Human health via consumption of water / [µg.l-1]

4  Major uses and Environmental Emissions

4.1 Uses and Quantities

Carbamazepine is an active pharmaceutical ingredient used for the treatment of epilepsy, trigeminal neuralgia, bipolar depression, excited psychosis, and mania.

Use as human pharmaceutical in Germany in 2001: 87604.9 kg (BLAC 2003)

4.2 Estimated Environmental Emissions

5  Environmental Behaviour

5.1 Environmental distribution

Master reference
Water solubility (mg.l-1) / 0,12 g/L at 25°C / Novartis Farma S.p.A.
Volatilisation
Vapour pressure (Pa) / 1,84 10-7 mm Hg
5,78 x 10-7 Torr at 25°C / Neely and Blau 1985
0.12 g/l at 25°C / Novartis internal data
Henry's Law constant (Pa.m3.mol-1)
Adsorption / The range - is used for derivation of quality standards.
Organic carbon – water partition coefficient (KOC) / KOC = 656 mL/g (pH=1,calculated) -
KOC = 677 mL/g (pH=4 – 10, calculated) / ACS Daten Bank 2004
ACS Daten Bank 2004
Sludge Koc < 57 L/kg (primary sludge); Koc = 3.5 L/kg (secondary sludge)
Soil Koc = 885-1250 L/kg
Soil Koc = 116.3 – 176.0 L/kg (0-5 cm soil layer)
Soil Koc = 188.5 - 213.3 L/Kg
Soil Koc = 132 – 521 L/kg
Soil Koc = 550 L/kg
Sediment Koc = 100-140 L/kg
Sediment logKoc = 2.45 – 3.74
Sediment Koc = 83 L/kg
Not found in leachates in soil column leaching experiments. / Ternes 2004
Williams 2006
Chefetz 2008
Drillia 2005
Yamamoto 2009
Scheytt 2005
Löffler 2005
Oppel 2004
Suspended matter – water partition coefficient(Ksusp-water) / KDOC = 90-440 L/kg (at pH 8),
KDOC = 250-870 L/kg (at pH 4) / Maoz 2010
Bioaccumulation / The BCF value - on fish is used for derivation of quality standards.
Octanol-water partition coefficient (Log Kow) / logKow = 2,45
logKow = 1,76 (25 °C)
logKow = 2,25 / Hansch, C. et al. 1995 Hanna et al. 1998
Novartis Farma S.p.A.
Mersmann 2003
1.68 (at 25°C)
1.51 / Novartis internal data
Scheytt 2005a
BCF (measured) / 61,3 (pH=1,calculated)
63,2 (pH=4-10,calculated) / ACS Daten Bank 2004
ACS Daten Bank 2004
0.8 – 4.2 / Fick 2010

5.2 Abiotic and Biotic degradations

Master reference
Hydrolysis / DT50= d at °C (distilled water)
DT50= d at °C (salt water)
Photolysis / DT50 ≈ 100 d (winter, 50 °N latitude)
T½ = 84 – 2100 h / Andreozzi 2003
Yamamoto 2009
Biodegradation / Not readily biodegradable (OECD 301E * 1981) / Novartis internal data
DT50 (seawater) > 100 d / Benotti 2009
DT50 (sediment/water system) = 328d; DT50 (water phase) = 47 d; DT90 (sediment/water systems) > 365 d / Löffler 2005
T½ (river water) = 3000 – 5600 h / Yamamoto 2009

According to Testa and Jenner (1976) the substance carbamazepine is hydrolytically stable. As a product of thermal degradation arises Iminostilben (Mersmann 2003). Carbamazepine reacts photochemically to cyclobutyl dimeres (Mersmann 2003).

6  Aquatic environmental concentrations

6.1 Estimated concentrations

Compartment / Predicted environmental concentration (PEC) / Master reference
Freshwater
Marine waters (coastal and/or transitional)
Sediment
Biota (freshwater)
Biota (marine)
Biota (marine predators)

6.2 Measured concentrations

Compartment / Measured environmental concentration (MEC) / Master reference
Freshwater / PEC1 = 0.42 µg/L
PEC2= 0.41 µg/L / [26]
Germany, Maximum of the average by station (n=94), year 2008 / 0,59 µg/L / [25] Umweltbundesamt (2010)
Germany, Maximum of analyses, year 2008 / 1,2 µg/L / [25] Umweltbundesamt (2010)
Marine waters (coastal and/or transitional)
WWTP effluent / 0.1-1.2 µg/l / Paxéus 2004
6.3 µg/l (max); 2.1 µg/l (median) / Ternes 1998
1.63 µg/l / Heberer 2002b
11.581 µg/l / Cunningham 2010
Sediment / 4.16 ppb / Thaker 2005
1.81 – 6.85 ng/g / Vazquez-Roig 2009
Biota
Biota (marine predators)

Summary statistics on the fraction water [26]

Analyses / 1867
Stations / 79
Member States (MSs) / 1
River Basin Districts (RBDs) / 8
PNEC / -
PEC 1 / 4.23e-1 ug/l
PEC 2 / 4.11e-1 ug/l
Analyses <= DLs (used in PEC2 calculation) / 160
% analysis <=DLs for which DLs>2PNEC / 0 %
Minimum of the average by station / 1.10e-2 ug/l
Maximum of the average by station / 7.46e-1 ug/l
Minimum of analyses / 5.00e-3 ug/l
Maximum of analyses / 3.70e+0 ug/l

7  Effects and Quality Standards

7.1 Acute and chronic aquatic ecotoxicity

ACUTE EFFECTS / Master reference
Algae & aquatic plants
(mg.l-1) / Freshwater / Desmodesmus subspicatus
EC50: 85 / Cleuvers 2001
Chlorella vulgaris / 48 h
EC50= 155 µM (36.6 mg/L) / Jos 2003
Marine / Gender species / d or h
EC50:
Invertebrates
(mg.l-1) / Freshwater / Daphnia magna
48h-EC50 > 13.8 mg/l
Cerodaphnia dubia
48h-EC50 = 77.7 mg/l
Daphnia magna
48h-EC50 > 100 mg/l
Daphnia magna
48h-EC50> 100 mg/l; 96h-EC50 = 76.3 mg/l
Daphnia magna
48h-EC50= 414 µM (97.8 mg/l) / Ferrari 2003
Cleuvers 2003
Kim 2007
Jos 2003
Marine / Gender species / d or h
EC50:
Sediment / Gender species / d or h
EC50:
Fish
(mg.l-1) / Freshwater / Danio rerio / 10d
NOEC : 25 / Ferrari et al 2003
Danio rerio / 96 h
LC50: 35.4 mg/l
Oryzias latipes / 96h
LC50 = 35.4 mg/l / Liebig 2005
Kim 2007
Marine / Gender species / d or h
EC50:
Sediment / Gender species / d or h
EC50:
Other taxonomic groups / Vibrio fischeri / 30 min
EC50: > 81 / Ferrari et al 2003
Vibrio fischeri
5min-EC50= 52.5 mg/L, 15min-EC50 = 52.2 mg/l
Vibrio fischeri
60min-EC50= 272 µM (64.3 mg/L) / Kim 2007
Non-standard endpoint: cell lines:
Vero cell line: EC50 = 19 µM (4.5 mg/L) / Jos 2003
CHRONIC EFFECTS / Master reference
Algae & aquatic plants
(mg.l-1) / Freshwater / Pseudokirchneriella subcapitata / 96h-NOEC> 100 mg/l
Desmodesmus subspicatus
EC50 = 74 mg/l
Lemna minor
7d-EC50 = 25.5 mg/l / Ferrari 2003
Cleuvers 2003
Lemna gibba and Myriophyllum sibiricum, 7 d
No phytotoxic effects / Brain 2004
Marine / Gender species / d
NOEC:
Invertebrates
(mg.l-1) / Freshwater / Ceriodaphnia dubia / 7d
NOEC: 0,025 / Ferrari et al 2003
Daphnia magna / 21 d
NOECmortality= 4 mg/l
NOECreproduction = 0.4 mg/l
NOECgrowth = 0.4 mg/l / Liebig 2005
Daphnia magna, single dose study:
Delay in age at first reproduction at 0.5 µg/L / Dietrich 2010
Daphnia pulex, reproduction
NOEC = 100 µg/L; LOEC = 200 µg/L / Lürling 2006
Marine / Gender species / d
NOEC:
Sediment, Freshwater / Chironomus riparius / 28d
NOEC= 0.8 mg/kg (nominal; 0.033 mg/kg measured)
Lumbriculus variegatus / 28d
NOEC= 10 mg/kg / Oetken 2005
Fish
(mg.l-1) / Freshwater / Danio rerio
10 d-NOEC= 25 mg/l
Non-standard endpoints:
Rainbow trout, 42 d, activities of antioxidant enzymes in brain and liver
LOEC = 0.2 mg/l / Ferrari 2003
Li 2010a and Li 2010b
Marine / Gender species / d
NOEC:
Sediment / Gender species / d
NOEC:
Other taxonomic groups / Brachionus calyciflorus / 2d
NOEC: 0,377 / Ferrari et al 2003
Tentative QSwater / Relevant study for derivation of QS / Assessment factor / Tentative QS
MACfreshwater, eco / Gender species / d or h
EC50: mg.l-1 / µg.l-1
MACmarine water, eco / µg.l-1
AA-QSfreshwater, eco / Cerodaphnia dubia / 7d-NOEC = 25 µg/l / µg.l-1
AA-QSmarine water, eco / µg.l-1
AA-QSfreshwater, sed. / - / EqP / - µg.kg-1ww
- µg.kg-1dw
AA-QSmarine water, sed. / - / EqP / - µg.kg-1ww
- µg.kg-1dw

Protection of aquatic bioceonoses

There are NOEC values for the groups of organisms like algae, small crustaceans available and a short-term NOEC for fish to calculate an environmental quality standard proposal. The lowest NOEC value of 25 µg/L was researched for small crustaceans (Ceriodaphnia dubia).The lowest acute value also belongs to the group of small crustaceans with > 18 000 µg/L. The small crustacean (Ceriodaphnia dubia). Even after further analysis of ecotoxicological data the small crustacean Ceriodaphnia dubia remains to be the most sensitive organism (NOEC = 25 µg/L). Further a high toxicity for the Invertebrate Chironomus riparius / 28d have been observed (NOEC= 0.8 mg/kg nominal; 0.033 mg/kg measured). Further aquatic and sediment test with Chironomus riparius should be performed, to confirme the result found by Oetken (2005).

These values are taken into consideration for estimation of a quality standard proposal, then according to the TGD-EQS is a safety factor of 50 to the lowest NOEC value of 25ug/L applied.

Calculated AA-EQS (proposal): 25 µg/L / 50 = 0,5 µg/L

Protection of sediment-dwelling organisms

Liebig (2005) had proposed a PNECsed value of £ 2,8 µg/kgdw. The corresponding concentration in water is approximately 0.014μg/L. Only a view Measurements of the concentration of carbamazepine in sediments are available. For a first assessment a proposed PNECsed value of £ 2,8 µg/kgdw may be used.

7.2 Secondary poisoning

Secondary poisoning of top predators / Master reference
Mammalian oral toxicity / Species / Oral / duration / Endpoint
NOAEL : mg.kg-1bw.d-1
NOEC : mg.kg-1biota ww (CF= )
Species / Oral / duration / Endpoint
NOAEL : mg.kg-1bw.d-1
NOEC : mg.kg-1biota ww (CF= )
Avian oral toxicity / Species / Oral / 14 d
EC 50 : mg.kg-1bw.d-1
NOEC : mg.kg-1biota ww
Tentative QSbiota / Relevant study for derivation of QS / Assessment
factor / Tentative QS
Biota / NOEC : mg.kg-1biota ww / -- µg.kg-1biota ww
corresponding to
-- µg.L-1 (freshwater)
-- µg.L-1 (marine waters)

Protection of fish-eating species

According to measured bioconcentration factor (BFC) in the range of 0.8 – 4.2 (Fick 2010) and LogKow values from 1.76 to 2.45 (Hansch, C.et al. 1995) a bioaccumulation, and therefore a secondary risk of intoxication is not relevant.

7.3 human health

Human health via consumption of fishery products / Master reference
Mammalian oral toxicity / Humans / Oral / hematological toxicity
LOAEL : 100 mg d-1; 1.43 mg/kd/day for an adult; 3.33 mg/kd/day for a child / Cunningham 2010
CMR / Not mutagenic; carcinogenic activity is considered as unclassifiable; However, classified by the FDAas pregnancy category D; ‘certain evidence of reproductive adverse effects at clinical doses’. / Novartis internal data
Tentative QSbiota, hh / Relevant study for derivation
of QSbiota, hh / Assessment
Factor / Tentative QSbiota, hh
Human health / -- mg.kg-1biota ww / -- µg.kg-1biota ww
(-- µg.L-1)
Human health via consumption of drinking water / Master reference
Existing drinking water standard(s) / The Drinking Water Regulation identifies no limit (ie no maximum limit) for Carbamazepine in the drinking water.. / Anonymus 2001
Any guideline / Predicted no effect concentration (PNEC) = 232 µg/l (for children)
Accepted daily intake = 15.9 µg/kg/day / Cunningham 2010

8  Bibliography, Sources and supportive information

The bibliography contains more references than used in the dossier. A revised biblograhpy was not made because of shortage of time. A revised biblograhpy and citation will be made after the next work group meeting (20.-21.04.2010).

[1]  Budavari, S. (ed). The Merck Index – Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ.: Merck and Co., Inc., 269 (1989).

[2]  Lide, D. R. (ed). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995, 3-143.

[3]  Hansch, C.; Leo, A.; Hoekman, D.: Exploring QSAR – Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society, 129, (1995)

[4]  Testa, B.; Jenner, P.: Drug Metabolismus: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 138 (1976)

[5]  Nichina, T. et al.: Rinsho kagaku shimpojumu 17, 78 (1978)

[6]  Johnston, C. K.; Lester, G. H.; Ann Clin Biochem 16 (4), 213 (1979)

[7]  Pantarotto C. et al: Anal. Biochem. 93 (1), 115 (1979)

[8]  Novartis Farma S.p.A. Torre Annunziata. Zitiert in: IUCLID: http://ecb.jrc.it/IUCLID-Data-Sheet/298464.pdf.

[9]  Arzneimittelwerk Dresden GmbH Radebeul. Zitiert in: IUCLID: http://ecb.jrc.it/IUCLID-Data-Sheet/298464.pdf.

[10]  NEELY, W.B. & BLAU, G.E. (1985): Environmental exposure from chemicals. - 2. Auflage; Boca Raton, Florida (CRC Press).

[11]  SYRACUSE SCIENCE CENTER (2002): Database of experimental octanol-water partition coefficients (LogP). – Homepage http://esc-plaza.syrres.com/interkow/kowdemo.htm.

[12]  HANNA, M., DE BIASI, V., BOND, B., SALTER, C., HUTT, A.J. & CAMILLERI, P. (1998): Estimation of the partitioning characteristics of drugs: a comparison of a large and diverse drug series utilizing chromatographic and electrophoretic methodology. - Anal. Chem. 70: 2092-2099.