Detaljerad miljöinformation

Identification and characterisation

CAS number: 1622-61-3 [1]

Molecular weight: 315.7 [1]

Brand name: Iktorivil [1]

Physico-chemical properties

Aqueous solubility: <100 mg/l (20 °C) (method not specified) [1]

Dissociation constant, pK_a: pK_a = 1.5 [1], pK_b = 10.5 [1]

Melting point: 236.5–238.5 °C (method not specified) [1]

Vapour pressure: 9.76*E^–09 Pa (25 °C) QSAR

Boiling point: ND

K_H: 8.6*E^–13 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) = 3.8 x 10^-4 μg/L

Where:

A Sold quantity = 2.50 kg/y (total sold amount API in Sweden year 2020, data from IQVIA)

R Removal rate = 0 % Default [2]

P Population of Sweden = 10 x 10⁶

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

D Factor for Dilution = 10 Default [2]

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Desmodesmus subspicatus): [4]

72 h ErC50 (growth rate) >240 mg/l loading rate (OECD 201)

72 h ErC50 (growth rate) >15.4 mg/l (solubility limit in algal medium, estimated) (OECD 201)

72 h NOEC = 2.46 mg/l loading rate (OECD 201)

(With respect to algal growth rate inhibition the following effects as compared to the untreated controls were observed at the respective loading rates: 240 mg/l (49%), 96 mg/l (46%), 38.4 mg/l (38%), 15.4 mg/l (34%) and 6.14 mg/l (16%). No significant effects were observed at 2.46 mg/l. Since no significant increase of toxicity occurred at concentrations >15.4 mg/l, this concentration can estimated to be the solubility limit in algal medium)

Water-flea (Daphnia magna): [5]

48 h EC₅₀ (immobilisation) = 30.3 mg/l mean measured concentration (FDA Technical Assistance Document 4.08) (the nominal concentrations were 5.4, 9.1, 15.1, 25.2, 42.0 and 70.0 mg/l, The respective analytically determined mean measured concentrations were 4.04, 7.08, 11.7, 19.1, 31.4 and 48.8 mg/l, respectively)

Rainbow trout (Oncorhynchus mykiss): [7]

96 h LC₅₀ >1000 mg/l (applied as an emulsion) (OECD 203)

96 h NOEC = 1000 mg/l (applied as an emulsion) (OECD 203)

Micro-organisms: [6]

NOEC (microbial growth) = 4.2 mg/l (FDA Technical Assistance Document 4.02)

(various pure cultures of bacteria, fungi, and cyanobacteria)

PNEC Derivation

The PNEC is based on the following data:

PNEC (mg/l) = lowest EC₅₀/1000, where 1000 is the assessment factor used. An estimated solubility limit of 15400μ g/l in algal medium has been used for this calculation.

PNEC = 15400 / 1000 = 15.4 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.00038 μg/L

PNEC Predicted No Effect Concentration = 15.4 μg/L

Ratio PEC/PNEC = 0.000024

PEC/PNEC = 0.00038/15.4 = 0.000024 for Clonazepam which justifies the phrase 'Use of Clonazepam has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability: ND

Inherent biodegradability: [7]

0% after 21 days of incubation BOD/ThOD (OECD 302 C)

Other degradation information: ND

Abiotic Degradation

Photodegradation: light sensitive [1]

Hydrolysis: ND

Clonazepam was not inherently biodegradable in a standard test. This justifies the phrase 'Clonazepam is potentially persistent.'

Bioaccumulation/Adsorption

logP_OW 2.53 QSAR

logD_OW 2.41 (25 °C, pH 7.4) (method not specified) [1]

K_OC 283 l/kg QSAR

BCF <20 QSAR

Clonazepam has low potential for bioaccumulation.

Excretion/metabolism

The elimination half-life of Clonazepam is between 20 and 60 hours (mean 30 hours). Within 4–10 days 50–70% of are excreted in the urine and 10–30% in the faeces, almost exclusively in the form of free or conjugated metabolites. Less than 0.5% appears as unchanged clonazepam in the urine. [3]

References

1. F. Hoffmann-La Roche Ltd (2018): Safety Data Sheet for Clonazepam, 31.01.2018; https://www.roche.com/sustainability/what_we_do/for_communities_
   and_environment/environment/safety_data_sheetsrow.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. electronic Medicines Compendium (eMC). 2017. https://www.medicines.org.uk/emc/.

4. BMG Engineering Ltd, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (2007). Clonazepam: Fresh water growth inhibition test with Desmodesmus subspicatus. BMG study no. 1226-07.

5. Toxikon Environmental Sciences, on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (1992). Clonazepam: Acute toxicity to the water flea Daphnia magna under static test conditions. Toxikon study no. J9108014b.

6. ABC Laboratories, Inc., on behalf of F. Hoffmann-La Roche Ltd, Basel, Switzerland (1992). Microbial inhibition with Clonazepam. ABC study no. 40067.

7. Roche internal ecotox report. 1981.