Maxipime^®

Detaljerad miljöinformation

PEC/PNEC = 2.61 x 10^-4 µg/L / 640 µg/L = 4.08 x 10^-7, i.e. PEC/PNEC ≤ 0.1 which means that the phrase “Use of the medicine has been considered to result in insignificant environmental risk” is used for Level 1 and 2.

The PEC is based on the following data:

A = 1.74 kg/year (data from Läkemedelsstatistik AB, LSAB)

PEC = 1.5 x 10^-4 x 1.74 = 2.61 x 10^-4 µg/L

Note the PEC is < 1 ng/L which is well below the 10 ng/L de minimis level used in the EU for environmental risk assessments for medicines.

The PNEC is derived from the acute daphnid toxicity data.

Note: This estimate does not account for any environmental depletion mechanisms.

Physical-Chemical properties:

General

Cefepime is an ionizable molecule that is sold in formulations containing the hydrochloride salt of the drug. The molecular weight of the free base is 480.58.

Water solubility

Cefepime is an ionizable molecule. As the hydrochloride (monohydrate) it has relatively high water solubility > 1% at pH 5, 7, and 9, approximately 0.7 mg/L.

Ionization constant

The pKa values for cefepime are 1.39 and 3.26.

Octanol/Water distribution coefficient

The log n-octanol/water distribution coefficients measured at pH 5, 7, and 9 are all approximately 2.5-2.6. (FDA 3,02)

Vapor pressure

Cefepime is not considered to be a volatile compound. The vapor pressure is 1.26 x 10⁷ Torr. (FDA 3,03)

Ecotoxicological Studies

Water-flea, Daphnia magna:

EC₅₀ 48 h > 640000 μg/l (OECD 202)

Note: The substance is considered to have low toxicity to daphnids.

Microorganisms

Sludge Respiration Inhibition:

IC50 for inhibition of respiration of activated sludge microorganisms was 201000 μg/l . (OECD 209)

Estimation of PNEC

The PNEC has been estimated using two approaches:

PNEC (μg/l) is estimated from the sludge respiration inhibition study as = EC₅₀/100, where 100 is the assessment factor used, per the guidance of the EU TGD Part II, 2003.

PNEC = 201000/100 = 2010 μg/L for sludge organisms

PNEC (μg/l) is estimated from the acute daphnid study as = EC₅₀/1000, where 1000 is the assessment factor used. Note: Per the EU TGD Part II, 2003, it is noted that when the acute aquatic base set is not complete, for example - low volume substances an assessment factor of 1000 should be used. As the annual use volumes of cefepime are very low (3 kg/annum), it is reasonable to use this approach.

PNEC = 640000/1000 = 640 μg/L for aquatic invertebrates

For the overall assessment of PEC/PNEC the daphnid PNEC is used as it is more conservative.

Degradation

Biodegradation

Cefepime undergoes rapid primary aerobic degradation with a half-life of 4.43 days. However, only a small percentage is mineralized to CO₂. (FDA 3,11)

Hydrolysis

The hydrolysis half-lives for cefepime are 25.7 and 14.4 days at pH 5 and 7, respectively, and 10.1 hours at pH 9. Cefepime was hydrolytically unstable, especially at the higher pH. (FDA 3,09)

Sorption

Cefepime is not expected to sorb significantly to soils based on low Kd values (ranging from 1-5). Additionally sorption to the organic carbon components is moderate (~150-325 based on soil source). (FDA 3,08)

Bioaccumulation

Cefepime is not expected to bioaccumulate based on the low log Kow.

Metabolism and Excretion

The majority of a dose of cefepime is excreted by patients as unchanged drug in the urine (~85%). Other metabolites were epimers or oxides of cefepime or the N-methyl pyrrolidine portion of the cefepime molecule.

Other information

This substance does not qualify as a PBT substance.

References

Cefepime - Water Solubility

Springborn (Laboratory now SpringbornSmithers) Study No. 92-3-4150

Cefepime - Hydrolysis in Water

Springborn (Laboratory now SpringbornSmithers) Study No. 92-1-4092

Cefepime - Ionization Constant

Springborn (Laboratory now SpringbornSmithers) Study No. 92-3-4168

Cefepime - Vapor Pressure

Springborn (Laboratory now SpringbornSmithers) Study No. 92-3-4158

Cefepime - Determination of Aerobic Biodegradation in Water

Springborn (Laboratory now SpringbornSmithers) Study No. 91-12-4048

Cefepime - Determination of the n-Octanol/Water Partition Coefficient

Springborn (Laboratory now SpringbornSmithers) Study No. 92-3-4169

Cefepime - Determination of Sorption and Desorption Properties

Springborn (Laboratory now SpringbornSmithers) Study No. 92-1-4087

Cefepime - Determination of Activated Sludge Respiration Inhibition

Springborn (Laboratory now SpringbornSmithers) Study No. 91-9-3924

Cefepime - Acute Toxicity to Water Fleas (Daphnia magna) Under Static Conditions

Springborn (Laboratory now SpringbornSmithers) Study No. 91-10-3972