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Ketoconazole

Summary

Persistence. Ketoconazole is potentially persistent.
Bioaccumulation. Ketoconazole has high potential for bioaccumulation.
Toxicity. Ketoconazole has very high chronic toxicity.
Risk. The use of ketoconazole has been considered to result in low environmental risk.

However, ketoconazole is as a potentially endocrine disruptor according to the assessment report.

The data on hazard are based on previous environmental information on fass.se. Environmental information is missing (2022-06-30). It is voluntary for manufacturers to provide information about environmental impact on fass.se. The risk comes from the report by Goodpoint.

Detailed information

Fass environmental information

Fass environmental information for Fungoral (ketokonazole) from Janssen (downloaded 2013-11-24).

Hazard

Persistence: Ketoconazole is not readily biodegradable (OECD 301F).

Bioaccumulation: Ketoconazole has bioaccumulation potential, log D = 3.78.

Toxicity: There are data for 3 trophic levels, most sensitive Green alga (Selenastrum capricornutum) NOEC 0.5 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year but it is not written from which year. PEC/PNEC = 0.651 which gives the risk low.

"PNEC (μg/l) = lowest NOEC/5, where 5 is the assessment factor used. The NOEC for the alga Selenastrum capricornutum (0.5 μg/l) has been used for this calculation since it is the most sensitive of the three species tested in chronic studies. Green algae and cyanobacterium have been shown to be the most sensitive species for triazole fungicides (Peterson 1994). Fungicides broadly classified as N-substituted imidazoles or triazoles depress fungal growth through inhibition of 14-demethylase (CYP51) activity, a key step in ergosterol formation (Van den Bossche et al, 1978; 1982). Expression of other CYP enzymes in fish, c17αhydroxylase, 17,20-lyase (CYP17), and aromatase (CYP19), were not affected by 7 day exposure to 30 ug/L ketoconazole (Zhang et al, 2008). Therefore, given the specific mode of action, an assessment factor of 5 was used instead of the default factor of 10. The selective activity of this compound is also demonstrated by the NOEC of greater than 1000 mg/L for effects on activiated sludge microorganisms."

Assessment report

Assessment report for Ketoconazole HRA, Laboratoire HRA Pharma, 25 September 2014, EMA/CHMP/534845/2014.

"As Ketoconazole is a potential endocrine disruptor, a phase II ERA is requested as outlined in the guideline. The PECsurface water using the refined Fpen value of 0.023 microg/L as requested by the CHMP, triggered the threshold value of 0.01 microg/L. Some data regarding aquatic effects are available in the literature and the applicant is requested to perform a full literature search in order to obtain all available information regarding ketoconazole effects on the environment, and to perform a gap analysis as a post-Marketing Authorisation commitment. A detailed program including missing studies necessary to complete the ERA for ketoconazole will be submitted for approval within 4 weeks after EC decision. Furthermore, a phase II ERA will be performed as a post Marketing commitment, as requested by the CHMP." No such updated information has been found on the EMA's website (2022-06-30).

Report from Goodpoint

Large margin between concentrations in the environment and the concentration that affects the environment. The primary source is shampoo for dandruff.

Pharmaceuticals residues in the aquatic environment in Region Stockholm

Ketoconazole is one of the substances analyzed in the aquatic environment in Region Stockholm, Sweden. Concentrations have been below the detection limits in 2020 and 2021. According to the report "Läkemedelsrester i Stockhoms vattenmiljö": Some so-called broad-spectrum antibiotics (ciprofloxacin, norfloxacin, tetracycline) are also well separated from incoming water, as is the fungicide ketoconazole, but they largely end up in the sludge instead.

Author: Health and Medical Care Administration, Region Stockholm