Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6 * A * (100 - R) = 1.37*10^-6 * 12.202 kg * 100 = 0.00672 μg/L = 1.672 ng/L

Where:

A = 12.2020 kg letrozole (total sold amount API in Sweden year 2022, data from IQVIA).

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0, if no data is available.

P = number of inhabitants in Sweden = 10 * 10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus) (OECD 201) (Ciba-Geigy Ecotoxicology Test No 948104)

EC50 72 h (growth rate) > 100.0 mg/L

Crustacean (Daphnia magna):

Acute toxicity

EC50 48 h (immobilisation) > 35.0 mg/L, maximum testing concentration due to water solubility limit (OECD 202) (Ciba-Geigy Ecotoxicology Test No 948109)

Fish:

Acute toxicity (Oncorhynchus mykiss, rainbow trout)

LC50 96 h (mortality) > 37.0 mg/L, maximum testing concentration due to water solubility limit (OECD203) (Ciba-Geigy Ecotoxicology Test No 948109)

Chronic toxicity (Oryzias latipes, red killifish)

NOEC 21 days (Decrease in fertility and reduced plasma vitellogenin levels in females as well as hatchability and time to hatching) = 0.005 mg/L (Sun et al. 2007)

Method:

Japanese medaka were kept in charcoal–dechlorinated tap water (pH 7.2–7.6; hardness 44.0–61.0 mg CaCO₃/L) at a constant temperature (25±1 °C), with a photoperiod of 16:8 h (light:dark). The brood stock was fed three times daily, once with newly hatched brine shrimp (Artemia sp.) and twice with commercial fish food (TetraMin®).

84 breeding pairs of medaka were selected for the reproductive test. Six pairs were randomly assigned to a 15-L glass aquarium and duplicate aquaria were used at each exposure level. A dilution apparatus equipped with a peristaltic pump and mixing chambers supplied a constant flow equivalent to 7 times the aquaria volume per day. Fish were exposed to nominal letrozole concentrations of 1, 5, 25, 125 and 625 μg/L.

Other ecotoxicity data:

Bacterial respiration inhibition

IC₅₀ 3 h > 20.2 mg/L

IC₀ = 20.2 mg/L (activated sludge respiration inhibition) (OECD209) (Ciba-Geigy Ecotoxicology Test No 948103)

PNEC derivation

PNEC = 50.0 ng/L

PNEC = available chronic NOEC for fish reproductive endpoints, where 100 is the assessment factor used, based on the availability of acute data for fish, Daphnia and algae and one long-term NOEC for fish. A NOEC of 0.005 mg/L for fish reproductive endpoints has been used for this calculation

The above described choice of the assessment factor is based on the fact that letrozole is a aromatase inhibitor and reproductive endpoints in fish are expected to be the most sensitive endpoints for this mechanism of action. This is in line with REACH guidance R.10 (see Table R.10-4 and p. 18), where knowledge of the mode of action including endocrine disrupting effects is stated as a possible justification for changing the assessment factor (ECHA, May 2008).

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 1.672 ng/L / 50 ng/L = 0.033, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of letrozole has been considered to result in insignificant environmental risk."

Degradation

Biotic degradation

Ready degradability:

1 % degradation in 29 days, not readily biodegradable (OECD 301B). (Ciba-Geigy Ecotoxicology Test No 948103)

Justification of chosen degradation phrase:

Letrozole does not pass the criteria for ready biodegradation. The phrase “Letrozole is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log P_ow = 2.5 (experimentally determined, method unknown). (Dave et al. 2015)

Justification of chosen bioaccumulation phrase:

Since log P_ow< 4, letrozole has low potential for bioaccumulation.

Excretion (metabolism)

Within 2 weeks after administration of 2.5 mg ¹⁴C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6 % of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to unchanged letrozole. (Femara^® Core Data Sheet)

References

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

• Ciba-Geigy Ecotoxicology Test No 948104. Report on the growth inhibition test of PBS 146991.8 to green algae (Scenedesmus subspicatus). Final report: 05 December 1994.

• Ciba-Geigy Ecotoxicology Test No 948109. Report on the acute toxicity test of PBS 146991.8 on Daphnia (Daphnia magna Straus 1820). Final report: 24 February 1995.                       

• Ciba-Geigy Ecotoxicology Test No 948110. Acute toxicity test of PBS 146991.8 to rainbow trout (Oncorhynchus mykiss) in the static system. Final report: 17 February 1995.        

• Dave N, Chow LM, Gudelsky GA, LaSance K, Qi X, Desai PB. Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas. Mol Cancer Ther. 2015 Apr;14(4):857-64. doi: 10.1158/1535-7163.MCT-14-0743. Epub 2015 Feb 18. PMID: 25695958; PMCID: PMC4631403                              

• Sun et al. 2007. Toxicity of the aromatase inhibitor letrozole to Japanese medaka (Oryzias latipes) eggs, larvae and breeding adults. Comparative Biochemistry and Physiology, Part C 145, p. 533-541.                                       

• ECHA, May 2008: ECHA Guidance for the implementation of REACH: Guidance on information requirements and chemical safety assessment, Chapter R.10: Characterisation of does[concentration]-response for environment                                                                                                

• Ciba-Geigy Ecotoxicology Test No 948103. Report on the test for ready biodegradability PBS 146991.8 in the carbondioxide evolution test. Final report: 10 November 1994.

• Femara^®(letrozole) Core data sheet, Version 2.0. 15 December 2016.h Europe B.V., Project 503057 Determination of Physico-Chemical propertie