Detaljerad miljöinformation

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula: (Ref. 1)

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100)

Where:

A (kg/yr)	0,08 kg	Total API sold (kg) in Sweden in 2020 (Ref. 2)
R	0 %	Removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation); use 0 if no data is available
P	10*106	Number of inhabitants in Sweden (Ref. 1)
V (L/day)	200	Volume of wastewater per capita and day (200 L/day is the default value) (Ref. 1;3)
D	10	Factor for dilution of wastewater by surface water flow (10 is the default value) (Ref. 1;3).

Note: The factor 10⁹ converts the quantity distressed from kg to mcg.

PEC (μg/L) = (0,08*10⁹*(100-0))/(365*10*10⁶*200*10*100)

PEC = 0,000011 μg/L

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of leuprorelin acetate is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit of 0,01 µg/L. (Ref. 1)

Predicted No Effect Concentration (PNEC)

Risk of environmental impact of leuprorelin acetate cannot be excluded, since no ecotoxicity data are available.

Ecotoxicological Studies

No ecotoxicity data are available.

Environmental Risk Classification (PEC/PNEC ratio)

Risk of environmental impact of leuprorelin acetate cannot be excluded, since no ecotoxicity data are available.

Degradation

The potential for persistence of leuprorelin acetate cannot be excluded, due to lack of data.

Bioaccumulation

Partitioning coefficient:

Log D_ow = -1,7 at pH 7

The K_d of leuprolide acetate, determined via octanol-water partitioning studies, was found to be 0,022. (Ref. 4)

The K_ow of leuprolide acetate was reported to be 0,02 at pH of 7. (Ref. 5)

The partition coefficients (log K_ow) for the amino acids that are contained within leuprorelin acetate are all less than 0 (range from –1,05 to –4,20). Therefore, the anticipated log K_ow of leuprorelin acetate is approximately 0. Thus, leuprorelin acetate is not likely to bioaccumulate. Additionally, if consumed by aquatic or terrestrial organisms, leuprorelin acetate would likely be broken down similar to any other consumed peptide or protein (supported by the high oral LD₅₀ values observed in mice and rats). Therefore, leuprorelin is not likely to bioaccumulate. (Ref. 6)

Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Leuprorelin acetate is excreted to less than 5% as parent compound and the pentapeptide metabolite and to unknown% as the remaining metabolites. The pharmacological activity of the metabolites is not known.

Metabolism of leuprorelin acetate leads to formation of smaller peptide occurring as a result of hydrolytic and oxidative processes as indicated by ¹⁴C metabolism of leuprorelin in rats and dogs.  It was shown that leuprorelin is metabolized to smaller inactive peptides, a pentapeptide (M-I), tripeptides (M-II and M-III), and a dipeptide (M-IV). The pentapeptide is considered to be the major metabolite. The breakdown products of leuprorelin acetate are also considered to be biologically inactive and not capable of eliciting a gonadotropic response. This is supported by the observation that cleavage of any peptide bond eliminates the biological activity of GnRH.  (Ref. 7) 

Furthermore, following (intramuscular) administration of Procren Depot® 3.75 mg leuprorelin acetate to 3 patients, less than 5% of the dose was recovered as the parent compound and the pentapeptide metabolite in the urine. These results indicate the significant breakdown of leuprorelin acetate that occurs with therapeutic use. Also with oral administration, similar to any peptide or protein, leuprorelin acetate is anticipated to be broken down to peptide fragments or amino acids, thus minimal amounts of the parent drug would be excreted in the urine or feces with oral ingestion. (Ref. 6)

References

1. FASS.se. Environmental classification of pharmaceuticals at www.fass.se. Guidance for pharmaceutical companies. V 2012 2.0. 2021.

2. IQVIA. 2020. IQVIA / LIF - kg consumption/2020.

3. European Chemicals Agency (ECHA). Guidance on Information Requirements and Chemical Safety Assessment Chapter R.16: Environmental exposure assessment. Version 3.0. 2016.

4. Lu, Mou-Ying; G. N. Subba Rao; and D. Y. Lee. Formulations and method of the percutaneous administration of leuprolide. United States Patent Office, Patent 5,446,025. Filed June 12, 1992. Appl. Number 07/897,680.

5. Adjei, A; S. Rao; J. Garren; G. Menon; M. Vadnere. 1993. Effect of ion-pairing on 1-octanol-water partitioning of peptide drugs. I: The nonapeptide leuprolide acetate. International Journal of Pharmaceutics 90: 141-149.

6. Abbott Laboratories. Environmental Risk Assessment, Lupron® (leuprorelin acetate) 30 mg (6 month), PDS, for Injection. July 13, 2009.

7. Abbvie. AbbVie Response to Swedish Agency's Overall Review of leuprorelin. September 12, 2014. November 6, 2014.