This summary information comes from the assessment report. Linaclotide is a peptide. A general exemption from an environmental risk assessment is granted for peptides in guideline (EMEA/CHMP/SWP/4447/00). However, these assumptions are not true for linaclotide. See further information under the heading detailed information.
Persistence. No data.
Bioaccumulation. Bioaccumulation of linaclotide should be considered very unlikely.
Toxicity. No data.
Risk. Risk of environmental impact of linaclotide cannot be excluded, due to the lack of environmental toxicity data.
Environmental information is missing on fass.se (2021-01-21). It is voluntary for manufacturers to provide information about environmental impact on fass.se.
Since 2006, an Environmental Risk Assessment (ERA) for the active pharmaceutical substance shall accompany an application for a marketing authorisation in EU for a medicinal product for human use. Parts of environmental data can be found in the public investigation report (PAR/EPAR for medicinal product through a centralized procedure). Since the benefit/risk assessment for human medicinal products at present does not include environmental effects, an update of the environmental risk assessment is not required for renewals of marketing authorizations. There is thus no requirement for companies to stay informed about the development of their substances from an environmental point of view and consequently to update the environmental risk assessment as new data are published.
"The active ingredient linaclotide is a peptide. A general exemption from an environmental risk assessment is granted for peptides in guideline (EMEA/CHMP/SWP/4447/00). This exemption is based on the assumptions that peptides are readily biodegradable, can only be administered in a parenteral way, are not excreted in an intact form and do not reach the environment. These assumptions are not true for linaclotide. Linaclotide is a member of the guanylin peptide family, which includes the natural hormones uanylin and uroguanylin as well as the bacterial heat stable enterotoxin, STa. Like STa, linaclotide is stable across a broad pH range including low pH found in the stomach. Due to its exceptional stability (compared to other peptides), linaclotide may be administered orally. In the human intestinal tract the 14th amino acid, Tyrosin, is cleaved resulting in an equally bioactive metabolite MM 419447. The active ingredient and its active metabolite are excreted to up to 6 % and might reach the environment. Therefore no general exemption can be granted from an environmental risk assessment for linaclotide. The environmental risk assessment at Phase I leads to a PECsurfacewater below 0.01 µg/L. According to EMEA/CHMP/SWP/4447/00 information on the octanol-water partitioning coefficient for the active ingredient is required in Phase I. However, the octanol/water partition coefficient that is normally used in Phase I to screen for potentially bioaccumulative substances is not a good predictor for this property for macromolecular compounds of the size of linaclotide. The applicant states that considering all available information (low Log Kow, high solubility and low permeability into Caco-2 cells) suggest that bioaccumulation of linaclotide should be considered very unlikely. This was accepted by the CHMP."
Persistence: No data.
Bioaccumulation: Log Dow (pH 7.4) likely below -2. "A PBT assessment has not been conducted. The available information from the PBT screening step (low log Dow, high solubility and low permeability into Caco-2 cells in virtro) suggests that bioaccumulation of linaclotide should be considered very unlikely."
Toxicity: No data.
PECsurfacewater, default = 0.00145 microg/L. "A Phase II assessment has not been conducted as PECsurfacewater is below the action limit of 10 ng/L."
Author: Health and Medical Care Administration, Region Stockholm