Oxidase, monoamine

Endpoint summary

Description of key information

Toxicokinetic studies performed on enzymes are very limited, but toxicokinetic information can be derived from the structure of enzymes combined with knowledge available for proteins in general since enzymes are proteins with catalytic activity.

 

Due to the combined information that skin absorption of enzymes is at a toxicologically insignificant level, that enzymes are degraded in the gastrointestinal tract and that they are only absorbed to a very low extent by the respiratory tract, the total bioavailability of enzymes can be concluded to be extremely low. Thus, systemic exposure following enzyme exposure at occupational and consumer exposure levels is without toxicological significance.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

Toxicokinetic studies performed on enzymes are very limited, but toxicokinetic information can be derived from the structure of enzymes combined with knowledge available for proteins in general since enzymes are proteins with catalytic activity.

 

Oral

CDX-616/CDX-656 has not been engineered for gastric stability and would be digested/hydrolyzed when ingested.  Like all proteins, enzymes that have not been engineered for low pH and/or gastric stability, CDX-616/CDX-656 will denature or degrade into amino acids.. As enzymes are simply a class of proteins, enzymes will undergo the same process as any food source.

 

In a study investigating the gastrointestinal absorption of enzymes in pigs with pancreatic insufficiency and treated with pancrelipase, analysis of plasma samples taken in the period of 0.5 to 48 hours after oral administration of the drug, did not result in treatment related changes of plasma enzyme levels indicating no gastric absorption of the administered enzymes [Gewert, et al., 2004].

 

Furthermore, a variety of enzymes are added to animal feed with the purpose to increase nutrient digestibility in the gastrointestinal tract. The safety of such enzymes active in the gastrointestinal tract are thoroughly evaluated as part of their approval process in the EU and elsewhere.

 

In conclusion, from the available data combined with the knowledge of the fate of proteins in the gastrointestinal system, it can be concluded that absorption of enzymes in toxicological significant amounts through the gastrointestinal tract is unlikely.  Therefore, a conservative value of 10% oral absorption is chosen.

 

Dermal

The physicochemical properties of a compound are decisive for the potential percutaneous penetration, in particular factors like ionization, molecular size and lipophilicity (ECHA, 2017). In general, non-ionized molecules easily penetrate the skin, with small molecules penetrating more easily than large molecules. Lipophilicity also facilitates penetration. Investigations of percutaneous absorption of peptides, proteins and other molecules of large size revealed that percutaneous absorption of proteins is extremely low and of no toxicological relevance [Basketter, et al., 2012]. Based on a consideration of the substance’s physicochemical properties and the results of percutaneous absorption studies of various proteins, a conservative value of 10% skin absorption is chosen.

 

Inhalation

Enzymes can be inhaled in the form of small dust particles or aerosols i.e. adhered to solid dust particles or as droplets of fluid. Absorption of hydrophilic substances such as enzymes by lung tissue is determined by diffusion and depends on molecular size. The transport channels in the alveolar membrane have a size of 1 nm (10Å) [Niesink, et al., 1996], which excludes the absorption of enzymes, since their size is above 1 nm. Removal of deposits depends on the site of deposition. In the alveoli where the main removal is via phagocytosis [Klaassen, 2019], the macrophages carrying the deposits can move to the interstitium, the ciliated epithelium or the lymphatic system indicating that there could be a risk of systemic exposure to enzymes by this route. However, due to the fact that enzymes are potential respiratory allergens, stringent risk management strategies have been introduced for the working environment leading to very low pulmonary exposure excluding any chance of toxicologically significant absorption. Furthermore, no bioaccumulation will occur after absorption due to rapid biological degradation and enzymes hydrophilic nature.  Therefore, a conservative value of 10% absorption following inhalation is chosen

 

Bioavailability:

Due to the combined information that skin absorption of enzymes is at a toxicologically insignificant level, that enzymes are degraded in the gastrointestinal tract and that they are only absorbed to a very low extent by the respiratory tract, the total bioavailability of enzymes can be concluded to be extremely low. Thus, systemic exposure following enzyme exposure at occupational and consumer exposure levels is without toxicological significance.

 

Due to the relatively low absorption of enzymes, metabolism and distribution are not relevant.

REFERENCES

Basketter, D., Berg, N., Broekhuizen, C., Fieldsend, M., Kirkwood, S., Kluin, C., Mathieu, S. and Rodriguez, C., 2012. Enzymes in cleaning products: an overview of toxicological properties and risk assessment/management. Regulatory Toxicology and Pharmacology, 64(1), pp.117-123.

 

ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Volume 3.0, July 2017. Available at: https://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5

 

Gewert, K., Holowachuk, S.A., Rippe, C., Gregory, P.C., Erlanson-Albertsson, C., Olivecrona, G., Kruszewska, D., Piedra, J.V., Weström, B. and Pierzynowski, S.G., 2004. The enzyme levels in blood are not affected by oral administration of a pancreatic enzyme preparation (Creon 10,000) in pancreas-insufficient pigs. Pancreas, 28(1), pp.80-88.

 

Klaassen CD, editor  (2019). Casarett and Doull's Toxicology: The Basic Science of Poisons, 9th edition. New York (NY): McGraw-Hill, Medical Publishing Division.

 

Niesink RJM, de Vries J, Hollinger MA. (1996). Toxicology, Principles and Applications CRC Press, Inc. and Open University of The Netherlands. Cited in: Enzymes REACH Consortium (2010). REACH Data waiving argumentation for technical enzymes.