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screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
Justification for type of information:
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. Exposure to enzymes will be limited because of the DMEL (derived minimum exposure levels) settings for workers, professionals and consumers to prevent respiratory allergy (supported by exposure scenarios and DMEL values) [1]. Apart from the irritation potential of some proteases, respiratory allergy is generally considered to be the only human health hazard of enzymes indicating that this is the most sensitive endpoint considering enzyme toxicity. Concentrations that are not expected to result in respiratory allergy will certainly not result in any other toxic effect [7]. This conclusion is substantiated by the material that follows.
Although endocrine disrupting chemicals are a broad group of chemicals consisting of man-made and natural compounds it is unlikely that enzymes have the potential to cause endocrine disruption. Testing of enzymes in currently available screening assays typically based on hormone receptor binding cannot be expected to provide any evidence for endocrine disruption due to the specific features of enzymes.
Data from acute and sub-chronic oral toxicity studies provide evidence that enzymes are of very low toxicological activity [2, 3, 4, 5, 6, 7, 8]. Typically, the derived NOAEL values are significantly higher than the maximum doses applied. None of the oral toxicity studies performed, as well as published data from other studies revealed any effect that indicates that enzymes could have an adverse effect on the reproduction system in males or females [1].
Enzymes have been produced and used for many years without any evidence for reproductive potential in humans. OEL for workers is set to be 60 ng/m3 to protect against respiratory sensitization [1]. In conclusion, toxicokinetic data together with the enzymatic structure and the weight of evidence from animal studies and human exposure provide no evidence for reproductive toxicity of enzymes.

[1] Basketter, D.A., Broekhuizen, C., Fieldsend, M., Kirkwood, S., Mascarenhas, R., Maurer, K., Pedersen, C., Rodriguez, C. and Schiff, H.E., 2010. Defining occupational and consumer exposure limits for enzyme protein respiratory allergens under REACH. Toxicology, 268(3), pp.165-170.
[2] Study numbers 0440RC130.001, 0437RC130.001, 0440SC130.002 and 0437RC130.001 Owner: Codexis, unpublished
[3] Study numbers CDX1783-R-2005, CDX1783-R-2021, CDX1783-NHP-2006 and CDX1783-NHP-2022 Owner: Codexis, unpublished
[4] Andersen, J.R., Diderichsen, B.K., Hjortkjaer, R.K., DE BOER, A.S., Bootman, J., West, H. and Ashby, R., 1987. Determining the safety of maltogenic amylase produced by rDNA technology. Journal of food protection, 50(6), pp.521-526.
[5] Greenough, R.J., Perry, C.J. and Stavnsbjerg, M., 1996. Safety evaluation of a lipase expressed in Aspergillus oryzae. Food and chemical toxicology, 34(2), pp.161-166.
[6] MacKenzie, K.M., Petsel, S.R.W., Weltman, R.H. and Zeman, N.W., 1989. Subchronic toxicity studies in dogs and in utero rats fed diets containing Bacillus stearothermophilus α-amylase from a natural or recombinant DNA host. Food and chemical toxicology, 27(9), pp.599-606.
[7] 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.
[8] Basketter, D., Berg, N., Kruszewski, F.H., Sarlo, K. and Concoby, B., 2012. The toxicology and immunology of detergent enzymes. Journal of immunotoxicology, 9(3), pp.320-326.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion