Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Alpha-amylase should not be classified as carcinogenic. (For further justification see discussion above).

Additional information

Enzyme proteins including alpha-amylase are not regarded as either genotoxic and/or carcinogenic substances. Genotoxicity testing is in general performed to confirm that the production strain does not produce any genotoxic or carcinogenic metabolites. Basically all enzyme substances have therefore been tested in the Ames test and in the Chromosome Aberration test in vitro and/or an in vitro micronucleus test, and a few enzyme substances also in the Mouse Lymphoma test (ref. 11-40). In none of these test systems did enzyme proteins show evidence of genotoxicity.

 

Enzymatic drugs have been used since the 19th century without providing any evidence of a genotoxic or carcinogenic effect (ref. 2-10; 41-44).

 

Review of the extensive literature concerned with the safety of enzymes from microbial sources strongly supports the general assumption that enzymes from non-toxigenic, non-pathogenic organisms are safe. Numerous tests for in vitro genotoxicity have failed to reveal the presence of a single mutagen or clastogen. These aspects were reviewed by Pariza and Johnson (ref. 1), who presented a compelling argument for the position that tests for genotoxic potential of enzyme preparations produced by well-characterized non-toxigenic microorganisms are unnecessary for safety evaluation.

 

In conclusion, the large amount of data on genotoxicity available together with structural knowledge, toxicokinetic and human data provide no evidence for genotoxic or carcinogenic potential of enzymes.

 

The low exposure to enzymes, the low bioavailability in case of exposure, the lack of genotoxic potential and the consequent absence of any evidence of carcinogenic properties from both human and animal data does not justify any requirement for conducting carcinogenicity studies.

 

References

1) Pariza, M.W. and Johnson, E.A. (2001) Evaluating the safety of microbial enzyme preparations used in food processing: Update for a new century. Regulatory Toxicology and Pharmacology 33, 173-186

2) Barra,E., Stolarczyk,A., Socha,J., Oralewska,B., Kowalska,M., Skoczen,M., and Wawer,Z. (1998) Efficacy of enzyme supplementation in children with cystic fibrosis. Pediatria Polska 73, 177-182

3) Borowitz,D., Goss,C.H., Stevens,C., Hayes,D., Newman,L., O'Rourke,A., Konstan,M.W., Wagener,J., Moss,R., Hendeles,L., Orenstein,D., Ahrens,R., Oermann,C.M., Aitken,M.L., Mahl,T.C., Young,K.R., Dunitz,J., and Murray,F.T. (2006) Safety and preliminary clinical activity of a novel pancreatic enzyme preparation in pancreatic insufficient cystic fibrosis patients. Pancreas 32, 258-263

4) Borowitz,D., Goss,C.H., Limauro,S., Konstan,M.W., Blake,K., Casey,S., Quittner,A.L., and Murray,F.T. (2006) Study of a novel pancreatic enzyme replacement therapy in pancreatic insufficient subjects with cystic fibrosis. Journal of Pediatrics 149, 658-662

5) Keller,J. and Layer,P. (2006) Are monolithic enteric-coated enzyme preparations effective in pancreatic exocrine insufficiency? A multicentre, double blind, placebo controlled cross-over trial. Gastroenterology 130, A517

6) Konstan,M.W., Stern,R.C., Trout,J.R., Sherman,J.M., Eigen,H., Wagener,J.S., Duggan,C., Wohl,M.E.B., and Colin,P. (2004) Ultrase MT12 and ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: Safety and efficacy. Alimentary Pharmacology and Therapeutics 20, 1365-1371

7) Konstan,M.W., Liou,T.G., Strausbaugh,S., Ahrens,R.C., Kanga,J.F., Graff,G.R., Moffett,K.S., Millard,S., Nasr,S.Z., Vezina,M., Spenard,J., and Grondin,J. (2008) Efficacy and safety of Ultrase (R) MT20 in treating pancreatic insufficiency in cystic fibrosis. Gastroenterology 134, A228-A229

8) Laake,K. (1980) ENZYMIC DRUGS. Side Effects of Drugs Annual 222-225

9) Patchell,C.J., Desai,M., Weller,P.H., Macdonald,A., Smyth,R.L., Bush,A., Gilbody,J.S., and Duff,S.A. (2002) Creon 10,000 Minimicrospheres vs. Creon 8,000 microspheres--an open randomised crossover preference study. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 1, 287-291

10) Saeed,Z., Wojewodka,G., Marion,D., Guilbault,C., and Radzioch,D. (2007) Novel pharmaceutical approaches for treating patients with cystic fibrosis. Current Pharmaceutical Design 13, 3252-3263

11) Ahmad,S.K., Brinch,D.S., Friis,E.P., and Pedersen,P.B. (2004) Toxicological studies on Lactose Oxidase from Microdochium nivale expressed in Fusarium venenatum. Regulatory toxicology and pharmacology: RTP 39, 256-270

12) 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 RECOMBINANT DNA TECHNOLOGY. Journal of Food Protection 50, 521-526

13) Ashby,R., Hjortkjaer,R.K., Stavnsbjerg,M., Gurtler,H., Pedersen,P.B., Bootman,J., Hodson-Walker,G., Tesh,J.M., Willoughby,C.R., and Et,A. (1987) SAFETY EVALUATION OF STREPTOMYCES-MURINUS GLUCOSE ISOMERASE. Toxicology Letters (Shannon) 36, 23-36

14) Bar,A., Krul,C.A.M., Jonker,D., and de,V.N. (2004) Safety evaluation of an alpha-cyclodextrin glycosyltranferase preparation. Regulatory Toxicology and Pharmacology 39, S47-S56

15) Brinch,D.S. and Pedersen,P.B. (2002) Toxicological studies on Laccase from Myceliophthora thermophila expressed in Aspergillus oryzae. Regulatory toxicology and pharmacology: RTP 35, 296-307

16) Brinch,D.S. and Pedersen,P.B. (2002) Toxicological studies on Polyporus pinsitus laccase expressed by Aspergillus oryzae intended for use in food. Food additives and contaminants 19, 323-334

17) Broadmeadow,A., Clare,C., and De Boer,A.S. (1994) An overview of the safety evaluation of the Rhizomucor miehei lipase enzyme. Food additives and contaminants 11, 105-119

18) Bui,Q., Geronian,K., Gudi,R., Wagner,V., Kim,D., and Cerven,D. (2004) Safety evaluation of marmanase enzyme, produced by Bacillus lentus, intended for use in animal feed. International Journal of Toxicology 23, 398

19) Baer,A., Til,H.P., and Timonen,M. (1995) Subchronic oral toxicity study with regular and enzymatically depolymerized sodium carboxymethylcellulose in rats. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 33, 909-917

20) Ciofalo,V., Barton,N., Kretz,K., Baird,J., Cook,M., and Shanahan,D. (2003) Safety evaluation of a phytase, expressed in Schizosaccharomyces pombe, intended for use in animal feed. Regulatory Toxicology and Pharmacology 37, 286-292

21) Coenen,T.M., Schoenmakers,A.C., and Verhagen,H. (1995) Safety evaluation of beta-glucanase derived from Trichoderma reesei: summary of toxicological data. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 33, 859-866

22) Coenen,T.M., Aughton,P., and Verhagen,H. (1997) Safety evaluation of lipase derived from Rhizopus oryzae: summary of toxicological data. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 35, 315-322

23) Coenen,T.M. and Aughton,P. (1998) Safety evaluation of amino peptidase enzyme preparation derived from Aspergillus niger. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 36, 781-789

24) Coenen,T.M., Bertens,A.M., de Hoog,S.C., and Verspeek-Rip,C.M. (2000) Safety evaluation of a lactase enzyme preparation derived from Kluyveromyces lactis. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 38, 671-677

25) Cook,M.W. and Thygesen,H.V. (2003) Safety evaluation of a hexose oxidase expressed in Hansenula polymorpha. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 41, 523-529

26) Deboer,A.S., Marshall,R., Broadmeadow,A., and Hazelden,K. (1993) Toxicological Evaluation of Acetolactate Decarboxylase. Journal of Food Protection 56, 510-517

27) Elvig,S.G. and Pedersen,P.B. (2003) Safety evaluation of a glucanase preparation intended for use in food including a subchronic study in rats and mutagenicity studies. Regulatory Toxicology and Pharmacology 37, 11-19

28) Greenough,R.J., Everett,D.J., and Stavnsbjerg,M. (1991) Safety evaluation of alkaline cellulase. Food Chem.Toxicol 29, 781-785

29) Greenough,R.J., Perry,C.J., and Stavnsbjerg,M. (1996) Safety evaluation of a lipase expressed in Aspergillus oryzae. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 34, 161-166

30) Harbak,L. and Thygesen,H.V. (2002) Safety evaluation of a xylanase expressed in Bacillus subtilis. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 40, 1-8

31) Hjortkjaer,R.K., Bille-Hansen,V., Hazelden,K.P., McConville,M., McGregor,D.B., Cuthbert,J.A., Greenough,R.J., Chapman,E., Gardner,J.R., and Ashby,R. (1986) Safety evaluation of Celluclast, an acid cellulase derived from Trichoderma reesei. Food Chem.Toxicol 24, 55-63

32) Hjortkjaer,R.K., Stavnsbjerg,M., Pedersen,P.B., Heath,J., Wilson,J.A., Marshall,R.R., and Clements,J. (1993) Safety evaluation of esperase. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 31, 999-1011

33) Kondo,M., Ogawa,T., Matsubara,Y., Mizutani,A., Murata,S., and Kitagawa,M. (1994) Safety evaluation of lipase G from Penicillium camembertii. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 32, 685-696

34) Landry,T.D., Chew,L., Davis,J.W., Frawley,N., Foley,H.H., Stelman,S.J., Thomas,J., Wolt,J., and Hanselman,D.S. (2003) Safety evaluation of an alpha-amylase enzyme preparation derived from the archaeal order Thermococcales as expressed in Pseudomonas fluorescens biovar I. Regulatory toxicology and pharmacology : RTP 37, 149-168

35) Lane,R.W., Yamakoshi,J., Kikuchi,M., Mizusawa,K., Henderson,L., and Smith,M. (1997) Safety evaluation of tannase enzyme preparation derived from Aspergillus oryzae. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 35, 207-212

36) Modderman,J.P. and Foley,H.H. (1995) Safety evaluation of pullulanase enzyme preparation derived from Bacillus licheniformis containing the pullulanase gene from Bacillus deramificans. Regulatory Toxicology and Pharmacology 21, 375-381

37) Ohshita,K., Nakajima,Y., Yamakoshi,J., Kataoka,S., Kikuchi,M., and Pariza,M.W. (2000) Safety evaluation of yeast glutaminase. Food and Chemical Toxicology 38, 661-670

38) Stavnsbjerg,M., Hjortkjaer,R.K., Billehansen,V., Jensen,B.F., Greenough,R.J., McConville,M., Holmstroem,M., and Hazelden,K.P. (1986) Toxicological Safety Evaluation of A Bacillus-Acidopullulyticus Pullulanase. Journal of Food Protection 49, 146-153

39) Pedersen,P.B. and Broadmeadow,A. (2000) Toxicological studies on Thermomyces lanuginosus xylanase expressed by Fusarium venenatum, intended for use in food. Food additives and contaminants 17, 739-747

40) Porter,M.C., Hartnagel,R.E., Jr., Kowalski,R.L., Clemens,G.R., Jasty,V., Bare,J.J., and Boguslawski,G. (1984) SAFETY EVALUATION OF GLUCOSE ISOMERASE DERIVED FROM FLAVOBACTERIUM-ARBORESCENS AND USED IN PRODUCTION OF HIGH FRUCTOSE CORN SYRUP. Journal of Food Protection 47, 359-371

41) Jensen,B.F. and Eigtved,P. (1990) Safety Aspects of Microbial Enzyme Technology, Exemplified by the Safety Assessment of An Immobilized Lipase Preparation, Lipozyme. Food Biotechnology 4, 699-725

42) Klinge,L., Straub,V., Neudorf,U., and Volt,T. (2005) Enzyme replacement therapy in classical infantile Pompe disease: Results of a ten-month follow-up study. Neuropediatrics 36, 6-11

43) Klinge,L., Straub,V., Neudorf,U., Schaper,J., Bosbach,T., Görlinger,K., Wallot,M., Richards,S., and Voit,T. (2005) Safety and efficacy of recombinant acid alpha-glucosidase (rhGAA) in patients with classical infantile Pompe disease: results of a phase II clinical trial. Neuromuscular disorders: NMD 15, 24-31

44) Scheindlin,S. (2007) Clinical enzymology: enzymes as medicine. Mol. Interv. 7, 4-8

Justification for selection of carcinogenicity via oral route endpoint:
See discussion below.

Justification for selection of carcinogenicity via inhalation route endpoint:
See discussion below.

Justification for selection of carcinogenicity via dermal route endpoint:
See discussion below.