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Safety Evaluation of Technical Enzyme Products with Regards to the REACH Legislation

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Safety Evaluation of Technical Enzyme Products with Regards to the REACH Legislation Safety evaluation of technical enzyme products with regards to the REACH legislation 09 June 2009 Brussels ENZYMES – What enzymes are Enzymes are proteins with highly specialized catalytic function PPdroduced an d nee ddbllliided by all living things Similar metabolic mechanisms utilized by all organisms to produce enzymes Building-blocks are the 20 naturally occurring amino acids Completely Biodegradable Catalytic function determined by 3-dimensional structure Enzymes are naturally adapted to changing environments thus enzymes in a given class may have wide variation in temperature stability, salt tolerance, etc. depending on the environment in which the host organism is found ENZYMES – How enzymes are made Enzyygyme mainly through fermentation of microor g(ganisms (but sometimes extracted from plant or animal) Usually Safe strain lineage organism is used in fermentation because Enzymes are used for technical as well as food & feed applications Manufacturers need reproducible and high yields and as little different processes as possible CtidUliltiContained Use legislation requ ires sa fe s ti(fGMM)trains (for GMMs) Subsequent recovery process for purposes of purifying the enzyme Centrifugg,ation, filtration, ultrafiltration Concentration Production organism is always completely absent in the final concentrate Formulation to make stable enzyme product ENZYMES – Safety of Strains Safe strains well established over the years Barbesgaard et al ., On the safety of Aspergillus oryzae: a review. Appl Microbiol Biotechnol 1992;36:569-72. de Boer & Diderichsen, On the safety of Bacillus subtilis and B. amyloliquefaciens: A review. Appl. Microbiol. Biotechnol. 1991; 36:1-4 Priest et al., On the industrial use of Bacillus licheniformis: a review. Appl. Mic rob i ol. Bi otechn ol 1 994 ; 4 0: 595-598 Nevalainen et al., On the safety of Trichoderma reesei. J. Biotechnol. 1994;37:193-200 van Dijck et al ., O n th e saf ety of a new generati on of DSM A spergill us niger enzyme production strains. Regul. Toxicol. Pharmacol. 2003; 38: 27-35 ENZYMES – Safety of concentrates (1) There is rich body of data obtained in 35 years of experience: Includes animal toxicity, ecotox and epidemiological data, e.g. HERA http://www.heraproject.com/RiskAssessment.cfm?SUBID=22 http://www.heraproject.com/RiskAssessment.cfm?SUBID=38 Most enzymes are ‘Generally Recognized As Safe’ (GRAS) by food safety experts and FDA GRAS Notice website: http://www.cfsan.fda.gov/~rdb/opa-gras.html; GRAS affirmed enzymes: 21CFR § 184 Zofia S. Olempska-Beer et al., 2006, FDA:: Food-processing enzymes from recombinant microorganisms- a review. Regulatory Toxicology and Pharmaco logy, Vo lume 45, Issue 2, Ju ly 2006, Pages 144-158 Pariza & Johnson: Evaluating the safety of microbial enzyme preparations used in food processing: update for a new century. Regul Toxicol Pharmacol 2001 Apr;33(2):173-86. ENZYMES – Safety of concentrates (2) General Toxicity N.B. test substance is concentrate incl. residual strain metabolites and fermentation nutrients General concl u sions The toxicology of enzyme concentrates is unremarkable Acute and sub-chronic toxicity is not of concern Enzyme concentrates are not reproductive or developmental toxins Enzyme concentrates are not mutagenic, and not clastogenic Only two potential hazards are known As with any protein, enzyme concentrates, when inhaled, have the potential to cause sensitisation and by repeated exposure elicit an allergic response in susceptible individuals Proteases can irritate eye, skin and mucous membranes due to cata ly tic ac tiv ity Continued Î ENZYMES – Safety of concentrates (3) General conclusions (cont’d.) Enzyme concentrates have low toxicity to aquatic systems Enzyme concen ttdtdddddbiddbltrates are denatured, degraded and biodegradable Enzymes are manufactured by living organisms and are consumed byygg living organisms They denature and biodegrade in the environment The potential for bio-accumulation is virtually nil as proteins are readily me ta bo lize d in liv ing sys tems ENZYMES – Safety of products Industry code of practice Determine need for tox studies case by case on the basis of: Existing knowledge of application (technical, food, feed) Existing knowledge of enzyme Existing knowledge of strain Existing knowledge of manufacturing process Internationally accepted toxicology package of 90-day oral study in rats (for food enzymes) , or in vitro cytotoxicity assay, plus a chromosome aberration study plus an Ames study. EU pppp(roduction approval (EU Contained Use Directive 98/81 ) EU Feed Additives Regulation 1831/2003 EU Food Enzymes Regulation 1332/2008 Contained Use Regulatory requirements …strain requirements Non-Pathogenic host (taxonomic determination required) As safe for man, animal and environment as the host or parental strain Has a proven and extensive history of safe use and/or is biologically contained (limited survival in nature): mutations for sporulation deficiency mutations limiting growth and survival in nature Contains only well-characterized and safe vectors, limited to the required trait: onlfllhly fully character ize d(d (sequence d an dfd funct ions known ) genet ic e lements No sequences present not needed in final strain Does not easily transfer DNA to other organisms Deficient in transfer genes (tra- mob-) additional production copies preferably integrated into the chromosome Does not contain antibiotic resistance markers alien to the species ENZYMES – Substance Identification (1) EINECS and ELINCS curren tly use on ly CAS num bers Example: Protease CAS 9001 -92-7 ; EINECS 232-642-4 IUBMB system is only available scientifically sound classification http://www.chem.qmul.ac.uk/iubmb/enzyme/index.html REACH REGULATION (EC) No 1907/2006, Whereas 45: Guidance for identification and naming of substances under REACH (4.3.2.3, 5 and 7.11). P.41: ………. ………. Substance according to REACH Preparation: Granulation materials and enzyme concentrate Other constituents Substance: + Enzyme concentrate Enzyme(dry matter) concentrate Active enzyme protein (aep) The toxicity of the other constituents is the main concern regarding toxicity of enzymes. There are three possible approaches to assess the safety of the other constituents: 1. Composition; 2. Safe strain; 3. Safe strain including composition Guidance for identification and naming of substances under REACH (4.3.2.3, 5 and 7.11). P.44: P.45: P.49: ENZYMES – SbtSubstance IdtifitiIdentification (2) IUBMB (EC) Example: Protease 3Hd3. Hydro lases 3.4 Acting on peptide bonds (peptidases), with subclasses: EC 3.4.1 a-Amino-Acyl-Peptide Hydrolases (now in EC 3.4.11) EC 3.4.2 Peptidyl-Amino-Acid Hydrolases (now in EC 3.4.17) EC 3.4.3 Dipeptide Hydrolases (now in EC 3.4.13) EC 3.4.4 Peptidyl Peptide Hydrolases (now reclassified within EC 3.4) EC 3.4.11 Aminopeptidases EC 3.4.12 Peptidylamino-Acid Hydrolases or Acylamino-Acid Hydrolases (now reclassified within EC 3.4) EC 3.4.13 Dipeptidases EC 3.4.14 Dipeptidyl-peptidases and tripeptidyl-peptidases EC 3.4.15 Peptidyl-dipeptidases EC 3.4.16 Serine-type carboxypeptidases EC 3.4.17 Metallocarboxypeptidases EC 3.4.18 Cysteine-type carboxypeptidases EC 3.4.19 Omega peptidases EC 3.4.21 Serine endopeptidases EC 3.4.22 Cysteine endopeptidases EC 3.4.23 Aspartic endopeptidases EC 3.4.24 Metalloendopppeptidases EC 3.4.25 Threonine endopeptidases EC 3.4.99 Endopeptidases of unknown catalytic mechanism ENZYMES – Substance Identification (3) Example: Protease (continued) Subclass 3.4.21 Serine endopeptidases contains: EC 3.4.21.1 chymotrypsin EC 3.4.21.2 chymotrypsin C EC 3.4.21.3 metridin EC 3.4.21.4 trypsin EC34215thrombinEC 3.4.21.5 thrombin EC 3.4.21.6 coagulation factor Xa EC 3.4.21.7 plasmin EC 3.4.21.8 now covered by EC 3.4.21.34 and EC 3.4.21.35 EC 3 .4 .21 . 9 enteropeptidase EC 3.4.21.10 acrosin EC 3.4.21.11 now covered by EC 3.4.21.36 and EC 3.4.21.37 EC 3.4.21.12 a-Lytic endopeptidase etc up to 3.4.21.105 Î detailed identification according to reaction catalysed Sp litting and M ergi ng of EINECS ent ri es (REACH Guidance for Data Sharing page 35) Splitting of EINECS entries (REACH Guidance for Data Sharing page 37) SIEF formation for a substance which is pre-registered with broad EINECS number Several SIEFs are expected within one EINECS number confirming that registrants agree on first IUB an d la ter sameness (sa fe s tra in /compos ition) No IUBMB IUBMB: 3.2.1.1 3.2.1.4 3.2.1.3 Merging of EINECS entries REACH Guidance for Data Sharing page 37 SIEF formation for a substance which is pre-registered under more than one EINECS number Registrants for identical IUB number are spread in several Pre-SIEFs With “similar substances”, we linked other relevant Pre-SIEFs where we expect to find registrants for the same IUB number SIEF under several EINECS entries should be formed confirming that all registrants in these EINECS numbers agree on first IUB and later sameness (safe strain/compp)osition) Enzymes are special – requires extra steps (splitting and merging of EINECS) for SIEF formation Substance according to REACH Preparation: Granulation materials and enzyme concentrate Other constituents Substance: + Enzyme concentrate Enzyme(dry matter) concentrate Active enzyme protein (aep) The toxicity of the other constituents is the main concern regarding toxicity of enzymes. There are three possible approaches to assess the safety of the other constituents: 1. Composition; 2. Safe strain; 3. Safe strain including composition Composition – ranges and specific examples If safety of the strain is not considered - Inorganic salts Active enzyme possibility of toxic metabolites can not (1-45%) protein (10- be excluded 80%) Each product has to be tested even Lipids (0-5%) thoug h the ac tive enzyme pro te in is the same Tox data requirements: Full REACH Other proteins Carbohydrates plus peptides requirements for tox data – all tests have (3-40%) andid amino to be performed acids (5-55%) Read across not applicable before Composition range for one sameness is established (due to differences in (uncharacterized) product might be very broad: production strains, fermentation Is this acceptable? processes, etc.).
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