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EC number: 849-290-8 | CAS number: 9001-97-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- sensitisation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- DMEL (Derived Minimum Effect Level)
- Value:
- 60 ng/m³
- Most sensitive endpoint:
- sensitisation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
Worker DMEL, acute short-term as well as long-term inhalation exposure:
Potential occupational exposure to levels of enzyme, which is
toxicologically relevant, is unrealistic due to the stringent work
practices and adherence to the voluntary Occupational Exposure
Guidelines at or below the established ACGIH (www.acgih.org) exposure
limit value of 60 ng/m3, based on pure enzyme protein for the benchmark
enzyme subtilisin. This was established due to the endpoint of concern,
which is risk of sensitisation by inhalation. Worker safety is assured
through current proper work practices, engineering controls, and if
needed of personal protective equipment. The industry has taken measures
to minimize occupational exposure. Worker DMEL has been discussed and
concluded by the involved industry in recent publications (Basketter et
al. 2010, 2012a, 2012b) and a limit of 60 ng/m3, expressed in pure
enzyme protein, was suggested (Basketter et al., 2010) in line with the
established ACGIH threshold limit value.
References:
-Basketter DA,
Broekhuizen C, Fieldsend M, Kirkwood S, Mascarenhas R, Maurer K,
Pedersen C, Rodriguez C, Schiff HE (2010). Defining occupational
and consumer exposure limits for enzyme protein respiratory allergens
under REACH. Toxicology, 268(3):165-170.
-Basketter D, Berg N,
Broekhuizen C, Fieldsend M, Kirkwood S, Kluin C, Mathieu S, Rodriguez C
(2012a). Enzymes in Cleaning Products: An Overview of
Toxicological Properties and Risk Assessment/Management. Regul.
Toxicol. Pharmacol., 64(1):117-123.
-Basketter D, Berg N,
Kruszewski FH, Sarlo K, Concoby B (2012b). The Toxicology and
Immunology of Detergent Enzymes. J. Immunotoxicol., 9(3):320-326.
Worker DNEL, acute short-term as well as long-term dermal exposure:
The physico-chemical properties of a compound are decisive for the potential percutaneous penetration, in particular, factors like ionization, molecular size and lipophilicity. 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. 2008, Smith Pease et al. 2002, Basketter et al. 2012a, 2012b). This is further supported by the physico-chemical data of enzymes. They are proteins with molecular weight above 13,000 D (http://www.brenda-enzymes.info), they have a low logPow value (<0, i.e. low lipophilicity), indicating that they have no bioaccumulation potential and can be anticipated to be readily biodegraded. Thus, systemic exposure following enzyme exposure at occupational exposure levels is without toxicological significance.
References:
-Basketter DA, English JS,
Wakelin SH, White IR(2008). Enzymes, detergents and skin: facts
and fantasies. Br. J. Dermatol., 158(6):1177-1181.
-Smith Pease CK, White IR,
Basketter DA(2002). Skin as a route of exposure to protein
allergens. Clin. Exp. Dermatol., 27(4):296-300.
-Basketter D, Berg N,
Broekhuizen C, Fieldsend M, Kirkwood S, Kluin C, Mathieu S, Rodriguez C
(2012a). Enzymes in Cleaning Products: An Overview of
Toxicological Properties and Risk Assessment/Management. Regul.
Toxicol. Pharmacol., 64(1):117-123.
-Basketter D, Berg N,
Kruszewski FH, Sarlo K, Concoby B (2012b). The Toxicology and
Immunology of Detergent Enzymes. J. Immunotoxicol., 9(3):320-326.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- sensitisation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- DMEL (Derived Minimum Effect Level)
- Value:
- 15 ng/m³
- Most sensitive endpoint:
- sensitisation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
Consumer DMEL, acute short-term as well as long-term inhalation
exposure:
Industry has documented that respiratory irritation or toxicity due
to enzyme preparations is a very rare phenomenon, which will not occur
at the low concentrations of enzymes found in consumer products (e.g.
detergents). The risk to consumers is considered very low and regarded
as toxicologically insignificant (Basketter et al. 2010, 2012a, 2012b).
This is supported by the positive safety outcome of a clinical study of
the highest reported consumer exposure level, 15 ng/m3, with spot
cleaning by spray (Weeks et al. 2011, SDA 2005). Consumer DMEL has been
discussed among the enzyme allergy specialists from enzyme and detergent
manufacturers and it was concluded by the involved industry partners in
a recent publication that the limit of 15 ng/m3 (Basketter et al. 2010).
References:
-Basketter DA, Broekhuizen
C, Fieldsend M, Kirkwood S, Mascarenhas R, Maurer K, Pedersen C,
Rodriguez C, Schiff HE (2010). Defining occupational and consumer
exposure limits for enzyme protein respiratory allergens under REACH. Toxicology,
268(3):165-170.
-Basketter D, Berg N,
Broekhuizen C, Fieldsend M, Kirkwood S, Kluin C, Mathieu S, Rodriguez C
(2012a). Enzymes in Cleaning Products: An Overview of
Toxicological Properties and Risk Assessment/Management. Regul.
Toxicol. Pharmacol., 64(1):117-123.
-Basketter D, Berg N,
Kruszewski FH, Sarlo K, Concoby B (2012b). The Toxicology and
Immunology of Detergent Enzymes. J. Immunotoxicol., 9(3):320-326.
-Weeks JA, Harper RA, Simon
RA, Burdick JD (2011).
Assessment of sensitization risk of a laundry pre-spotter containing
protease. Cutan. Ocul. Toxicol., 30(3):272-279.
-The Soap and Detergent Association (SDA) (2005). Risk assessment
guidance for enzyme-containing products.
Consumer DNEL, acute short-term as well as long-term dermal exposure:
The physico-chemical properties of a compound are decisive for the
potential percutaneous penetration, in particular, factors like
ionization, molecular size and lipophilicity. 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. 2008, Smith Pease et al. 2002, Basketter et
al. 2012a, 2012b). This is further supported by the physico-chemical
data of enzymes. Braching enzymes are proteins with molecular weight
above 40000 D (http://www.brenda-enzymes.info), they have a low logPow
value (<0, i.e. low lipophilicity), indicating that they have no
bioaccumulation potential and can be anticipated to be readily
biodegraded. Thus, systemic exposure following enzyme exposure at
occupational exposure levels is without toxicological significance.
References
-Basketter DA, English JS,
Wakelin SH, White IR(2008). Enzymes, detergents and skin: facts
and fantasies. Br. J. Dermatol., 158(6):1177-1181.
-Smith Pease CK, White IR,
Basketter DA(2002). Skin as a route of exposure to protein
allergens. Clin. Exp. Dermatol., 27(4):296-300.
-Basketter D, Berg N,
Broekhuizen C, Fieldsend M, Kirkwood S, Kluin C, Mathieu S, Rodriguez C
(2012a). Enzymes in Cleaning Products: An Overview of
Toxicological Properties and Risk Assessment/Management. Regul.
Toxicol. Pharmacol.,64(1):117-123.
-Basketter D, Berg N,
Kruszewski FH, Sarlo K, Concoby B (2012b). The Toxicology and
Immunology of Detergent Enzymes. J. Immunotoxicol., 9(3):320-326.
Consumer DNEL, acute short-term as well as long-term systemic oral exposure:
Proteins are digested into amino acids by gastric juices, digestive enzymes and pancreatic proteolytic enzymes in the lumen of the gastrointestinal tract [1]. As enzymes are simply a class of proteins, enzymes will undergo the same process as any food source based on proteins. Absorption of enzymes in toxicological significant amounts through the gastrointestinal tract is unlikely. Furthermore, enzymes have been used for decades in treatment of both adults and children with exocrine pancreatic insufficiency. Typical enzymatic drugs (e.g. Creon® from Solvay Pharmaceuticals or Pancrease Microtabs from Jansson/Cilaq) are a combination of the enzymes alpha-amylase, lipase and protease, which are also used in a wide range of industrial applications. These medical drugs are typically administered orally at therapeutic concentrations (i.e. at concentrations where a digestive effect can be expected). Clinical trials and crossover studies confirm the safe use of these compounds in patients, both in adults and children, confirming the low toxicity of the enzymes [3-13].
References
1) Niesink RJM, de Vries J, Hollinger MA. (1996). Toxicology, Principles and Applications CRC Press, Inc. and Open University of The Netherlands.
2) Barra E, Stolarczyk A, Socha J, Oralewska B, Kowalska M, Skoczen M, Wawer Z. (1998). Efficacy of enzyme supplementation in children with cystic fibrosis. Pediatria Polska, 73:177-182.
3) Borowitz D, Goss CH, Stevens C, Hayes D, Newman L, O'Rourke A, Konstan MW, Wagener J, Moss R, Hendeles L, Orenstein D, Ahrens R, Oermann CM, Aitken ML, Mahl TC, Young KR Jr, Dunitz J, Murray FT. (2006). Safety and preliminary clinical activity of a novel pancreatic enzyme preparation in pancreatic insufficient cystic fibrosis patients. Pancreas, 32(3):258-263
4) Borowitz D, Goss CH, Limauro S, Konstan MW, Blake K, Casey S, Quittner AL, Murray FT. (2006). Study of a novel pancreatic enzyme replacement therapy in pancreatic insufficient subjects with cystic fibrosis. J. Pediatr., 149(5):658-662.
5) Domínguez-Muñoz JE, Iglesias-García J, Iglesias-Rey M, Figueiras A, Vilariño-Insua M. (2005). Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: A randomized, three- way crossover study. Aliment Pharmacol Ther., 21(6):993-1000.
6) Halm U, Löser C, Löhr M, Katschinski M, Mössner J. (1999). A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency. Aliment Pharmacol Ther., 13(7), 951-957.
7) Heubi JE, Boas SR, Blake K, Nasr ARH, Woo MS, Graff GR, Hardy KA, Maro-Galvez R, Latino M, Lee C. (2008). Zentase, a novel pancreatic enzyme product (Pep), is effective in mild, moderate, and severe exocrine pancreatic insufficiency (Epi). Gastroenter., 134:A583-A584.
8) Keller J, Layer P. (2006). Are monolithic enteric-coated enzyme preparations effective in pancreatic exocrine insufficiency? A multicentre, double blind, placebo controlled cross-over trial. Gastroenter., 130:A517.
9) Konstan MW, Stern RC, Trout JR, Sherman JM, Eigen H, Wagener JS, Duggan C, Wohl ME, Colin P.(2004). Ultrase MT12 and ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: Safety and efficacy. Aliment Pharmacol Ther., 20(11-12):1365-1371.
10) Konstan MW, Liou TG, Strausbaugh S, Ahrens RC, Kanga JF, Graff GR, Moffett KS, Millard S, Nasr SZ, Vezina M, Spenard J, Grondin J. (2008). Efficacy and safety of Ultrase (R) MT20 in treating pancreatic insufficiency in cystic fibrosis. Gastroenter., 134:A228-A229.
11) Laake K. (1980). ENZYMIC DRUGS. Side Effects of Drugs Annual., 222-225.
12) Patchell CJ, Desai M, Weller PH, Macdonald A, Smyth RL, Bush A, Gilbody JS, Duff SA.(2002). Creon 10,000 Minimicrospheres vs. Creon 8,000 microspheres - an open randomised crossover preference study. J. Cyst. Fibros., 1(4):287-291.
13) Saeed Z, Wojewodka G, Marion D, Guilbault C, Radzioch D. (2007). Novel pharmaceutical approaches for treating patients with cystic fibrosis. Curr. Pharm. Des., 13 (31):3252-3263.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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