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EC number: 232-877-2 | CAS number: 9032-08-0
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16 November 2005 - 5 October 2006
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- This assessment of sub-chronic systemic toxicity (according to OECD TG 408) has been performed due to data requirements from the European Food Safety Authority (EFSA), as this enzyme also comply with the regulatory system of FIAP [REGULATION (EC) No 1331/2008 and EFSA CEF guidance from 2009/2013]. Moreover; it has been generated in accordance with Directive 2010/63/EU.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- Adopted 1998
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Active enzyme protein of glucan 1,4-alpha-glucosidase (EC no. 232-877-2, CAS no. 9032-08-0, EC name: Amylase, gluco-, Enzyme Class No.: 3.2.1.3)
- Molecular formula:
- Not available.
- IUPAC Name:
- Active enzyme protein of glucan 1,4-alpha-glucosidase (EC no. 232-877-2, CAS no. 9032-08-0, EC name: Amylase, gluco-, Enzyme Class No.: 3.2.1.3)
- Reference substance name:
- Protein as a constituent of enzyme deriving from the fermentation or extraction process
- Molecular formula:
- Not available
- IUPAC Name:
- Protein as a constituent of enzyme deriving from the fermentation or extraction process
- Reference substance name:
- Inorganic salts as a constituent of enzyme deriving from the fermentation or extraction process
- Molecular formula:
- Not available. See remarks.
- IUPAC Name:
- Inorganic salts as a constituent of enzyme deriving from the fermentation or extraction process
- Reference substance name:
- Carbohydrates constituent of enzyme deriving from the fermentation or extraction process
- Molecular formula:
- Not available. See remarks.
- IUPAC Name:
- Carbohydrates constituent of enzyme deriving from the fermentation or extraction process
- Reference substance name:
- Lipids as a constituent of enzyme deriving from the fermentation or extraction process
- Molecular formula:
- Not available. See remarks.
- IUPAC Name:
- Lipids as a constituent of enzyme deriving from the fermentation or extraction process
- Test material form:
- liquid
- Details on test material:
- - Lot/batch No.: PPY24900
- Expiration date of the lot/batch: 10 May 2015
Constituent 1
Constituent 2
Constituent 3
Constituent 4
Constituent 5
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, UK, Ltd
- Age at study initiation: 45-49 days
- Weight at study initiation: 230-293 g for males; 150-191 g for females
- Fasting period before study: None
- Housing: 5 animals per cage, separate sex
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
- Temperature: 19-23°C
- Humidity: 40-70 % RH
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2005-11-16 To: 2006-02-28
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- Purified water obtained by reverse osmosis
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Concentration in vehicle: 10, 33 and 100%, corresponding to 15, 50 and 152 mg enzyme concentrate dry matter/mL
- Amount of vehicle (if gavage): constant volume 10 mL/kg b.w.
- Purity: Purified water obtained by reverse osmosis - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of achieved concentration with regard to the enzyme activity was performed on samples taken once during weeks 1, 6 and 13. The mean achieved enzyme activities were between 98.7 to 102% of the intended, demonstrating satisfactory formulation.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 519.2 mg/kg bw/day (nominal)
- Remarks:
- Expressed in mg enzyme concentrate dry matter/kg bw/day
- Dose / conc.:
- 501.3 mg/kg bw/day (nominal)
- Remarks:
- Expressed in mg enzyme concentrate dry matter/kg bw/day
- Dose / conc.:
- 151.9 mg/kg bw/day (nominal)
- Remarks:
- Expressed in mg enzyme concentrate dry matter/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The doses used in this study were selected on the basis of results from studies performed on other similar enzyme preparations. The highest dose (10 mL/kg/day) was the maximum practical dose and represents administration of the enzyme, as received, at a volume-dose of 10 mL/kg bodyweight, which is the maximum practical volume-dose for repeat dose oral administration. The lower doses were selected using an approximate ratio of 3.3 between doses.
- Positive control:
- Not included
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily during the first week of treatment, twice weekly during Weeks 2 to 4 and weekly thereafter, detailed observations were recorded
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each cage, i.e. sum of five animals, was determined and mean daily diet consumption per group calculated as g feed/rat/week: Yes
FOOD EFFICIENCY:
- Body weight gain in g/food consumption in g per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION : Yes
- Time schedule for examinations: weekly, over a 3-day period in each week
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before treatment started and during week 13
- Dose groups that were examined: control and highest dose group
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 13
- Anaesthetic used for blood collection: Yes (isoflurane anaesthesia)
- Animals fasted: yes, overnight
- How many animals: From all animals
- Parameters checked:
Haemoglobin (Hb)
Erythrocyte count (RBC)
Mean cell haemoglobin (MCH)
Mean cell haemoglobin concentration (MCHC)
Mean cell volume (MCV)
Total white cell count (WBC)
Differential WBC count
Neutrophils (N)
Lymphocytes (L)
Eosinophils (E)
Basophils (B)
Monocytes (M)
Large unstained cells (LUC)
Platelet count (Plt)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 13
- Animals fasted: yes, overnight
- How many animals: From all animals
- Parameters checked:
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma-glutamyl transpeptidase (gGT)
Total bilirubin (Bili)
Urea
Creatinine (Creat)
Glucose (Gluc)
Total cholesterol (Chol)
Triglycerides (Trig)
Sodium (Na)
Potassium (K)
Chloride (Cl)
Calcium (Ca)
Inorganic phosphorus (Phos)
Total protein (Total Prot)
Albumin (Alb)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: yes
- Time schedule for examinations: During week 12
- Dose grouat were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / : yes - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- FAECAL ANALYSIS: No
Weight of individual organs: Yes
- Time schedule for collection of organs: At necropsy - Statistics:
- Statistical evaluation of grip strength, motor activity, bodyweight, haematology, blood chemistry, organ weights and any data derived from these was performed. The level of probability chosen as significant was p<0.05.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- The changes that were identified were not considered of toxicological significance.
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- HISTOPATHOLOGY: NON-NEOPLASTIC : Histopathology indicated an increased incidence of cortical vacuolisation in the adrenal glands of males in the high and mid dosed groups. This was considered a slight exacerbation of a normal background finding in young CD rats, which is not toxicologically significant.
At the time of the study, the issue of cortical vacuolation was addressed by expanding the microscopic examination of the adrenals to include group 2 and 3, in addition to group 1 (control) and group 4 (high dose group), to have the full dose-response pattern of the cortical vacuolation seen in the adrenal glands of males (pls see table for results in next information box). Further, the negative control rats from seven unrelated and recent 13-week oral toxicity studies were investigated to get useful baseline information on this specific parameter for the used strain of rats.
The reason why the small increase in the incidence and severity of cortical vacuolation in the adrenal gland of males is regarded of no toxicological significance is based on the following elements:
1. The cortical vacuolation in the adrenals was the only effect seen, there was no indication of degeneration, inflammation or necrosis, and the females did not show this effect at all. Further, the organ weight of the adrenals was not increased. This is important and indicates that the homeostasis of the adrenals was fully retained. The cortical vacuolation in the males was therefore not regarded as a toxicological response but rather a normal physiological response of the adrenal cortex (the secretion of glucocorticoids) in response to the increasing dose of protein as a result of the administration of the enzyme.
Minimal vacuolation of the adrenal cortex was also reported in two untreated Control males of the present study, i.e. incidence 20%, and in up to 42% of untreated animals from the other recent 13-week studies. Therefore, the result of the present study lies within the normal range of this rat strain.
2. The Contract Research Organisation, Huntingdon Life Sciences, Ltd., Cambrigdeshire, England, is a top quality institute with long term experience in preclinical testing with lots of experts in toxicology and pathology. The present conclusion is based on their evaluation, which adds to the solidity of the present data and conclusion.
It is therefore concluded that the findings in the adrenals of the male rats are unlikely to be of any toxicological significance.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 519.2 mg/kg bw/day (nominal)
- Based on:
- other: Expressed in mg enzyme concentrate dry matter/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
The cortical vacuolation was found in the adrenals of the males only (for further background and discussion, please see details on results of histopathology above) :
Group/sex
|
1M
|
2M
|
3M
|
4M
|
||
Dose (mL/kg/day) |
0 |
1.0 |
3.3 |
10.0 |
||
Cortical vacuolation |
Total |
2 |
2 |
4 |
5 |
|
|
Minimal |
2 |
2 |
3 |
4 |
|
|
Slight |
0 |
0 |
1 |
1 |
|
Number of animals examined |
|
10 |
10 |
10 |
10 |
Applicant's summary and conclusion
- Conclusions:
- The No Observed Adverse Effect Level (NOAEL) in rats is 10 mL of the undiluted glucoamylase batch/kg bw/day equivalent to 1519.3 mg enzyme concentrate dry matter/kg bw/day.
- Executive summary:
The repeated dose oral toxicity was a subchronic toxicity test conducted according to OECD guideline 408 (adopted 1998), and in compliance with GLP.
In conclusion, oral administration (by gavage) of glucoamylase, PPY 24900, to rats at dosages of up tothe highest dose level tested, equivalent to 10 mL of the undiluted Glucoamylase batch/kg bw/day or 1519.3 mg enzyme concentrate dry matter/kg bw/day for thirteen weeks was well-tolerated and did not produce any toxicologically significant changes. Necropsy and the following microscopic examination revealed no treatment related effects apart from an increased incidence or increased severity of cortical vacuolation in the adrenal glands of males given 3.3 or 10.0 mL/kg/day, but this was considered a slight exacerbation of a normal background finding in young CD rats which was not considered toxicologically significant.
Consequently, the No Observed Adverse Effect Level (NOAEL) was considered to be the highest dose level administered, equivalent to 10 mL tox batch/kg bw/day or 1519.3 mg enzyme concentrate dry matter/kg bw/day.
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