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EC number: 232-619-9 | CAS number: 9001-62-1
- 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:
- October 26, 2006 – August 7, 2007
- 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:
- 2 007
- Report date:
- 2007
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Active enzyme protein of Lipase, triacylglycerol (EC no. 232-619-9, CAS no. 9001-62-1, EC name: Lipase, triacylglycerol, Enzyme Class no. 3.1.1.3)
- Molecular formula:
- Not applicable, see remarks.
- IUPAC Name:
- Active enzyme protein of Lipase, triacylglycerol (EC no. 232-619-9, CAS no. 9001-62-1, EC name: Lipase, triacylglycerol, Enzyme Class no. 3.1.1.3)
- 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.: PPW 26090
- Expiration date of the lot/batch: 06 September 2016
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: Rat, SPF Sprague Dawley of the Ntac:SD strain from Taconic Europe A/S, Ejby, Denmark
- Age (at Delivery): 5 weeks
- Body Weight Range (at Acclimatization): within +/- 20 rams for each sex.
- Housing: Animal room no. 118 in transparent polycarbonate cages (floor area: 1500 cm2) with two or three in each cage, males and females separated.
- Diet (e.g. ad libitum): A complete pelleted rodent diet “Altromin 1314 Fortified” (for growing animals) was available ad libitum until Day 53 of the dosing period. On Day 54 and throughout the study, animals were offered ad libitum “Altromin 1324 Fortified” (for adult animals).
- Water: Acidified domestic quality drinking ad libitum
- Acclimation period: At least 5 days in order to reject animals in poor condition or at the extremes of the weight range.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%):55 ± 15%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hours light
IN-LIFE DATES: Animals arrived on 22 November 2006. Treatment started on 29 November 2006. In-life phase ended on 01 March 2007.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- Lipase was administered daily by oral gavage in tap water (vehicle), dose volume was 10 mL/kg.
Dose levels were 0 (vehicle), 124.8 (low), 411.94 (medium) and 1248.3 (high) mg/kg body weight/day based on enzyme concentrate dry matter for a period of 13 weeks. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The measured concentration of the dosing solutions expressed in enzymes activity units per g was found close to the intended content of the test material formulations for the high, medium and low dose groups in week 1, 6 and 13.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- given in mg enzyme concentrate dry matter
- Dose / conc.:
- 124.8 mg/kg bw/day (nominal)
- Remarks:
- given in mg enzyme concentrate dry matter
- Dose / conc.:
- 411.9 mg/kg bw/day (nominal)
- Remarks:
- given in mg enzyme concentrate dry matter
- Dose / conc.:
- 1 248.8 mg/kg bw/day (nominal)
- Remarks:
- given in mg enzyme concentrate dry matter
- No. of animals per sex per dose:
- 10 female and 10 male rats
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Doses were selected based on previous experience with lipase in 13 wk oral gavage toxicity studies in rats.
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
At least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
Clinical signs were recorded daily and detailed clinical observations were performed outside the home cage once a week.
BODY WEIGHT: Yes
Animals were weighed on the day of arrival, on the first day of treatment (Day 1) and weekly thereafter.
FOOD CONSUMPTION: Yes
Starting Day 1, the consumption of food was recorded weekly for each cage
WATER CONSUMPTION: Yes
The consumption of water was recorded twice weekly for each cage.
OPHTHALMOSCOPIC EXAMINATION: Yes
Before treatment started. Before termination of treatment, animals in group 1 and 4 were to be re-examined; however, as a deviation to the study plan, this was not done.
CLINICAL CHEMISTRY: Yes
HEMATOLOGY: Yes
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
Weekly observations included observations for changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g., excessive grooming, repetitive circling) or bizarre behaviour (e.g., self-mutilation, walking backwards). Moreover, on one occasion during the last two weeks of the study, all animals were examined in the Open field and stimuli-induced test and were observed with respect to reactivity to different types of stimuli (e.g. auditory, visual, tactile), grip strength and motor activity (open field test). - Sacrifice and pathology:
- At the end of the treatment period (week 13), blood samples were withdrawn for haematology and plasma biochemistry analyses. All animals were then sacrificed in CO2/O2. At necropsy a bone marrow smear was taken from the femur of all animals. Gross pathology was performed and histopathology was performed in the control group (Group 1) and in the high dose group (Group 4).
- Other examinations:
- Weight of individual organs: yes
- Statistics:
- Data were processed to give group mean values and standard deviations where appropriate.
Thereafter each continuous variable was tested for homogeneity of variance with Levene’s test. If the variance was homogeneous, analysis of variance was carried out for the variable. If any significant differences were detected, possible inter-group differences were assessed with Dunnett’s test (comparing treated groups with a control group). If the variance was heterogeneous, each variable was tested for normality by the Shapiro-Wilk method. In case of normal distribution, possible inter-group differences were identified with Student's t-test.
Otherwise the possible inter-group differences were assessed by Kruskal-Wallis's test. If any significant inter-group differences were detected, the subsequent identification of the groups was carried out with Wilcoxon Rank-Sum test. For all tests, the level of significance was defined as p<0.05. The statistical analyses were made with SAS® procedures (version 8.2) described in "SAS/STAT® User's Guide, SAS OnlineDoc®, 1999, SAS Institute Inc., Cary, North Carolina 27513, USA.
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:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- The haematological findings were considered incidental findings.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- The clinical chemistry findings were considered incidental findings
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- The neurobehavioural findings were considered incidental findings
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 248.3 mg/kg bw/day (nominal)
- Based on:
- other: Enzyme concentrate dry matter
- Sex:
- male/female
- Basis for effect level:
- other: There were no adverse effects observed at the highest does tested.
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Oral administration (gavage) of Lipase to Sprague-Dawley rats at doses up to 1248.3 mg enzyme concentrated dry matter/kg/day for a period of 13 weeks was generally well tolerated.
No test item-related deaths occurred and no changes in daily or weekly observations as well as functional observational battery (performed during week 13) including grip strength and locomotor activity were observed. Furthermore, no test item-related effects on body weights or food consumption, no ophthalmoscopic findings, no changes in clinical laboratory investigations of toxicological relevance as well as no macroscopic and microscopic findings were noted.
Based on the results of this study, the no observed adverse effect level (NOAEL) for the lipase was set at 1248.3 mg enzyme concentrate dry matter/kg/day. - Executive summary:
The repeated dose oral toxicity study was a 13-week subchronic toxicity study conducted in rats according to OECD guideline No. 408 (revised in 1998) and in compliance with GLP.
The test material used in this study, the lipase (batch no. PPW 26090) was dissolved in tap water. The test material was given to 10 animals/sex/group in a constant volume of 10 mL/kg bw by gavage to achieve the desired concentrations of 124.8, 411.9 and 1248.3 mg enzyme concentrated dry matter/kg bw/day for 90 consecutive days. Tap water given at the same volume served as vehicle control. The test material in solution was tested for stability, and concentration in dosing solutions was verified by analysis. Clinical observations were made daily whereas feed and body weight were recorded weekly. Clinical chemistry, hematology, open field and stimuli-induced tests, necropsy, organ weights, and macroscopic- and histopathological examinations were conducted at study termination as required by the guideline. One deviation to the guideline was that ophthalmoscopy by mistake was not performed before termination. However, the histopathological examination revealed no pathological findings in the eyes of any of the animal.
There were no treatment related effects found in any of the parameters investigated.
In summary, oral administration of lipase to rats of both sexes at dose levels up to 1248.3 mg enzyme concentrate dry matter/kg bw/day for 13 consecutive weeks did not result in any systemic, behavioural or pathological changes.
The No Observed Adverse Effect Level (NOAEL) was therefore established at the highest dose tested, 1248.3 mg enzyme concentrate dry matter/kg body weight/day.
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