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EC number: 618-333-0 | CAS number: 9001-85-8
- 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
Endpoint summary
Administrative data
Description of key information
It is concluded that oral administration of lysophospholipase to CD rats at dosages up to 10.0 ml/kg/day for 13 weeks was well-tolerated and did not produce any toxicological significant change. Consequently the no observed adverse effect level (NOAEL) in this study was considered to be the highest dose administered 10.0 ml/kg/day, which is the equivalent to 2.42 g TOS/kg/day.
Based on repeated dose oral study and weight of evidence, lysophospholipase does not exert any repeated dose oral, dermal or inhalation toxicity to workers or consumers.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 7 April 2003 to 6 February 2004
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- revised 1997
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:CD® (SD)IGS BR
- 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 to 49 days
- Weight at study initiation: 226 to 266 g for males; 158 to 203 g for females
- Fasting period before study: None
- Housing: 5 animals of one sex per cage.
- Diet: Standard rodent diet Rat and Mouse No. 1 Maintenance Diet from Special Diets Services Ltd., Witham, Essex, England), ad libitum, except overnight before routine blood sampling
- Water: Tap 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: 2003-06-02 To: 2003-09-02
OTHER: Before the start of treatment, one male with non-resolving ophthalmic lesions, one female with ill health and three males and two females with bodyweights at the extreme of the weight range were replaced with spare animals of suitable weight from the same batch. - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Purified water obtained by reverse osmosis.
- Concentration in vehicle: 10, 33 and 100% (equivalent to 0.24, 0.80 or 2.42g TOS/kg/day).
- Amount of vehicle (if gavage): At the same volume-dosage.
- Purity: Water for formulation - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Significant differences were found in the low dose group of week 6 when compared to the same group in week 1. The measured activity in the low dose group in week 6 was indeed 13% lower than expected but 12% variation is accepted on this analytical method. This is only a small deviation from the expected value and this is considered as having no significance. No activity was found in any of the analysed control samples. It was further investigated if the enzyme activity for the high dose group was equal to the activity in the test material. No significant differences were found between the test material and the high dose group.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
- Dose / conc.:
- 1 other: mL/kg/day
- Remarks:
- Equivalent to 0.24 g TOS/kg/day
- Dose / conc.:
- 3.3 other: mL/kg/day
- Remarks:
- Equivalent to 0.80 g TOS/kg/day
- Dose / conc.:
- 10 other: mL/kg/day
- Remarks:
- Equivalent to 2.42 g TOS/kg/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 previous work with this compound where it was concluded that oral administration of lysophospholipase, PPW 22320, to CD rats at dosages up to 10.0 ml/kg/day for two weeks was well-tolerated and did not produce any toxicologically significant changes. The lower doses were selected using an approximate ratio of 3.3 between doses.
- Positive control:
- Not included
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were inspected daily for evidence of ill-health.
Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.
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 in relation to dose administration.
BODY WEIGHT: Yes
- Time schedule for examinations: At the day that treatment commenced (Week 0), weekly throughout the treatment period, and before necropsy.
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 AND COMPOUND INTAKE: Yes, visual.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before treatment started and during week 13
- Dose groups that were examined: Before treatment all animals. During week 13 Group 1 (control) and Group 4 (highest dose group)
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 13 (before dosing)
- Anaesthetic used for blood collection: Yes (isoflurane anaesthesia)
- Animals fasted: yes, overnight
- How many animals: From all animals
- Parameters checked:
Haematocrit (Hct)
Haemoglobin concentration (Hb)
Red blood cell 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)
Prothrombin time (PT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 13 (before dosing)
- Animals fasted: yes, overnight
- How many animals: From all animals (80)
- Parameters checked:
Alkaline phosphatase (ALP)
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 groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / : yes
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, full macroscopic examination
HISTOPATHOLOGY: Yes. Adrenals, brain, femur with joint, heart, ileum, kidneys, liver, lungs, salivary glands, spinal cord, sternum, stomach, thyroid and uterus were preserved and for the control group and the high dose group these tissues were examined. - 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. Significant differences between Control and treated groups were expressed at the 5% (p<0.05) or 1% (p<0.01).
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- Following routine blood sampling during Week 13 of treatment, one male receiving 10.0 ml/kg/day sustained physical trauma to the eye and was killed for humane reasons. The death of this animal was clearly incidental, and not attributed to treatment.
- 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
- Description (incidence and severity):
- Water consumption was visual.
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no haematological changes in Week 13 that could, with any confidence, be attributed to treatment.
Prothrombin times were increased, when compared with Controls, for females receiving 3.3 or 10.0 mL/kg/day with the differences attaining statistical significances (p<0.05). In veiw of the small difference from Controls, and the absence of a similar finding amongst the males, this finding is of doubtful toxicological significance. - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- Biochemical examination of the plasma during Week 13 indicated, when compared with the Controls, high glucose concentration for males and females receiving 10.0 mL/kg/day. Plasma potassium concentrations were increased for animals receiving 10.0 mL/kg/day. In the absence of any change in food intake or histopathology of the liver, the change in glucose concentration is not considered toxicologically significant. The change in potassium concentration was not associated with any histopathological change in the kidney and is therefore also not considered toxicologically significant.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Two males in each of the groups receiving 1.0 or 3.3 mL/kg/day and three males receiving 10.0 mL/kg/day failed to show a touch response (Grade 1) and three males receiving 10.0 ml/kg/day displayed a weak (Grade 2) auditory startle reflex. The findings for the auditory startle reflex were within historical background control data, though the incidence of animals failing to show a touch response was slightly higher than the historical control data. Since all males showed a normal response to the tail pinch test, and in the absence of any similar findings in the females, these findings are attributed to inter-animal variation.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- When compared with Controls, absolute and adjusted brain weights were increased for females given 10.0 ml/kg/day, attaining statistical significance (p<0.05). The difference from Control was small and was attributed to normal biological variation.
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- An increased incidence of prominent ultimobranchial cysts in the thyroids in males that received 10.0 mL/kg/day attained statistical significance (p<0.05). This is a congenital finding often seen in the thyroids of rats. The increased incidence in males treated at 10.0 mL/kg/day was considered fortuitous and not related to treatment.
- Histopathological findings: neoplastic:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 2 420 mg/kg bw/day (actual dose received)
- Based on:
- other: total organic solids (TOS)
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Critical effects observed:
- no
- Conclusions:
- It is concluded that oral administration of lysophospholipase, PPW 22320 to CD rats at dosages up to 10.0 mL/kg/day for 13 weeks was well-tolerated and did not produce any toxicological significant change. Consequently the no-observed-adverse-effect-level (NOAEL) in this study was considered to be the highest dose administered 10.0 mL/kg/day, which is the equivalent to 2.42g TOS/kg/day.
- Executive summary:
The repeated dose oral toxicity study was a subchronic toxicity test conducted according to OECD guideline 408 (revised 1997), and in compliance with GLP.
The systemic toxic potential of lysophospholipase, PPW 22320 a food enzyme, to Crl:CD® (SD)IGS BR rats by oral administration was assessed over a period of 13 weeks. Three groups of ten male and ten female rats received lysophospholipase, PPW 22320 by gavage at dosages of 1.0, 3.3 or 10.0 mL/kg/day (equivalent to 0.24, 0.80 or 2.42g TOS/kg/day). A similarly constituted Control group received the vehicle (purified water obtained by reverse osmosis) at the same volume-dosage. During the study, clinical condition, detailed physical and arena observations, sensory reactivity, grip strength, motor activity, bodyweight, food consumption, haematology, blood chemistry, organ weight, macroscopic and microscopic pathology investigations were undertaken.
There were no signs related to treatment and the functional observation battery investigations also did not indicate any changes that were attributable to treatment. One male died during the treatment period, though this was not attributed to treatment, but rather was done for humane reasons. Bodyweight gain, food consumption and food conversion efficiency were unaffected by treatment. There were no treatment related ophthalmic findings. Haematological investigations in Week 13 did not indicate any treatment-related changes. Biochemical examination of the plasma during Week 13 indicated increased glucose and potassium concentration for animals receiving 10.0 mL/kg/day, but it was considered not to be toxicologically significant. There were no treatment-related organ weight, macroscopic or histopathological changes after 13 weeks of treatment.
It is concluded that oral administration of lysophospholipase, PPW 22320 to CD rats at dosages up to 10.0 mL/kg/day for 13 weeks was well-tolerated and did not produce any toxicological significant change. Consequently the no-observed-adverse-effect-level (NOAEL) in this study was considered to be the highest dose administered 10.0 mL/kg/day, which is the equivalent to 2.42 g TOS/kg/day.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 420 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Toxicological data has been generated within the enzyme producing industry during the last 40 years. Substantial documentation on the safety of the production strains has been generated, and the enzyme test materials are thoroughly characterized. High quality studies for all relevant endpoints for in vivo studies as well as in vitro studies show that industrial enzymes from well-known and well characterized production strains have very similar safety profiles across the catalytic activities. Read-across can therefore be applied for the majority of toxicological endpoints. The database can therefore be considered of high quality.
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
It is concluded that oral administration of lysophospholipase to CD rats at dosages up to 10.0 ml/kg/day for 13 weeks was well-tolerated and did not produce any toxicological significant change. Consequently the no observed adverse effect level (NOAEL) in this study was considered to be the highest dose administered 10.0 ml/kg/day, which is the equivalent to 104039 LLU/kg/day or 2.42 g TOS/kg/day.
The repeated dose inhalation and dermal toxicity studies were waived.
- The dermal study was waived because of the low likelihood of absorption of enzymes through the skin due to the physico-chemical properties of the enzyme protein.
- The inhalation study was waived because exposure is too low to exert any toxicity. Potential exposure by inhalation to an amount of enzyme that toxicologically relevant is unrealistic, due to the formulation of enzymes and the stringent work practices, enforced because of the risk of sensitisation by inhalation.
Justification for classification or non-classification
Based on repeated dose oral study and weight of evidence, lysophospholipase does not exert any repeated dose oral, dermal or inhalation toxicity to workers or consumers.
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