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EC number: 225-403-0 | CAS number: 4826-71-5
- 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
The available data refer to the degradation products of calcium phosphorylcholine chloride (choline and inorganic phosphate):
- Key study. Method similar to OECD 452. The lethal dose 0 (LD0) of Choline chloride is 500 mg/kg/day (1%) in rats, after 72-week oral administration.
- Key study. Method similar to OECD 408 and according to ISO 10993. Beta-calcium pyrophosphate has a NOAEL higher than 30 mg/kg/day in rats, after 90-day oral administration.
- Key study. OECD 408. Tetrasodium pyrophosphate was found to have a NOAEL of 500 mg/kg/day and the target organ appears to be the kidney in rats, after 90-day oral administration.
- Supporting study: Phosphoric acid has a NOAEL>386 mg/kg/day in rats, after administration in diet for more than twelve months.
Based on this information, it can be concluded that the substance phosphoryl choline chloride has a
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:
- 2009
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Dose: 30 mg/kg bw/day instead of 1000 mg/kg bw/day
- Qualifier:
- according to guideline
- Guideline:
- other: ISO 10993 Biological evaluation of Medical Devices
- Version / remarks:
- Part 11 (1995): tst for systemic toxicity/6.7 subchronic oral application
- Deviations:
- no
- GLP compliance:
- not specified
- Remarks:
- Not specified in the publication
- Limit test:
- yes
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: beta-calcium pyrophosphate (beta-CPP) was prepared by reacting high-purity Ca2P2O7 (99.99% Sigma-aldrich Co., St. Louis, Missouri, USA) with CaCO3 (99.99% High Purity Chemicals, Sakado, Japan) in the solid state. Porous beta-CPP was prepared by using polyurethane foams with randomly interconnected pores (60 ppi). Polyurethane foams were coated with beta-CPP slurry and then burned and sintered at 1.100-1300ºC for 2 hours. The resulting porous beta-CPP contained interconnected pores (pore size, 300-500 µm) and a porosity of 80%, which is similar to that of natural spongy bone.
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: to produce aqueous extracts for the administration experiments, 0.1026 g of beta-CPP was dissolved in 34.2 mL of saline at 70 ± 2ºC for 24 hours. - Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Dae Han Biolin, Inc., ChoongChung-BukDo, Korea
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 5 week-old
- Weight at study initiation: males: 183 ± 8 g, females: 163 ± 6 g
- Fasting period before study: no
- Housing: not specified
- Diet (e.g. ad libitum): commercial feed (Purina feed for rats, Nestle Purina Pet Care Co., St. Louis, USA) ad libitum
- Water (e.g. ad libitum): water ad libitum
- Acclimation period: 7 days
DETAILS OF FOOD AND WATER QUALITY: food irradiated (25-40kGy, Greenpia, Yugookun, korea), water autoclaved (121ºC, 15 minuts)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24ºC
- Humidity (%): 45-50%
- Air changes (per hr): 12-18 times/ hour
- Photoperiod (hrs dark / hrs light): 12 hours (from 7:00 to 7:00 pm)
IN-LIFE DATES: 90 days - Route of administration:
- oral: unspecified
- Vehicle:
- physiological saline
- Details on oral exposure:
- VEHICLE
- Justification for use and choice of vehicle (if other than water): physiological saline is used for beta-calcium pyrophosphate extraction.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- Daily
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: the maximum dose required for repeated-dose toxicity studies was chosen
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice-daily
BODY WEIGHT: Yes
- Time schedule for examinations: baseline and then weekly until scheduled sacrifice 90 days later
FOOD EFFICIENCY:
Average daily consumptions of water and food were determined weekly by weighing, and overall mean weekly consumptions during the 90-day treatment period were calculated.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at the end of the treatment period
- Dose groups that were examined: all treatment groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 90
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Not specified
- How many animals: All animals
- Parameters checked in table 2 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day 90
- Animals fasted: Not specified
- How many animals: all animals
- Parameters checked in table 2 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: during the 90-day treatment period
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked: urine volume and urine color, specific gravity (SG), pH, leukocyte esterase, nitrite, protein, glucose, ketone bodies, urobilinogen, bilirrubin and occult blood. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 3)
HISTOPATHOLOGY: Yes
All gross lesions were fixed and preserved in 10% neutral buffered formalin. Tissue samples from all animals were further processed for histopathology. The following tissues and organs were sectioned at 2 µm and H&E (hematoxylin and eosin) stained: digestive system (esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, liver, gall bladder, salivary gland, and pancreas), urinary system (kidney and urinary bladder), respiratory system lung and trachea), cardiovascular system (heart and aorta), hematopoietic system (spleen, thymus, limph nodes, and bone marrow), endocrine system (adrenal, pituitary, thyroid, and parathyroid glands), nervious system (skeletal muscle, femur, and sternum), male reproductive system (testes, epididymides, prostate, and seminal vesicle), female reproductive system (ovaries, uterus, mammary glands, and vagina), skin, tongue, and eyes. - Statistics:
- Mean and standard deviations were calculate for all quantitative data. If warrented and based on group size constraints, the test and control groups were compared by using one-way analysis of variance, followed by the Dunnett's multiple comparison test. Homogeneity of variances was tested by using Barlett's test, and when differences were significant (P<0.05), the Kruskal-Wallis test was performed. When these results were significant, the Wilcoxon-Mann-Whitney rank-sum tests, and Nemenye-Kruskal-Wallis multiple comparisons were performed. The chi-square test was used to determine the significances of histopathological changes.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs or motor activity changes were observed that could be attributed to treatment.
- Mortality:
- no mortality observed
- Description (incidence):
- No mortalities ocurred during the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Control and treated groups gained weight equally over the treatment period. No statistically significant differences in mean body weight gain were observed.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- No diet-related effects on feed intake were observed. No statistically significant differences in mean body weight gain or meanfeed efficiency were observed.
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related abnormalities in treated or control animals during the test period were observed.
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean serum chloride level in beta-CPP-treated males was signifiicantly higher than in controls. Mean aPTT (activated partial thromboplastin time), cholesterol, and AST(GOT) levels in beta-CPP females were significantly lower than in control females. Nevertheless, these four parameters were within the normal range in both female subgroups (see table 2).
No differences were observed between the beta-CPP and control groups with respect to other hematologic response and response variables. - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No significant differences were observed between beta-CPP and control males or famales in terms of urinalysis response variables by randon sampling.
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No behavioral changes were observed that could be attributed to treatment.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No differences were found between the two study groups with respect to other hematologic response and response variables.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Histopathology revealed no evidence of changes that could be attributed to beta-CPP treatment. All observed findings were typical for the Sprague-Dawley strain.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- food consumption and compound intake
- haematology
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- no
- Conclusions:
- Beta-calcium pyrophosphate has a NOAEL higher than 30 mg/kg/day in rats, after 90-day oral administration.
- Executive summary:
A 90 -day repeated dose toxicity study was performed on Sprague-Dawley rats similar to OECD 408. Beta-calcium pyrophosphate was orally administered to 10 male and 10 female Sprague-Dawley rats, at 30 mg/kg/day. Body weights were recorded at baseline and weekly after. Mortality, feed intake, and body weight were monitored. Urinalysis was assessed during the 90-day treatment period. On day 90, all animals were anesthetized, euthanized, and weighed, and blood samples were collected for haematology and serum biochemistry. In males, mean serum chloride level in beta-CPP-treated was significantly higher than in controls. In females, mean aPTT (activated partial thromboplastin time), cholesterol, and AST(GOT) levels in the treated group were significantly lower than in the control group. No mortality occurred throughout the study and no clinical signs were observed. Under these conditions, the test item was found to have a NOAEL higher than 30 mg/kg/day in rats.
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1986
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Deviations:
- yes
- Remarks:
- only 30 males and 1 dose
- GLP compliance:
- no
- Limit test:
- yes
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source: Fisher Chemical Company - Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kigston, NY
- Age at study initiation: not specified
- Weight at study initiation: 50-60 g
- Fasting period before study: no
- Housing: three per cage in plactic shoebox cages
- Diet (e.g. ad libitum): ad libitum a natural ingredient chow (Wayne Laboratory Blox Allied Mills, Inc., Chicago, IL) alone or supplemented with 1% choline cloride
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days
DETAILS OF FOOD AND WATER QUALITY: not specified
ENVIRONMENTAL CONDITIONS: not specified
IN-LIFE DATES: 103 weeks - Route of administration:
- oral: feed
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): 1% choline (Fisher Chemical Company) in a natural ingredient ground chow (Wayne Laboratory Blox Allied Mills, Inc., Chicago, IL) - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 72 weeks
- Frequency of treatment:
- Daily
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- Recalculated dose of 1%
- No. of animals per sex per dose:
- 30 males
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- BODY WEIGHT: Yes
- Time schedule for examinations: weekly for 16 weeks and biweekly thereafter. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Two animals per group were sacrificed at 28 weeks for an interim assessment of the experiment's progress. Afterwards all the animals dying or sacrificed during the study were necropsied. liver weights and body weights were taken at necropsy. All internal organs were examined.
HISTOPATHOLOGY: Yes
The livers and all other organs bearing gross abnormalities were routinely removed and fixed in buffered formalin. They were then sectioned and stained with hematoxylin and eosin for histological examination. - Statistics:
- The comparisons between the incidences of tumors in different groups were analysed by Fischer's exact test. The survival data were analysed by the computer program developed by Thomas et al. (1977). Kaplan-Meier survival curves were derived by using this procedure. Comparison among survival of different experimental groups were made by Cox's test and P value based on the chi-square test from Cox's analysis. The incidences of liver and lung tumors and of leukemias in each group were based upon the number of animals surviving at 1 year since the first instance of each of the tumors occurred between weeks 55 and 60.
- Clinical signs:
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- Choline did not seem to alter survival of rats in any group.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No marked effect on growth was observed.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No significant differences between control and treated groups.
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- No significant differences between control and treated groups.
- Other effects:
- not specified
- Key result
- Dose descriptor:
- other: LD0
- Effect level:
- ca. 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- histopathology: neoplastic
- mortality
- Key result
- Critical effects observed:
- no
- Conclusions:
- The lethal concentration 0 of Choline chloride in rats is 500 mg/kg/day (1%), after 72-week oral administration.
- Executive summary:
A 72-week repeated dose toxicity study was performed on rats similar to OECD 452. Choline chloride was orally administered to 30 male Fischer 344 rats, at 1% (500 mg/kg/day). Body weights were taken at weekly intervals for 16 weeks and biweekly thereafter. Two animals per group were sacrificed at 28 weeks for an interim assessment of the experiment's progress. Afterwards, all the animals dying or sacrificed during the study were necropsied. Liver weights and body weights were taken at necropsy. The livers and all other organs bearing gross abnormalities were routinely removed and fixed in buffered formalin. They were then sectioned and stained with haematoxylin and eosin for histological examination. No marked effect on growth was observed and no mortality occurred throughout the study. The histological distribution of liver tumours showed no significant differences between the control and treated group. Under these conditions, Choline chloride has a lethal concentration 0 of 500 mg/kg/day in rats (1%), after 72-week oral administration.
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1952
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- secondary literature
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test: To evaluate the effect of a prolonged intake of phosphoric acid in rats
- Short description of test conditions: Rats were fed to appetite on a basal diet and phosphoric acid added at different concentrations. The groups were kept in the experiment after 6 months, and observations continued through 2 filial generations.
- Parameters analysed / observed: Effect on growth in 3 generations, reproduction and blood parameters of the first two generations. - GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- not specified
- Details on species / strain selection:
- No data
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: No data
- Females (if applicable) nulliparous and non-pregnant: No data
- Age at study initiation: No data
- Weight at study initiation: No data
- Diet (e.g. ad libitum): basal diet ad libitum.
- Water (e.g. ad libitum): ad libitum - Route of administration:
- oral: feed
- Details on route of administration:
- Basal diet containing casein 6%, dried whole milk 10%, whole wheat flour 34.5%, potato flour 33%, groundnut oil 6.5%, cod liver oil 0.5%, linseed oil 0.5%, brewer's yeast 5% and salt mixture 4%, phosphoric acid at 0.4 or 0.75%.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- More than 52 weeks
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0.4 other: %
- Remarks:
- 21 mg/kg/day (extrapolation from level of compound in diet assuming 0.35-kg rat eats 18 g food/day)
- Dose / conc.:
- 0.75 other: %
- Remarks:
- 386 mg/kg/day (extrapolation from level of compound in diet assuming 0.35-kg rat eats 18 g food/day)
- No. of animals per sex per dose:
- No data
- Control animals:
- not specified
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Not specified
DETAILED CLINICAL OBSERVATIONS: Not specified
BODY WEIGHT: Yes
- Time schedule for examinations: No data
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: 18 g food/0.35 kg/day
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified
OPHTHALMOSCOPIC EXAMINATION: Not specified
HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: No data
- Parameters checked: No data
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: Not specified
- How many animals: No data
- Parameters checked: No data
URINALYSIS: Not specified
NEUROBEHAVIOURAL EXAMINATION: Not specified
IMMUNOLOGY: Not specified - Clinical signs:
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- There was no treatment-related mortality in the animals treated with the test substance during the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There was no differences in weight between control and treated groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There was no differences in food consumption between control and treated groups.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There was no differences in haematological parameters between control and treated groups.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There was no differences in clinical biochemistry parameters between control and treated groups.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 386 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- haematology
- Key result
- Critical effects observed:
- no
- Conclusions:
- Phosphoric acid has a NOAEL>386 mg/kg/day in rats, after administration in diet for more than twelve months.
- Executive summary:
A long-term repeated dose toxicity study of phosphoric acid was performed on rats. Male and female rats were administered on a basal diet with the addition of phosphoric acid at 0.4% or 0.75%. The groups were kept in the experiment after six months, and observations continued through two filial generations (more than twelve months). Effect on growth in three generations, reproduction and blood parameters of the first two generations. No adverse effects were noted at up to 0.75%. The NOEL for this study was 0.75% or more of phosphoric acid in the diet, which was equivalent to 386 mg/kg/day or more, assuming a 0.35 kg rat consumes 18 g food/day. Therefore, the test item has a NOAEL>386 mg/kg/day in rats, after administration in diet for more than twelve months.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2011
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- not specified
- Remarks:
- Not specified in the publication
- Limit test:
- no
- Specific details on test material used for the study:
- - Source: Sigma-aldrich (Korea)
- Batch number: 048K0049 - Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Orient Bio Co., Ldt. (Gyeonggi-do, Korea)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: young adults
- Fasting period before study: not specified
- Housing: animals were housed in groups of two to three in stainless steel wire mesh cages
- Diet (e.g. ad libitum): comercial roden show (2.0 Mrad gamma-ray sterilized EP pellet, Cargill Agri purina Korea Ltd, korea) ad libitum
- Water (e.g. ad libitum): sterilized tap water ad libitum
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3ºC
- Humidity (%): 55 ± 5%
- Air changes (per hr): 10-18 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hour light (from 8:00 to 20:00)/ 12 hour dark - Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- Five times a week
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The doses were selected based on the results of the acute toxicity study and a 14-day dose range study (No toxicity or mortality was observed in any of the five male and female rats treated with Tetrasodium pyrophosphate at the dose of 2000 mg/kg for 14 days).
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a day
BODY WEIGHT: Yes
- Time schedule for examinations: once a week
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of treatment
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table 2 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:at the end of treatment
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table 3 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: during the last week of administration
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Yes
- Parameters examined: glucose, bilirubin, ketone body, specific gravity, blood, pH, protein, urobilinogen, nitrite and leukocyte levels - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see tables 3 and 4)
HISTOPATHOLOGY: Yes (see table 5) - Statistics:
- The results are presented as the mean ± standard deviation (SD). The differences in parameters (BWs, organ wtights, and the results of the blood biochemistry and hematology) between groups in the acute and sub-chronic toxicity test were assessed by a standard two-way analysis of variance (ANOVA). If these showed statistical significance, Duncan's of Dunnett's multiple range test were used to compare groups (SPSS version 12.0 [SPSS Inc., Chicago, IL, USA]). P-vallues < 0.05 were considered statistically significant.
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was no clinical signs in rats administered with 2000 mg/kg of tetrasodium pyrophosphate.
Female rats treated with 500 and 1000 mg/kg of the test substance showed hair loss. No significant clinical signs were observed in any other group. - Mortality:
- no mortality observed
- Description (incidence):
- There were no dead animals in the treatment group administered with 2000 mg/kg of tetrasodium pyrophosphate.
There was no treatment-related mortality in the animals treated with the test substance during the study. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The terminal body weight of male rats treated with 1000 mg/kg of test substance was lower than that of the control group, while there were no differences in body weight between the 250, 500 mg/kg, and control group. There was no treatment-related change in body weight in female rats.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A significant decrease in food consumption was observed in the 1000 mg/kg group of males at week 8 and 9. Food consumption in females increased significantly in the 1000 mg/kg group at week 4. There were no significant changes in food consumption in the other groups (Table 1).
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no significant changes in hematology in the 250 mg/kg group.
WBC and neutrophil counts were ignificantly increased in males and females of the 1000 mg/kg group, whereas the lymphocyte count was significantly lower in males and females of the 1000 mg/kg group, whereas the lymphocyte count was significantly lower in males and females of the 1000 mg/kg geoup. RBC, HB, HCT, PT, and APTT were signidicantly reduced in the males of the 1000 mg/kg group, and PT was significantly reduced in males of the 500 mg/kg group (Table 2). - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no significant changes in the serum biochemistry of males and females in the 250 mg/kg group.
Total protein was significantly reduced in both sexes in the 500 and 1000 mg/kg group. Albumin was significantly reduced in males of the 500 and 1000 mg/kg group, and in females of the 1000 mg/kg group. The A/G ratio was significantly increased in females of the 500 and 1000 mg/kg group. T-BIL was significantly increased in femaels of the 1000 mg/kg group, and ALP was significantly reduced in females of the 1000 mg/kg group, but ALT was significantly reduced in females of the 1000 mg/kg group. AST was significantly increased in males of the 1000 mg/kg group. TG were significantly increased in both sexes in the 1000 mg/kg group, while Ca, IP, Na, K, and Cl were significantly reduced in both sexes in this group. IP was also reduced in males of the 500 mg/kg group (Table 3). - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- There were no specific symptoms in urinalysis at the doses of 250, 500 and 1000 mg/kg.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no significant changes in organ weight in males and females of the 250 mg/kg group. The relative weight of the liver in the males of the 500 mg/kg and 1000 mg/kg groups showed a significant increase. The absolute and relative weight of the liver in females of the 500 mg/kg and 1000 mg/kg groups were also significantly incrased (Table 4,5).
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There was no grossly visible findings or lesions in any group.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- No exposure-related histopathological changes were observed in any of the organs examined in SD rats, with the exception of kidney lesions. Cortical tubular basophila of the renal tubule was more evident in males of the 1000 mg/kg group and mineralization of the kidney was evident in females of the 1000 mg/kg group. Other background lesions were observed in the 0, 250, 500 and 1000 mg/kg groups in both sexes (Table 6).
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- gross pathology
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- urinalysis
- Dose descriptor:
- NOEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- gross pathology
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- urinalysis
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Conclusions:
- Tetrasodium pyrophosphate was found to have a NOAEL of 500 mg/kg/day and the target organ appears to be the kidney in rats.
- Executive summary:
A 90 -day repeated dose toxicity study was performed on Sprague-Dawley rats according to OECD 408. Tetrasodium pyrophosphate was orally administered to 10 male and 10 female Sprague-Dawley rats, at 0, 250, 500 and 1000 mg/kg/day five times a week for 90 days. Body weights were recorded at baseline and weekly after. Mortality, feed intake, and body weight were monitored. There were no significant changes in body weight in the 1000 mg/kg treatment group, or food consumption, urinalysis, and haematology in any group. The levels of total protein, albumin, A/G ratio, triglyceride, calcium and inorganic phosphate were altered at doses 500 and 1000 mg/kg. However, no changes were observed at the dose of 250 mg/kg. No mortality occurred throughtout the study and no clinical signs were observed. Regarding histopathological findings, cortical tubular basophila of the kidney increased at the dose of 1000 mg/kg, but not at doses of 250 and 500 mg/kg. No significant changes were observed in other organs at doses of 250, 500 and 1000 mg/kg. Based on these results, the test item was found to have a NOEL and a NOAEL of 250 and 500 mg/kg/day respectively and the target organ appears to be the kidney in rats.
Referenceopen allclose all
Table 1. Body-weight changes in male and female rats given control and test substance (mean ± standard deviation, g)
|
Control |
Treat |
P-value |
|||
|
Male |
Female |
Male |
Female |
Male |
Female |
Body weight week 0 |
183 ± 8 |
163 ± 6 |
182 ± 8 |
163 ± 7 |
0.7771 |
0.8614 |
Body weight week 1 |
231 ± 10 |
187 ± 7 |
231 ± 8 |
189 ± 12 |
0.8414 |
0.7871 |
Body weight week 2 |
283 ± 11 |
211 ± 12 |
287 ± 9 |
211 ± 16 |
0.3943 |
0.9580 |
Body weight week 3 |
311 ± 13 |
228 ± 16 |
321 ± 11 |
225 ± 17 |
0.0693 |
0.6310 |
Body weight week 4 |
335 ± 17 |
240 ± 15 |
346 ± 14 |
235 ± 15 |
0.1533 |
0.5384 |
Body weight week 5 |
355 ± 20 |
250 ± 15 |
367 ± 19 |
248 ± 20 |
0.2108 |
0.8170 |
Body weight week 6 |
375 ± 20 |
262 ± 15 |
388 ± 22 |
261 ± 17 |
0.1935 |
0.8990 |
Body weight week 7 |
381 ± 21 |
265 ± 17 |
395 ± 23 |
260 ± 14 |
0.1703 |
0.4692 |
Body weight week 8 |
397 ± 22 |
272 ± 19 |
408 ± 25 |
272 ± 20 |
0.2900 |
0.9364 |
Body weight week 9 |
407 ± 22 |
276 ± 15 |
421 ± 26 |
274 ± 18 |
0.2051 |
0.8067 |
Body weight week 10 |
421 ± 23 |
279 ± 18 |
432 ± 26 |
282 ± 19 |
0.3290 |
0.6678 |
Body weight week 11 |
431 ± 23 |
282 ± 16 |
445 ± 26 |
283 ± 19 |
0.1938 |
0.9063 |
Body weight week 12 |
439 ± 25 |
287± 16 |
456 ± 27 |
285 ± 17 |
0.1491 |
0.7587 |
Table 2. Hematology and biochemical values of male and female rats (mean ± standard deviation)
|
RV |
Control |
Treat |
P-value |
|||
|
|
Male |
Female |
Male |
Female |
Male |
Female |
WBC (x 103/mm3) |
3.0 -15.0 |
5.5 ± 1.2 |
5.1 ± 1.1 |
5.5 ± 0.6 |
4.3 ± 1.2 |
0.8496 |
0.2720 |
RBC (x 106/mm3) |
5.0 -12.0 |
7.12 ± 0.52 |
6.64 ± 0.39 |
7.34 ± 0.4 |
6.67 ± 0.43 |
0.2413 |
0.6500 |
Hb (g/dL) |
11.1 – 18.0 |
14.6 ± 0.6 |
13.9 ± 0.6 |
14.7 ± 0.7 |
14.3 ± 0.6 |
0.5960 |
0.3219 |
Hct (%) |
36.0 -52.0 |
40.6 ± 2.6 |
38.0 ± 1.8 |
41.1 ± 2.8 |
39.0 ± 2.1 |
0.6498 |
0.4488 |
Platelet (x 103/mm3) |
500-1300 |
691.7 ± 59.1 |
717.1 ± 27.6 |
671.6 ± 54.5 |
701.7 ± 58.7 |
0.5706 |
0.3074 |
MCV (fL) |
44-69 |
57.0 ± 2.3 |
57.3 ± 1.6 |
56.0 ± 2.0 |
58.5 ± 1.6 |
0.3029 |
0.1383 |
MCH (pg) |
12.0-24.5 |
20.6 ± 1.2 |
21.0 ± 1.1 |
20.1 ± 0.8 |
21.4 ± 1.0 |
0.3066 |
0.2890 |
MCHC (g/dL) |
21.6-42.0 |
36.0 ± 1.2 |
36.7 ± 1.1 |
35.9 ± 1.3 |
36.6 ± 1.2 |
0.4718 |
0.4263 |
Monocyte (%) |
0-5 |
1.4 ± 1.4 |
2.1 ± 1.7 |
1.0 ± 0.7 |
1.5 ± 1.5 |
0.6641 |
0.4176 |
Basophil (%) |
0-1.5 |
0.1 ± 0.3 |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.3306 |
1.0000 |
Eosinophil (%) |
0-6 |
0.0 ± 0.0 |
0.1 ± 0.3 |
0.0 ± 0.0 |
0.0 ± 0.0 |
1.0000 |
0.3306 |
Neutrophil (%) |
9-34 |
20.8 ± 11.4 |
18.7 ± 5.4 |
19.0 ± 2.9 |
17.4 ± 7.5 |
0.9396 |
0.5699 |
Lymphocyte (%) |
65-85 |
77.7 ± 11.5 |
79.1 ± 5.6 |
80.0 ± 3.1 |
81.1 ± 7.5 |
0.9394 |
0.5948 |
PT seconds (seconds) |
12.5-18.7 |
15.4 ± 0.4 |
15.4 ± 0.7 |
15.5 ± 0.6 |
15.4 ± 0.6 |
0.3047 |
0.8201 |
aPTT (seconds) |
18.4-45 |
28.3 ± 3.1 |
28.1 ± 2.0 |
28.8 ± 2.2 |
25.5 ± 3.0 |
0.9397 |
0.0210* |
Calcium (mg/dL) |
5.3-13.0 |
9.8 ± 0.3 |
9.8 ± 0.2 |
9.8 ± 0.4 |
9.9 ± 0.3 |
0.8188 |
0.3761 |
Phosphorus (mg/dL) |
5.6-9.6 |
7.3 ± 0.6 |
6.8 ± 0.6 |
7.1 ± 0.4 |
7.3 ± 1.1 |
0.3422 |
0.3825 |
Glucose (mg/dL) |
50-135 |
112 ± 35 |
73 ± 16 |
120.0 ± 24 |
89 ± 22 |
0.6232 |
0.1618 |
BUN (mg/dL) |
15-21 |
25 ± 2 |
25 ± 3 |
23 ± 3 |
24 ± 4 |
0.1008 |
0.4700 |
Choresterol (mg/dL) |
40-130 |
104 ± 16 |
112 ± 11 |
99 ± 15 |
102 ± 18 |
0.5960 |
0.0491* |
T.Protein (g/dL) |
5.6-7.6 |
6.1 ± 0.2 |
6.3 ± 0.2 |
6.2 ± 0.2 |
6.3 ± 0.2 |
0.1075 |
1.0000 |
Albumin (g/dL) |
3.8-4.8 |
6.6 ± 10.0 |
3.8 ± 0.1 |
3.5 ± 0.1 |
3.8 ± 0.1 |
0.9687 |
0.4097 |
T.Bil. (mg/dL) |
0.20-0.55 |
0.1 ± 0.0 |
0.2 ± 0.1 |
0.1 ± 0.0 |
0.1 ± 0.1 |
1.0000 |
0.6934 |
Alkaline phosphatase (IU/L) |
60-300 |
59 ± 12 |
39 ± 8 |
58 ± 6 |
41 ± 5 |
0.9698 |
0.5681 |
AST (GOT) (IU/L) |
47-155 |
135 ± 46 |
170 ± 21 |
123 ± 31 |
133 ± 34 |
0.6500 |
0.0256* |
ALT (GPT) (IU/L) |
17-56 |
36 ± 7 |
29 ± 5 |
32 ± 5 |
26 ± 3 |
0.4256 |
0.0792 |
Creatinine (mg/dL) |
0.2-0.8 |
0.6 ± 0.1 |
0.7 ± 0.0 |
0.6 ± 0.1 |
0.7 ± 0.1 |
0.1197 |
0.6770 |
Na (mmol/L) |
135-145 |
146 ± 2 |
146 ± 1 |
147 ± 2 |
145 ± 2 |
0.8777 |
0.6696 |
K (mmol/L) |
3.5-5.5 |
4.7 ± 0.3 |
4.0 ± 0.2 |
4.7 ± 0.2 |
4.1 ± 0.3 |
0.6193 |
0.3381 |
Cl (mmol/L) |
98-110 |
102 ± 2 |
104 ± 1 |
104 ± 1 |
104 ± 1 |
0.0262* |
0.0738 |
TG (mg/dL) |
0-200 |
55 ± 16 |
48 ± 13 |
43 ± 11 |
46 ± 15 |
0.1400 |
0.7616 |
A/G |
- |
1.3 ± 0.1 |
1.5 ± 0.2 |
1.3 ± 0.1 |
1.5 ± 0.1 |
0.3384 |
0.4594 |
RV, reference values
* Groups significantly different (P<0.05) by the one-way analysis of variance test or the Wilcoxon rank-sum test.
RBC: red blood count; WBC: white blood count; MCV: mean corpuscular volume (MCV); MCH: mean corpuscular haemoglobin; MCHC: mean corpuscular haemoglobin concentration; PTs: prothrombin times; aPTT: activated partial thromboplastin time; TG: triglyceride; BUN: blood urea nitrogen; ALT: alanine transaminase; AST: aspartate transaminase; ALP: alkaline phosphatase.
Table 3. Summary of male and female rats absolute and relative organ weights (mean ± standard deviation, g).
|
Control |
Treat |
P-value |
|||
|
Male |
Female |
Male |
Female |
Male |
Female |
Body weight |
417 ± 25 |
271 ± 17 |
428 ± 28 |
265 ± 20 |
0.3595 |
0.5097 |
Brain |
1.960 ± 0.083 |
1.789 ± 0.159 |
2.005 ± 0.074 |
1.840 ± 0.055 |
0.2206 |
0.5706 |
Thymus |
0.296 ± 0.041 |
0.249 ± 0.024 |
0.357 ± 0.080 |
0.240 ± 0.071 |
0.1041 |
0.4961 |
Lung |
1.566 ± 0.169 |
1.364 ± 0.089 |
1.697 ± 0.265 |
1.321 ± 0.095 |
0.4274 |
0.3053 |
Spleen |
0.711 ± 0.063 |
0.556 ± 0.051 |
0.699 ± 0.082 |
0.543 ± 0.054 |
0.7159 |
0.5813 |
Pituitary |
0.012 ± 0.003 |
0.014 ± 0.003 |
0.012 ± 0.003 |
0.013 ± 0.003 |
0.9404 |
0.7743 |
Heart |
1.354 ± 0.135 |
0.874 ± 0.043 |
1.355 ± 0.137 |
0.881 ± 0.070 |
0.9754 |
0.8089 |
Prostate |
0.688 ± 0.167 |
|
0.683 ± 0.086 |
|
0.5450 |
|
Liver |
10.550 ± 1.200 |
6.050 ± 0.339 |
10.485 ± 0.979 |
5.790 ± 0.589 |
0.8965 |
0.2420 |
Adrenal |
0.025 ± 0.002 |
0.032 ± 0.005 |
0.023 ± 0.003 |
0.027 ± 0.005 |
0.1394 |
0.0665 |
Kidney |
1.261 ± 0.113 |
0.797 ± 0.049 |
1.265 ± 0.080 |
0.764 ± 0.046 |
0.9371 |
0.1365 |
Testis |
1.794 ± 0.139 |
|
1.844 ± 0.102 |
|
0.3748 |
|
Ovary |
|
0.064 ± 0.009 |
|
0.067 ± 0.014 |
|
0.5067 |
Relative brain |
0.0047 ± 0.0003a |
0.0066 ± 0.0003a |
0.0047 ± 0.0003 |
0.0070 ± 0.0005 |
0.8871 |
0.1016 |
Relative thymus |
0.0007 ± 0.0001 |
0.0009 ± 0.0001 |
0.0008 ± 0.0001 |
0.0009 ± 0.0002 |
0.0731 |
0.8117 |
Relative lung |
0.0038 ± 0.0003 |
0.0050 ± 0.0003 |
0.0040 ± 0.0006 |
0.0050 ± 0.0004 |
0.5674 |
0.6598 |
Relative spleen |
0.0017 ± 0.0002 |
0.0021 ± 0.0001 |
0.0016 ± 0.0002 |
0.0020 ± 0.0002 |
0.4365 |
0.7751 |
Relative pituitary |
0.00003 ± 0.00001 |
0.00005 ± 0.00001 |
0.00003 ± 0.00000 |
0.00005 ± 0.00001 |
1.0000 |
0.7007 |
Relative heart |
0.0032 ± 0.0002 |
0.0032 ± 0.0002 |
0.0032 ± 0.0002 |
0.0033 ± 0.0002 |
0.3104 |
0.3480 |
Relative prostate |
0.0017 ± 0.0004 |
|
0.0016 ± 0.0002 |
|
0.9694 |
|
Relative liver |
0.0253 ± 0.0016 |
0.0224 ± 0.0017 |
0.0245 ± 0.0011 |
0.0218 ± 0.0018 |
0.2118 |
0.4048 |
Relative adrenal |
0.00006 ± 0.00001 |
0.00012 ± 0.00002 |
0.00005 ± 0.00001 |
0.00010 ± 0.00002 |
0.1519 |
0.1602 |
Relative kidney |
0.0030 ± 0.0002 |
0.0030 ± 0.0003 |
0.0030 ± 0.0002 |
0.0029 ± 0.0001 |
0.5535 |
0.2790 |
Relative testis |
0.0043 ± 0.0003 |
|
0.0043 ± 0.0003 |
|
0.9388 |
|
Relative ovary |
|
0.0002 ± 0.0000 |
|
0.0003 ± 0.0000 |
|
0.6506 |
aExpressed as a percentage of body weight.
Table 1. The histological distribution of liver tumors in male weaning F344 rats fed withsaline or 1% of choline.
Group |
Survival at wk |
Body wt at wk |
Relative liver wt (%) |
No. of animals bearing liver tumors |
||||||
Neoplastic nodules |
Hepatocellular carcinomas |
Cholangiomas + cholangiocarcinomas |
Lung metastases |
|||||||
Control |
28 |
28 |
23 |
253 |
408 |
3.60 |
2 |
1 |
0 |
0 |
Choline chloride 1% |
28 |
28 |
24 |
258 |
406 |
3.40 |
2 |
0 |
0 |
0 |
Table 1. Food consumption of SD rats orally treated with tetrasodium pyrophosphate for 90 days.
|
Male |
Female |
||||||
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
1 |
27.1 ± 1.0 |
27.0 ± 1.6 |
26.7 ± 0.9 |
27.1 ± 1.8 |
19.1 ± 1.4 |
20.6 ± 1.7 |
19.9 ± 1.5 |
20.2 ± 1.0 |
2 |
30.4 ± 0.9 |
28.5 ± 6.4 |
30.7 ± 1.7 |
29.2 ± 1.4 |
21.1 ± 2.6 |
21.3 ± 3.9 |
21.4 ± 2.1 |
20.3 ± 2.1 |
3 |
33.8 ± 1.9 |
34.1 ± 2.2 |
32.9 ± 3.1 |
30.4 ± 3.6 |
22.6 ± 2.2 |
22.6 ± 2.7 |
21.8 ± 2.1 |
21.7 ± 1.0 |
4 |
30.9 ± 1.2 |
31.6 ± 2.5 |
31.8 ± 6.6 |
28.5 ± 3.2 |
19.7 ± 2.5 |
20.5 ± 1.4 |
21.3 ± 1.5 |
22.7 ± 1.3* |
5 |
33.4 ± 2.8 |
30.8 ± 1.2 |
31.8 ± 2.7 |
30.5 ± 2.1 |
21.7 ± 0.6 |
20.3 ± 3.3 |
19.3 ± 2.5 |
22.9 ± 2.7 |
6 |
29.3 ± 3.9 |
27.9 ± 2.6 |
29.2 ± 1.9 |
27.9 ± 2.9 |
18.1 ± 2.0 |
17.1 ± 3.7 |
18.2 ± 1.8 |
19.2 ± 1.3 |
7 |
33.1 ± 2.7 |
33.3 ± 2.6 |
33.8 ± 1.2 |
32.9 ± 3.2 |
24.3 ± 2.0 |
21.9 ± 2.0 |
23.2 ± 2.8 |
23.9 ± 2.9 |
8 |
31.5 ± 2.1 |
31.3 ± 2.1 |
33.0 ± 1.6 |
28.3 ± 0.5Ɨ |
20.8 ± 2.0 |
20.3 ± 2.9 |
21.7 ± 2.8 |
21.0 ± 2.2 |
9 |
31.8 ± 2.1 |
31.3 ±1.7 |
30.5 ± 1.1 |
28.2 ± 2.5* |
20.6 ± 3.8 |
18.8 ± 2.7 |
19.9 ± 1.4 |
19.8 ± 2.1 |
10 |
32.7 ± 2.0 |
31.6 ± 2.3 |
31.9 ± 1.1 |
28.8 ± 1.8 |
21.2 ± 1.3 |
18.9 ± 3.8 |
21.2 ± 2.4 |
19.4 ± 1.7 |
11 |
29.8 ± 2.7 |
30.3 ± 3.0 |
29.6 ± 2.0 |
27.8 ± 1.6 |
20.5 ± 3.5 |
19.5 ± 2.3 |
21.1 ± 3.7 |
21.0 ± 3.9 |
12 |
33.8 ± 0.5 |
33.5 ± 0.5 |
33.2 ± 0.6 |
33.4 ± 0.5 |
20.2 ± 1.8 |
19.7 ± 3.1 |
21.5 ± 2.0 |
20.3 ± 2.9 |
13 |
30.1 ± 2.2 |
29.4 ± 2.3 |
31.2 ± 1.8 |
28.5 ± 1.7 |
20.1 ± 1.5 |
18.6 ± 1.9 |
20.4 ± 3.6 |
21.1 ± 2.5 |
*p<0.05,Ɨp<0.01
Table 2. Hematological values of SD rats orally treated with tetrasodium pyrophosphate for 90 days.
|
Male |
Female |
||||||
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
WBC (K) |
7.20 ± 1.83 |
6.62 ± 0.71 |
7.76 ± 1.58 |
9.35 ± 1.31* |
3.72 ± 1.86 |
6.84 ± 2.09 |
4.44 ± 0.66 |
6.39 ± 1.83Ɨ |
Neutrophil (%) |
14.2 ± 4.6 |
18.6 ± 6.2 |
20.1 ± 6.6 |
24.8 ± 4.9 |
12.2 ± 3.7 |
17.7 ± 5.0 |
17.3 ± 7.3 |
20.9 ± 6.3* |
Lymphocyte (%) |
80.1 ± 4.5 |
74.8 ± 6.2 |
73.6 ± 6.9 |
68.7 ± 6.0 |
81.4 ± 5.0 |
74.4 ± 6.1 |
75.4 ± 7.4 |
73.2 ± 7.0* |
Monocyte (%) |
3.6 ± 1.1 |
3.9 ± 1.6 |
3.4 ± 1.1 |
4.1 ± 1.8 |
3.6 ± 1.5 |
3.7 ± 0.2 |
3.8 ± 1.7 |
3.3 ± 0.9 |
Eosinophil (%) |
1.4 ± 0.5 |
1.9 ± 0.5 |
2.3 ± 0.7* |
1.8 ± 0.6 |
2.1 ± 0.9 |
1.9 ± 0.3 |
2.6 ± 1.1 |
2.1 ± 0.6 |
Basophil (%) |
0.2 ± 0.1 |
0.2 ± 0.1 |
0.2 ± 0.1 |
0.3 ± 0.1 |
0.2 ± 0.1 |
0.2 ± 0.0 |
0.2 ± 0.1 |
0.2 ± 0.1 |
RBC (M) |
8.56 ± 0.19 |
8.43 ± 0.34 |
8.55 ± 0.42 |
8.19 ± 0.19Ɨ |
7.82 ± 0.28 |
8.16 ± 0.40 |
7.96 ± 0.23 |
7.82 ± 0.25 |
Hb (g/dl) |
15.3 ± 0.5 |
14.9 ± 0.7 |
14.8 ± 0.8 |
14.4 ± 0.3Ɨ |
14.4 ± 0.5 |
14.5 ± 0.6 |
14.6 ± 0.4 |
14.1 ± 0.4 |
Hct (%) |
45.5 ± 1.4 |
44.3 ± 1.8 |
44.4 ± 2.2 |
43.1 ± 0.8Ɨ |
42.3 ± 1.5 |
43.1 ± 2.0 |
42.8 ± 1.3 |
42.0 ± 1.2 |
MCV (fL) |
53.1 ± 1.1 |
52.5 ± 1.3 |
52.0 ± 2.7 |
52.7 ± 0.9 |
54.1 ± 1.2 |
52.0 ± 2.4 |
53.8 ± 1.3 |
53.7 ± 0.9 |
MCH (pg) |
17.9 ± 0.4 |
17.6 ± 0.5 |
17.3 ± 1.0 |
17.6 ± 0.4 |
18.5 ± 0.5 |
17.5 ± 0.9 |
18.3 ± 0.5 |
18.1 ± 0.2 |
MCHC (g/dL) |
33.8 ± 0.5 |
33.5 ± 0.5 |
33.2 ± 0.6 |
33.4 ± 0.5 |
34.1 ± 0.4 |
33.0 ± 1.4 |
34.1 ± 0.2 |
33.7 ± 0.4 |
Reticulocyte (%) |
2.04 ± 0.34 |
2.1 ± 0.3 |
2.38 ± 0.52 |
2.37 ± 0.38 |
1.79 ± 0.41 |
2.11 ± 0.26 |
2.02 ± 0.49 |
2.27 ± 0.42 |
PLT (K) |
1148.2 ± 124.4 |
1071.6 ± 98.4 |
1213.9 ± 123.4 |
1264.5 ± 171.4 |
1153.7 ± 171.4 |
1153.2 ± 105.1 |
1169.5 ± 427.3 |
1441.4 ± 210.2 |
PT (sec) |
17.7 ± 0.5 |
17.6 ± 0.6 |
16.7 ± 0.6Ɨ |
16.9 ± 0.6Ɨ |
16.9 ± 0.8 |
17.1 ± 0.6 |
17.1 ± 1.0 |
16.2 ± 0.9 |
APTT (sec) |
20.3 ± 1.2 |
19.5 ± 1.9 |
19.4 ± 1.2 |
18.4 ± 1.1* |
16.4 ± 0.8 |
18.8 ± 1.5 |
16.5 ± 0.9 |
16.7 ± 0.8 |
WBC: white blood cell, RBC: red blood cell, Hb haemoglobin, Hct: haematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular haemoglobin, MCHC: mean corpuscular hemoglobin concentration, PLT. Platelet, PT: prothrombin time, APTT: activated partial thromboplastin time.
*p<0.05,Ɨp<0.01
Table 3. Biochemical values of SD rats orally treated with tetrasodium pyrophosphate for 90 days.
|
Male |
Female |
||||||
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
TP (g/dL) |
6.2 ± 0.4 |
6.0 ± 0.2 |
5.4 ± 0.3Ɨ |
4.8 ± 0.3Ɨ |
6.7 ± 0.3 |
6.5 ± 0.3 |
5.8 ± 0.5Ɨ |
4.9 ± 0.3Ɨ |
Albumin (g/dL) |
2.5 ± 0.2 |
2.4 ± 0.1 |
2.3 ± 0.1* |
2.1 ± 0.1Ɨ |
3.0 ± 0.2 |
2.9 ± 0.2 |
2.7 ± 0.2 |
2.3 ± 0.2Ɨ |
A/G ratio |
0.67 ± 0.05 |
0.68 ± 0.06 |
0.73 ± 0.02 |
0.74 ± 0.05* |
0.78 ± 0.06 |
0.84 ± 0.05 |
0.88 ± 0.06* |
0.87 ± 0.06* |
T-BIL (mg/dL) |
0.078 ± 0.010 |
0.071 ± 0.010 |
0.075 ± 0.015 |
0.076 ± 0.031 |
0.104 ± 0.010 |
0.096 ± 0.013 |
0.083 ± 0.017 |
0.075 ± 0.024Ɨ |
ALP (U/L) |
270 ± 49.0 |
278 ± 36.0 |
277 ± 74.0 |
227 ± 55.0 |
146 ± 40.0 |
139 ± 35.0 |
118 ± 23.0 |
103 ± 26.0* |
AST (U/L) |
99 ± 21.0 |
117 ± 20.0 |
103 ± 16.0 |
138 ± 25.0Ɨ |
113 ± 32.0 |
128 ± 50.0 |
109 ± 25.0 |
110 ± 25.0 |
ALT (U/L) |
35 ± 5.0 |
37 ± 10.0 |
31 ± 4.0 |
39 ± 13.0 |
28 ± 7.0 |
39 ± 28.0 |
24 ± 4.0 |
17 ± 1.0Ɨ |
CRN (mg/dL) |
0.6 ± 0.0 |
0.6 ± 0.0 |
0.6 ± 0.0 |
0.6 ± 0.1 |
0.7 ± 0.1 |
0.7 ± 0.1 |
0.7 ± 0.0 |
0.7 ± 0.1 |
BUN (mg/dL) |
11.5 ± 1.4 |
11.5 ± 2.2 |
12.2 ± 1.3 |
13.6 ± 1.7 |
12.8 ± 2.6 |
14.3 ± 1.7 |
12.8 ± 1.7 |
11.8 ± 1.8 |
CHOL (mg/dL) |
71 ± 14.0 |
67 ± 8.0 |
78.0 ± 19.0 |
75 ± 11.0 |
78 ± 18.0 |
81 ± 16.0 |
79 ± 12.0 |
74 ± 8.0 |
TG (mg/dL) |
118 ± 29.0 |
106 ± 38.0 |
178 ± 68.0 |
183 ± 57.0* |
25 ± 17.0 |
39 ± 22.0 |
91 ± 68.0 |
141 ± 96.0* |
GLU (mg/dL) |
143 ± 21.0 |
138 ± 15.0 |
139 ± 24.0 |
132 ± 14.0 |
143 ± 26.0 |
137 ± 13.0 |
128 ± 8.0 |
135 ± 18.0 |
Ca (mg/dL) |
10.0 ± 0.2 |
9.9 ± 0.3 |
9.7 ± 0.4 |
9.2 ± 0.3Ɨ |
10.1 ± 0.4 |
10.0 ± 0.3 |
9.7 ± 0.2 |
9.0 ± 0.2Ɨ |
IP (mg/dL) |
7.3 ± 0.4 |
6.7 ± 0.5 |
6.4 ± 0.5Ɨ |
5.7 ± 0.4Ɨ |
6.1 ± 0.6 |
6.1 ± 0.8 |
5.6 ± 0.4 |
4.7 ± 0.4* |
CK (IU/L) |
354 ± 221.0 |
504 ± 233.0 |
449 ± 268.0 |
617 ± 181 |
533 ± 259.0 |
556 ± 203.0 |
569 ± 433 |
612 ± 318.0 |
Na (mmol/L) |
142 ± 2.0 |
141 ± 2.0 |
140 ± 2.0 |
139 ± 1.0 |
142 ± 1.0 |
141 ± 1.0 |
140 ± 1.0Ɨ |
139 ± 2.0 |
K (mmol/L) |
4.6 ± 0.3 |
4.6 ± 0.1 |
4.6 ± 0.2 |
4.2 ± 0.3* |
4.3 ± 0.2 |
4.2 ± 0.2 |
4.3 0.2 |
4.0 ± 0.3 |
Cl (mmol/L) |
107 ± 2.0 |
108 ± 1.0 |
106 ± 2.0 |
103 ± 3.0* |
107 ± 1.0 |
106 ± 1.0 |
105 ± 1.0 |
105 ± 2.0 |
TP: total protein, T-BIL: total bilirubin, ALP: alkaline phosphatase, AST: aspartate aminotransferase, ALT: alanine aminotransferase, CRN: creatinine, BUN: blood urea nitrogen, CHOL: total cholesterol, TG: triglycerides, GLU: glucose, Ca: calcium, IP phosphorus, CK: cratitnine kinase, Na: sodium, K: potassium, Cl: chloride.
*p<0.05,Ɨp<0.01
Table 4. Absolute organ weights of SD rats orally treated with tetrasodium pyrophosphate for 90 days.
Organs (g) |
Male |
Female |
||||||
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Liver |
14.54 ± 1.24 |
14.26 ± 2.17 |
16.28 ± 2.55 |
14.53 ± 1.59 |
7.33 ± 0.83 |
7.25 ± 0.87 |
8.09 ± 0.60 |
9.06 ± 1.09 |
Kidney left |
1.77 ± 0.15 |
1.76 ± 0.23 |
1.82 ± 0.17 |
1.69 ± 0.19 |
0.99 ± 0.13 |
0.97 ± 0.07 |
1.02 ± 0.07 |
1.06 ± 0.10 |
Kidney right |
1.70 ± 0.19 |
1.74 ± 0.20 |
1.82 ± 0.20 |
1.72 ± 0.18 |
1.00 ± 0.09 |
0.89 ± 0.32 |
1.05 ± 0.06 |
1.08 ± 0.12 |
Adrenal gland left |
0.036 ± 0.008 |
0.029 ± 0.004 |
0.031 ± 0.005 |
0.035 ± 0.006 |
0.032 ± 0.007 |
0.034 ± 0.003 |
0.033 ± 0.007 |
0.036 ± 0.005 |
Adrenal gland right |
0.035 ± 0.004 |
0.032 ± 0.004 |
0.030 ± 0.004 |
0.031 ± 0.004 |
0.033 ± 0.007 |
0.034 ± 0.005 |
0.034 ± 0.006 |
0.037 ± 0.009 |
Testis/ovary left |
1.76 ± 0.13 |
1.76 ± 0.13 |
1.74 ± 0.15 |
1.70 ± 0.11 |
0.041 ± 0.011 |
0.041 ± 0.013 |
0.043 ± 0.009 |
0.046 ± 0.008 |
Testis/ovary right |
1.76 ± 0.11 |
1.73 ± 0.13 |
1.73 ± 0.14 |
1.71 ± 0.11 |
0.043 ± 0.011 |
0.043 ± 0.008 |
0.044 ± 0.006 |
0.045 ± 0.008 |
Brain |
2.14 ± 0.09 |
2.10 ± 0.12 |
2.10 ± 0.08 |
2.07 ± 0.11 |
1.96 ± 0.10 |
1.95 ± 0.13 |
1.95 ± 0.11 |
1.97 ± 0.11 |
*p<0.01
Table 5. Relative organ weights of SD rats orally treated with tetrasodium pyrophosphate for 90 days.
Organs (g) |
Male |
Female |
||||||
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Liver |
2.5 ± 0.16 |
2.53 ± 0.18 |
2.76 ± 0.17* |
2.80 ± 0.17* |
2.41 ± 0.10 |
2.42 ± 0.10 |
2.81 ± 0.18Ɨ |
2.94 ± 0.25 |
Kidney left |
0.30 ± 0.03 |
0.31 ± 0.02 |
0.32 ± 0.03 |
0.33 ± 0.03 |
0.33 ± 0.04 |
0.33 ± 0.04 |
0.35 ± 0.03 |
0.34 ± 0.04 |
Kidney right |
0.31 ± 0.03 |
0.31 ± 0.02 |
0.32 ± 0.01 |
0.33 ± 0.03 |
0.33 ± 0.02 |
0.30 ± 0.11 |
0.36 ± 0.02 |
0.35 ± 0.04 |
Adrenal gland left |
0.006 ± 0.001 |
0.005 ± 0.001 |
0.005 ± 0.001 |
0.007 ± 0.001 |
0.010 ± 0.002 |
0.011 ± 0.002 |
0.011 ± 0.003 |
0.012 ± 0.001 |
Adrenal gland right |
0.006 ± 0.001 |
0.006 ± 0.001 |
0.006 ± 0.001 |
0.006 ± 0.001 |
0.011 ± 0.002 |
0.012 ± 0.002 |
0.012 ± 0.002 |
0.012 ± 0.003 |
Testis/ovary left |
0.30 ± 0.02 |
0.32 ± 0.04 |
0.30 ± 0.04 |
0.33 ± 0.04 |
0.014 ± 0.04 |
0.014 ± 0.004 |
0.014 ± 0.003 |
0.015 ± 0.003 |
Testis/ovary right |
0.30 ± 0.01 |
0.31 ± 0.04 |
0.30 ± 0.05 |
0.33 ± 0.04 |
0.014 ± 0.03 |
0.015 ± 0.003 |
0.014 ± 0.001 |
0.015 ± 0.003 |
Brain |
0.37 ± 0.03 |
0.38 ± 0.04 |
0.37 ± 0.04 |
0.40 ± 0.04 |
0.65 ± 0.08 |
0.66 ± 0.09 |
0.65 ± 0.05 |
0.64 ± 0.05 |
*p<0.05,Ɨp<0.01
Table 6. Incidence of histopathological findings in SD rats orally treated with tetrasodium pyrophosphate for 90 days.
Findings |
Male |
Female |
||||||
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
Liver |
|
|
|
|
|
|
|
|
Centrolobular vacuolation |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
Periportal vacuolation |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
2 |
Parenchymal degeneration |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Kidney |
|
|
|
|
|
|
|
|
Cortical tubular basophilia |
3 |
3 |
3 |
7 |
0 |
1 |
0 |
6 |
Medullary tubular basophilia |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
Interstitial inflammatory cells |
2 |
3 |
1 |
0 |
0 |
0 |
0 |
0 |
Cortical mineralization |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
3 |
Medullary mineralization |
0 |
0 |
0 |
0 |
0 |
0 |
2 |
9 |
Medullary cyst |
2 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
Papillary epithelial hyperplasia |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
Cortical scarring |
0 |
0 |
2 |
0 |
1 |
0 |
0 |
0 |
Transitional epithelial hyperplasia |
0 |
0 |
2 |
0 |
0 |
0 |
0 |
0 |
Pelvic transitional epithelial Inflammatory cells |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
Adrenal gland |
|
|
|
|
|
|
|
|
Cortical vacoulation |
4 |
7 |
5 |
2 |
0 |
0 |
0 |
1 |
Hypertrophy-zona glomerulosa |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
Cortical cyst |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
Heart |
|
|
|
|
|
|
|
|
Myocardial inflammatory cells |
1 |
8 |
6 |
5 |
0 |
0 |
2 |
0 |
Myocardial fibrosis |
2 |
1 |
3 |
0 |
0 |
0 |
0 |
4 |
Spleen |
|
|
|
|
|
|
|
|
Extramedullary hematopoiesis |
1 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
*p<0.05,Ɨp<0.01
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 500 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Klimisch 2
- System:
- urinary
- Organ:
- kidney
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
- Key study: A 72-week repeated dose toxicity study was performed on rats similar to OECD 452. Choline chloride was orally administered to 30 male Fischer 344 rats, at 1% (500 mg/kg/day). Body weights were taken at weekly intervals for 16 weeks and biweekly thereafter. Two animals per group were sacrificed at 28 weeks for an interim assessment of the experiment's progress. Afterwards, all the animals dying or sacrificed during the study were necropsied. Liver weights and body weights were taken at necropsy. The livers and all other organs bearing gross abnormalities were routinely removed and fixed in buffered formalin. They were then sectioned and stained with haematoxylin and eosin for histological examination. No marked effect on growth was observed and no mortality occurred throughout the study. The histological distribution of liver tumours showed no significant differences between the control and treated group. Under these conditions, Choline chloride has a lethal concentration 0 of 500 mg/kg/day in rats (1%), after 72-week oral administration.
- Key study: A 90 -day repeated dose toxicity study was performed on Sprague-Dawley rats similar to OECD 408. Beta-calcium pyrophosphate was orally administered to 10 male and 10 female Sprague-Dawley rats, at 30 mg/kg/day. Body weights were recorded at baseline and weekly after. Mortality, feed intake, and body weight were monitored. Urinalysis was assessed during the 90-day treatment period. On day 90, all animals were anesthetized, euthanized, and weighed, and blood samples were collected for haematology and serum biochemistry. In males, mean serum chloride level in beta-CPP-treated was significantly higher than in controls. In females, mean aPTT (activated partial thromboplastin time), cholesterol, and AST(GOT) levels in the treated group were significantly lower than in the control group. No mortality occurred throughout the study and no clinical signs were observed. Under these conditions, the test item was found to have a NOAEL higher than 30 mg/kg/day in rats.
- Key study: A 90 -day repeated dose toxicity study was performed on Sprague-Dawley rats according to OECD 408. Tetrasodium pyrophosphate was orally administered to 10 male and 10 female Sprague-Dawley rats, at 0, 250, 500 and 1000 mg/kg/day five times a week for 90 days. Body weights were recorded at baseline and weekly after. Mortality, feed intake, and body weight were monitored. There were no significant changes in body weight in the 1000 mg/kg treatment group, or food consumption, urinalysis, and haematology in any group. The levels of total protein, albumin, A/G ratio, triglyceride, calcium and inorganic phosphate were altered at doses 500 and 1000 mg/kg. However, no changes were observed at the dose of 250 mg/kg. No mortality occurred throughout the study and no clinical signs were observed. Regarding histopathological findings, cortical tubular basophila of the kidney increased at the dose of 1000 mg/kg, but not at doses of 250 and 500 mg/kg. No significant changes were observed in other organs at doses of 250, 500 and 1000 mg/kg. Based on these results, the test item was found to have a NOEL and a NOAEL of 250 and 500 mg/kg/day respectively and the target organ appears to be the kidney in rats.
- Key study: A long-term repeated dose toxicity study of phosphoric acid was performed on rats. Male and female rats were administered on a basal diet with the addition of phosphoric acid at 0.4% or 0.75%. The groups were kept in the experiment after six months, and observations continued through two filial generations (more than twelve months). Effect on growth in three generations, reproduction and blood parameters of the first two generations. No adverse effects were noted at up to 0.75%. The NOEL for this study was 0.75% or more of phosphoric acid in the diet, which was equivalent to 386 mg/kg/day or more, assuming a 0.35 kg rat consumes 18 g food/day. Therefore, the test item has a NOAEL>386 mg/kg/day in rats, after administration in diet for more than twelve months.
Justification for classification or non-classification
Based on available data, the substance is not classified for repeated dose toxicity according to CLP Regulation (EC) No. 1272/2008.
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