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EC number: 266-442-3 | CAS number: 66669-53-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Not indicated
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- The test substance is not fully specified on composition and purity and no analytical verification of the test substance was performed. Nevertheless, as the performance of study was scientifically-toxicologically correct (and a purity lower than 100% would most likely increase the NOAEL), reliability 2 was assigned.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 976
- Report date:
- 1976
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Principles of method if other than guideline:
- The OECD original guideline 408 was adopted in 1981, the current guideline was adopted in 1998, but the study was performed in 1976.
Maybe for this reason,
- physical nature, purity and physico-chemical properties of the test substance are not explicitly indicated
- identification data of the test substance is not indicated
- no analytical verification of the test substance was performed
- ophthalmological examinations are not (explicitly) cited.
- sensory tests of reactivity to stimuli are not (explicitly) cited.
A dose of 0, 50, 200, 1000, or 5000 ppm corresponds with an ingestion of the test substance for male rats of 0, 4.17, 14.91, 84.11, or 424.41 mg/kg bw/day) and for female rats of 0, 6.05, 12.51, 125.48 or 632.65 mg/kg bw/day) - GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate
- EC Number:
- 266-442-3
- EC Name:
- Tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate
- Cas Number:
- 66669-53-2
- Molecular formula:
- C7H7Na4O9P
- IUPAC Name:
- tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate
- Details on test material:
- technical sodium 2-phosphonatobutane-1,2,4-tricarboxylate
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- SPF
- Source: Winkelmann, Kirchborchen, Germany
- Age at study initiation: 28-32 days
- Weight at study initiation (male rats): Average 80-85 g
- Weight at study initiation (female rats): Average 78-81 g
- Housing: cages Makrolon, type II; 1 animals per cage
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/-1°C
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- NA
- Duration of treatment / exposure:
- 3 months
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
50 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
200 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
1000 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
5000 ppm
Basis:
nominal in diet
- No. of animals per sex per dose:
- Test group: 15 animals / sex/ dose level
Control group: 30 animals / sex - Control animals:
- yes, plain diet
- Details on study design:
- OBSERVATIONS:
- The animals were observed for changes and symptoms daily.
BODY WEIGHT AND FOOD/WATER CONSUMPTION:
- The weekly food consumption was calculated by weighing the feed before and after one week of consumption.
- The bodyweights of all involved animals were recorded weekly.
EXAMINATIONS:
- The clinical investigations were undertaken with 5 male and 5 female rats per dose level one and three months after start of this the feeding study.
Haematology:
- Determination of haemoglobin concentration according to the cyan-methemoglobin method (VAN KAMPEN and ZIJLSTRA, 1961)
- Determination of haematocrit (microhematocrit method by centrifugation)
- Counting of erythrocytes and leucocyte by the Coulter counter, model ZF.
- Determination of mean corpuscular haemoglobin concentration (MCHC)
- Determination of mean corpuscular volume (MCV)
- Counting of reticulocytes (stained with cresyl brilliant blue)
- Counting of thrombocytes by the Coulter counter, model FN
- Assessment of the differential blood count (staining according to WRIGHT; 630-times magnified)
- Determination of the thromboplastine time (according to QUICK, 1951)
Liver function test:
The following enzymes were determined in the heparin plasma:
- alkaline phosphatase (according to HAUSAMEN et al., 1967)
- glutamic oxal acetic transaminase (GOT, according to KARMEN et al., 1955)
- glutamate-pyruvate transaminase (GPT according to WROBLEWSKI and LA DUE, 1955)
- bilirubin (according to JENDRASSIK and GROF, 1938)
- total protein (according to WEICHSELBAUM, 1946)
Urinalysis and kidney function test:
- 16h urine was sampled and analysed for glucose, haemoglobin, pH and bile colour by test stripes
- urine protein (according to RICHTERICH, 1968)
- microscopic investigations of urine sediment after centrifugation of the urine
- determination of urea (acc. FAWCETT and SCOTT, 1960) and creatinine (acc. POPPER et al., 1937)
Moreover, the electrolytes sodium, potassium and calcium were determined by flame photometry.
Blood sugar and cholesterol:
- glucose: enzymatic colorimetric with glucose-oxidase-peroxidase (acc. HUGGET and NIXON, 1957)
- cholesterol (acc. to WATSON, 1960)
Determination of sodium, ferrum, phosphorus, potassium and calcium in blood serum:
- sodium, potassium and calcium by flame photometry
- ferrum (acc. TRINDER, 1956)
- inorganic phosphorus (acc. RAABE, 1955)
PATHOLOGY:
The weights of the following organs of all animals were determined: thyroid, thymus, heart, lungs, liver, spleen, kidneys, adrenal glands, testes, and ovaries.
For histological examinations the organs of five male and five female rats were fixated, plastinated and stained:
Aorta, eyes, large and small intestines, brain, urinary bladder, heart, testes, hypotheses, liver, lungs, lymph nodes, stomach, spleen, A. quadriceps, epididymis, adrenal glands, kidneys, oesophagus, parotid gland, Os femoris, ovaries, pancreas, prostate, seminal vesicle, thyroid, sternum, thymus, trachea and uterine horn.
All these organs of animals that had received the highest dose (5000 ppm) were hispathologically examined.
The following organs of animals that had received doses of 50, 200, or 1000 ppm were also examined: Heart, testes, hypotheses, liver, spleen, epididymis, adrenal glands, kidneys, Os femoris, ovaries, pancreas, thyroid, sternum, thymus and uterine horn. - Positive control:
- No positive control.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATION and DETAILED CLINICAL OBSERVATIONS: Yes
- The animals were observed for changes and symptoms daily (appearance, e.g. of fur, behaviour, e.g. concerning drinking and eating, motor activity ).
BODY WEIGHT: Yes
- The bodyweights of all involved animals were recorded weekly.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal was determined weekly. Based on that the mean daily consumption was calculated and given as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: One and three months after start of the feeding study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 per sex and dose level
- Parameters examined: See "study design"
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: One and three months after start of the feeding study
- Animals fasted: No data
- How many animals: 5 per sex and dose level
- Parameters examined: See "study design
URINALYSIS: Yes
- Time schedule for collection of urine: Not indicated
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: See "study design
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- A 3-months feeding study was performed in 15 female and 15 male rats with technical tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate (50, 200, 1000, 5000 ppm = male rats: 0, 4.17, 14.91, 84.11, 424.41 mg/kg bw/day, female rats: 0, 6.05, 12.51, 125.48, 632.65 mg/kg bw/day). The control animals (30 females, 30 males) received no test substance (0 ppm).
All doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (NA, K, Ca), Ferrum and Phosphorus were not affected by doses up to 5000 ppm. The same was proven for the kidneys by urinalyses, clinical chemistry and pathological and histopathological examinations. Gross necropsy and histological examinations did not reveal any adverse effects due to the test substance.
Thus, the NOAEL is equal or higher than 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats). - Statistics:
- For statistical evaluation of the study results, the rank-sum test (distribution free) according to WILCOXON (see also WINNE) was applied.
The p values less than 0.05 were regarded as significant.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- All doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (NA, K, Ca), Ferrum and Phosphorus were not affected by doses up to 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats).
- Mortality:
- no mortality observed
- Description (incidence):
- All doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (NA, K, Ca), Ferrum and Phosphorus were not affected by doses up to 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats).
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- All doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (NA, K, Ca), Ferrum and Phosphorus were not affected by doses up to 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats).
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- All doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (NA, K, Ca), Ferrum and Phosphorus were not affected by doses up to 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats).
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- All doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (NA, K, Ca), Ferrum and Phosphorus were not affected by doses up to 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats).
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- All doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (NA, K, Ca), Ferrum and Phosphorus were not affected by doses up to 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats). The same was proven for the kidneys by urinalyses and clinical chemistry.
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Gross necropsy and histological examinations did not reveal any adverse effects due to the test substance.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Gross necropsy and histological examinations did not reveal any adverse effects due to the test substance.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- Gross necropsy and histological examinations did not reveal any adverse effects due to the test substance.
- Other effects:
- no effects observed
- Details on results:
- Based on the body weights at the middle of the study and the food consumption of one day, the 5000 ppm dose was equivalent to 424 mg test substance/ kg bw for male rats and 632 mg test substance / kg bw for female rats. No test animal died over the whole test period.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 5 000 ppm
- Sex:
- male/female
- Basis for effect level:
- other: highest dose level
- Remarks on result:
- other: 5000 ppm = equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats.
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
No remarks
Applicant's summary and conclusion
- Conclusions:
- Doses of up to 5000 ppm tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate applied over 3 months were tolerated without any effects.
The NOAEL of the tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate is equal or higher than 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats). - Executive summary:
A 3-months feeding study was performed in 15 female and 15 male rats with technical tetrasodium hydrogen 2-phosphonatobutane-1,2,4-tricarboxylate (50, 200, 1000, 5000 ppm = male rats: 0, 4.17, 14.91, 84.11, 424.41 mg/kg bw/day, female rats: 0, 6.05, 12.51, 125.48, 632.65 mg/kg bw/day). The control animals (30 females, 30 males) received no test substance (0 ppm).
All doses were tolerated without any effects as could be shown by overall observations and examinations: Appearance, behaviour, development, and mortality as well as blood, blood glucose and cholesterol, metabolism of electrolytes (NA, K, Ca), Ferrum and Phosphorus were not affected by doses up to 5000 ppm. The same was proven for the kidneys by urinalyses, clinical chemistry and pathological and histopathological examinations. Gross necropsy and histological examinations did not reveal any adverse effects due to the test substance.
Thus, the NOAEL is equal or higher than 5000 ppm (equivalent to about 424 mg/kg bw for male rats and 632 mg/kg bw for female rats).
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